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  1. Butyrate Way back when we talked about SCFAs positive effects on inflammation and permeability of the gut, we said we would get back to its actions outside of the gut, and here we are. In addition to butyrate’s peripheral anti-inflammatory effects via keeping LPS contained inside the gut, it also directly inhibits TNF-alpha and the inflammatory response to LPS (460, 461). Elimination of the gut microbiome (thus SCFA production) with antibiotics decreases IGF-1, which is restored with SCFA administration (462). Dietary administration of fellow SCFA, propionate, up-regulated the expression of GH, IGF1 and down-regulated myostatin (463). Butyrate improves insulin-resistance in skeletal muscle, along with its induction of Akt (464, 465). And, it increased muscle fiber cross-sectional area along with improving glucose metabolism in aged subjects (466). Let’s take a closer look at some of the several mechanisms through which it works. GLP-1 Activation of Free Fatty Acid Receptors (FFAR2 & FFAR3) in the gut by butyrate stimulates the release glucagon-like peptide-1 (GLP-1) which then enters the blood stream (467, 468). Much like insulin, GLP-1 activates the anabolic Akt/mTOR pathway (469, 470, 471, 472). It also promotes dilation of muscle microvascular (473, 474). This enhances nutrient uptake in the muscle cell and is dependent on Akt/mTOR upregulation of nitric oxide production (475, 476). Its effects in this regard were both independent of, and additive to, insulin (477, 478). Recall also the positive effects of NO on satellite cell activation, muscle regeneration, and repair discussed earlier. In addition to skeletal muscle microvasculature, GLP-1 also significantly increases vasodilation and blood flow in large vessels like the brachial and radial arteries and femoral vein (479, 480). Treatment with GLP-1 improves exercise capacity and mitochondrial function, as well as skeletal muscle mass and strength (481, 482). HDAC While GLP-1’s positive effects in muscle begin with butyrate activity in the gut, butyrate, itself, is also taken up from the gut and enters the systemic circulation producing direct actions that support muscle growth. One of the primary mechanisms is its function as a Histone De-Acetylase (HDAC) inhibitor. This is epigenetic stuff. To put it simply, epigenetics involves (heritable) changes in gene expression without change to the DNA sequence, itself. It basically changes how the DNA is interpreted, similar to translating a foreign language book. The original book (DNA) stays the same, but a different author (epigenetics) is going to translate it differently. Negative epigenetic changes are a huge part of the build-up of dysfunction with aging in everything from metabolism, to muscle mass, to the brain, with inflammation being a particular culprit (483, 484, 485). Propionate and acetate also augment histone acetylation, but the bulk of the data is on butyrate (486, 487). HDAC inhibition amplifies Akt/mTOR signaling, as well as preventing induction of atrophy genes (488). Increased histone acetylation blocks downstream activity of glucocorticoids, including FoxO (489, 490). Inhibition of HDAC during muscle disuse significantly attenuated both disuse muscle fiber atrophy and contractile dysfunction via FoxO (491). The effects of acetylation on FoxO, and other targets such as mTOR, appear to be quite similar to phosphorylation with Akt, though data is still new and scarce (492, 493). But, that will definitely be something to keep an eye on. Finally, inhibition of HDAC activity significantly enhanced androgen receptor mediated protein synthesis (494). You have likely heard the term “muscle memory”, but you may not know that skeletal muscle stem cells do indeed have a memory that is created epigenetically. Stem cells from muscles of young, aged, physically active, and diabetic subjects carry on their altered metabolic characteristics when isolated and cultured (495). In other words, the bad (or good) epigenetic build-up semi-permanently alters them to such an extent that it is maintained when they are taken out of subjects and grown in a lab. HDAC inhibitors promote muscle regeneration through epigenetic regulation of both satellite stem cells and differentiated muscle cells (496). Via upregulation of follistatin (basically the anti-myostatin), HDAC inhibition also blocks the adipogenic potential of stem cells, pushing them toward the formation of muscle cells rather than adipocytes (497, 498). The importance of HDAC inhibition reversing long-term damage from inflammation and aging basically cannot be understated. Heat Shock Proteins Butyrate also induces Heat Shock Proteins (499, 500). Heat Shock Proteins (HSPs) are called such because they were initially discovered in cells subjected to hyperthermia, but they function as a protective and subsequent regenerative and repair mechanism against all kinds of cellular stressors (501). Other HDAC inhibitors induce HSPs as well, suggesting this as butyrate’s mechanism in this regard (502, 503). Induction of HSPs protects intestinal epithelial tight junction barriers, decreasing LPS leakage, and reducing the inflammatory response (504). Increased HSP levels also reduce TLR-4, and the subsequent production of TNF-alpha and NF-κB (505). HSPs strongly blunt increases of cortisol to stressors (506, 507). The synthetic glucocorticoid dexamethasone decreased myotube diameter and protein content, and heat stress prevented this along with recovering Akt signaling (508). HSPs directly bind to and protect Akt, and HSP induction defends against glucocorticoid induction of catabolic FoxO via Akt (509, 510). Silencing of HSP genes decreases Akt and myotube diameter while increasing FoxO, and treatment with an HSP inducer reverses this (511). Exercise also increases HSPs, along with Akt and downstream anabolic signaling (512). Aged subjects have a blunted HSP response to exercise, along with decreased muscle repair, which is reversed with HSP overexpression (513). HSPs’ positive effects on muscle repair and regeneration seems to be to some extent from protection of satellite cells (514). Androgens and Clenbuterol also strongly upregulate HSP expression, with this likely being particularly important for Clen’s anabolic effects (515, 516, 517, 518). Angiotensin II Last but not least, butyrate protects against the negative effects of Angiotensin II (Ang II). Like butyrate, itself, Ang II produces effects both inside and outside the gut. But, its effects are negative. It is kind of a wingman of LPS in that regard. It also displays bi-directional communication between the gut and brain in hypertension, much like cortisol with stress (519). In addition to its effects on blood pressure, it is strongly induced by LPS and mediates some of the inflammatory response to it (520, 521, 522). LPS induction of Ang II may be through TNF-alpha, but it is also a direct ligand for TLR-4, just as LPS is (533, 534, 535). It is a really interesting molecule, and Renin-Angiotensin a really interesting system, as it ties high blood pressure in with inflammation, insulin resistance, and the cardiovascular system in Metabolic Syndrome. You will likely hear a lot more about it over the next 5-10 years, but parts of the understanding are still relatively in their infancy, so we are going to keep it fairly brief. There is a decrease in microbial richness and diversity in hypertension and with Ang II infusion, as well as decreases in acetate and butyrate producing bacteria (536). This is accompanied by increased intestinal permeability and decreased tight junction proteins (537). Butyrate administration elevated Akkermansia levels, with significant positive effects on inflammation and ROS, and led to improvement of hypertension (538). Butyrate significant reduces blood pressure, as well as TNF-alpha, in response to Ang II infusion (539, 540). Data on other HDAC inhibitors indicate that this may be a primary mechanism for butyrate’s antagonism of Ang II’s actions. HDAC inhibitors prevented inflammation and ROS from Angiotensin II (541). They also protected against Ang II induced hypertension and vasoconstriction (542). And, again, the semi-permanent nature of epigenetics makes this especially important. Outside of the gut, Ang II basically does all of the same bad stuff as LPS because, as we mentioned, it mediates some of LPS signaling, plus shares signaling downstream from TLR-4. It shares the same link between inflammation and insulin resistance, and ACE inhibitors or Ang II receptor blockade reverses these (543, 544, 545). It reduces protein synthesis and increases catabolism, leading to muscle atrophy (546). Ang II inhibits the insulin and IGF-1 signaling pathways via Akt inhibition (547, 548). It impairs insulin stimulated nitric oxide and vasodilation (549). This is, once again, via the Akt/mTOR pathway (550, 551). As a result, Ang II also reduces muscle regeneration and satellite cell differentiation into muscle fibers (552). Finally, it increases the glucorticoid/myostatin catabolic pathways (553, 554). Will it work for me and what to expect With the science out of the way, the obvious question is “How much do you need and/or should you want pro- and prebiotics to fix your gut and your body?” Because the gut and systemic inflammation affect every system, and basically every cell, in your body, a good probiotic/prebiotic combo kind of stands apart from any other category of supplement. It is most analogous to going from a shitty diet to a good diet or from an okay diet to a perfect one. We briefly mentioned hardgainers and the “skinny fat” phenotype, earlier. You definitely want to fix your gut. I would expect around an extra 10 lbs of muscle in a year, as your body starts living up to its genetic potential. For significantly fat people (and, even moreso, if showing signs of glucose intolerance), you absolutely need to fix your gut. I would expect very noticeable body composition changes in 1-3 months, and borderline miraculous ones in a year. This article has been about muscle mass, but as we alluded to with the mention of Metabolic Syndrome, the gut and inflammation play a huge role in health, as well. Other general parameters pointing toward its usefulness for you are being over 30, the fatter you are, the worse your diet is, being in a calorie surplus, and having a (personal or family) history of inflammatory related conditions (heart disease, blood pressure, auto-immune, IBS/IBD, etc.). On other hand, if you are 19, quite lean, on great diet with low-moderate carbs including fruits and veggies, with an iron stomach, and in a calorie deficit, it is not going to noticeably do a lot for you. It would be much more of a preventative measure to keep your cells young as you get older, to keep you still being awesome 5-10+ years from now. A big exception would be during bulking phases – and, the dirtier the bulk, the more it would help. Likewise, if you tend to go off the rails during holidays or vacations, it is damage control.
  2. Outside of the Gut If you are not already convinced of the benefits of pro- and prebiotics on muscle mass, it gets even more interesting outside of the gut. Getting back to Lipopolysaccharide (LPS) produced by a dysfunctional microbiota, once it has escaped the leaky gut, it sets off an anti-anabolic, pro-catabolic cascade of inflammation and reactive oxygen species (ROS), systemically (298). As we have mentioned, your body views LPS as an outside, pathogenic invasion via TLR-4. And, it literally is, as these bacteria are living, foreign invaders, thus immune defenses are activated. In such an attack, metabolically expensive skeletal muscle is not prioritized – quite the opposite, in fact. Amino acids and protein synthesis are prioritized for the immune response, at the expense of muscle tissue (299). The activity of insulin and other growth factors like IGF-1 are reduced, as are the levels and signaling of testosterone (300). At the same time, catabolic signals such as glucocorticoids, myostatin, NF-kB, and FoxO are upregulated, activating atrophy producing genes, which initiate the physical breakdown of proteins in muscle (301, 302). Obviously, that is all very bad for muscle size and body composition, so let’s take a look at these pathways in more detail. These will be kind of complicated, so some may better visualize and understand by also viewing the attached GRAPHIC LPS and Anabolic Pathways This is simplified, but the anti-anabolic signaling pathways of LPS basically proceed as follows: LPS/TLR-4/TNF-a/ROS DECREASES Insulin&IGF-1 signaling/Akt/mTOR/Protein Synthesis LPS/TLR-4/TNF-a/ROS DECREASES Amino Acid signaling/mTOR/Protein Synthesis LPS/Cortisol/ROS/Myostatin DECREASES Akt/mTOR/Protein Synthesis To reiterate at risk of being repetitive, the body views lipopolysaccharide (aka endotoxin) as an attack. LPS is a ligand of TLR-4, which literally exists to recognize molecular patterns of pathogens and toxins, then subsequently activate the inflammatory immune response in self-defense. This is great, when your body needs to occasionally protect itself. It is very bad when it is constant and chronic because of diet and lifestyle. LPS injections result in a 50% fall in protein synthesis in skeletal muscle, along with a 60-100% increase in muscle protein degradation (303). Decreases in muscle protein content from LPS are equivalent to those with starvation (304). However, the rate of protein synthesis in the liver and plasma proteins, especially albumin and immunoglobulins, is greatly increased to match (305, 306). Basically, amino acids from diet and muscles are being commandeered for the battle (307). You are not going to get that high of LPS levels from dysbiosis of the microbiota, unless you have sepsis inducing food poisoning or the like, but it goes to show how powerful LPS is as an anti-anabolic, pro-catabolic trigger. Obesity and type-2 diabetes are known to be associated with a chronic, low-grade inflammatory state, and this is accompanied by impairment of protein metabolism such as a lack of stimulation of protein synthesis by insulin and amino acids, as well as lower inhibition of proteolysis by the same (308, 309). The protein synthetic response to exercise is blunted in obesity compared to the lean as well (310). Disruption of the mTOR pathway, and its stimulation of protein synthesis, is also seen in these subjects (311) (312). However, chronic excessive energy intake and increased adiposity, without the metabolic disturbances, do not induce any changes in tissue protein synthesis rates, indicating the primacy of inflammatory pathways in these effects (313). LPS diminishes the anabolic sensitivity to BCAAs and EAAs (314, 315). It also reduces IGF-I levels (316). Repeated LPS administration decreases muscle weight and muscle fiber cross sectional area (317). In addition, LPS treatment reduces blood flow in muscle by as much as 70% (318). So, not only are your muscles less sensitive to various anabolic signals, less of those are even getting there. Exercise reduces the LPS receptor, TLR-4, along with LPS induced inflammation (319). Via TLR-4, LPS massively increases TNF-alpha, the next step in the inflammatory equation – and, inhibition of TLR-4 reverses this (320, 321). TNF-alpha is highly involved in muscle wasting and kicks off the ROS cascade that invokes myostatin, NF-kB, and ceramides, which we will get into in a bit (322, 323, 324). LPS induced TNF-alpha increases result in decreased body and skeletal muscle weight, and TNF-alpha shares with LPS an elevated rate of BCAA oxidation (325, 326). LPS promotes TNF-alpha mRNA transcription, with subsequent declines in IGF-1 (327, 328). Direct TNF-alpha administration also lowers IGF-1, along with gastrocnemius weight (329, 330). TNF-alpha completely prevents insulin-mediated augmentation of capillary recruitment and blood-flow as well, inhibiting skeletal muscle glucose uptake by more than half (331). Reducing TLR-4 and TNF-alpha increases the anabolic signal transducer “Akt”, which we will talk a bit about, now (332). Akt You possibly have never even heard of it, but Akt (also known as Protein Kinase is one of the most important molecular signals controlling skeletal muscle mass. It affects both anabolism, through mTOR regulation of protein synthesis, and catabolism, through FoxO regulation of protein degradation (333, 334). Anabolic growth factors such as insulin, IGF-1, and testosterone, as well as factors inhibiting anabolism such as TNF-alpha and myostatin, transmit their cellular signals on hypertrophy and atrophy by altering the activity of Akt and its phosphorylation of its numerous downstream substrates (335). Basically, Akt turns pro-muscle growth targets on, and anti-muscle growth targets off. Genetic activation of the Akt/mTOR pathway causes hypertrophy and prevents atrophy, whereas genetic silencing blocks hypertrophy in vivo (336). Testosterone administration activates Akt signaling (337, 338). It upregulates the insulin-dependent Akt/mTOR signal transduction pathways in an androgen receptor dependent manner (339). Another androgen, Nandrolone, increases IGF-1 expression and its activation of Akt/mTor signaling while decreasing catabolic FoxO transcription (340). Resistance training induced muscle hypertrophy increases Akt and phosphorylation of mTOR, with a parallel drop in FoxO, and detraining does the opposite on all parameters (341). Mechanical overload also induces muscle hypertrophy via activation of Akt and its downstream anabolic pathways (342). LPS decreases Akt, along with its phosphorylation (thus, activation) of mTOR, as well as upregulating catabolic NF-kB and FoxO (343, 344). Increases in TLR-4 and TNF-alpha also downregulate Akt (345). Akt downregulation by TNF-alpha reduces skeletal muscle protein synthesis and increases protein degradation (346). Inflammatory cytokines like TNF-alpha decrease IGF-1’s activation of Akt, subsequently increasing expression of muscle atrophy-related genes (347). Elevated reactive oxygen species (ROS) production by TNF-alpha inhibits Akt/mTOR pathways and upregulates atrophy promoting genes (348, 349). And, as would be expected, ROS directly promote resistance to insulin signaling in skeletal muscle (350, 351). Amino acids and insulin fail to stimulate activation of Akt/mTOR mediated muscle protein synthesis in aged rats, a model of chronic, low-grade inflammation (352). Likewise, insulin resistant subject have reduced muscle Akt phosphorylation and negligible Akt mediated anabolic response to physiological insulin levels (353). mTOR You may be at least somewhat familiar with mTOR, as it is known to mediate increased protein synthesis from BCAAs such as leucine (354). LPS administration reduces phosphorylation of mTOR by Akt in skeletal muscle (355). Activation of TLR-4 by LPS inhibited the Akt/mTOR pathway, decreasing protein synthesis (356). Unlike insulin, amino acid action on mTOR induced protein synthesis is not modulated by Akt (357, 358). LPS also blocks leucine stimulated muscle protein synthesis, independently of Akt (359). Nitric Oxide and Satellite Cells The Akt/mTOR pathway also mediates the upregulation of nitric oxide (NO) by insulin (360, 361). Prolonged exposure to insulin (i.e. insulin resistance) desensitizes this pathway and blunts NO production (362). You probably are familiar with NO, as it is one of the more popular supplement categories, but we will still take a quick look at a bit of data. NO is a key messenger in myogenesis, particular in response to repairing muscle damage, such as from working out (363). It promotes muscle satellite cell activation and proliferation, as well as induction of myogenic genes such as myogenin and follistatin (364, 365). This satellite cell activation is dependent on the Akt/mTOR upregulation of NO production (366). Aging (which is associated with inflammation, hindered insulin signaling, and muscle loss) results in reduced activation and speed of satellite cell migration to half of that of young cells, which is reversed by NO (367, 368). Ceramides Ceramides are reactive lipid species that, for all intents and purposes, behave like reactive oxygen species (ROS) within muscle tissue (369). It is a 2nd messenger in TNF-alpha inflammatory signaling cascades (370). Ceramide accumulation in muscle is higher in obese and aged subjects, concomitant with decreased sensitivity to insulin and its anabolic effects (371, 372). Ceramide also decreases sensitivity of mTOR to amino acid induction of protein synthesis (373). In addition to insulin signaling, it diminishes anabolic responsiveness to IGF-1 by elevating Akt degradation (374, 375, 376). As would be expected, ceramide also reduces glucose uptake and glycogen synthesis, via inhibition of Akt/mTOR (377, 378). Of note, even though we are focusing on the anabolic and anti-catabolic actions when discussing insulin signaling pathways, uptake up glucose and amino acids, as well as glycogen synthesis, are generally increased when insulin sensitivity is increased. These are not divergent pathways. It simply is not our main focus, here. In addition to decreased anabolic activity, the decreased activity of Akt by TNF-alpha and ceramides also takes the breaks off of catabolic signaling via FoxO and NF-kB, promoting muscle atrophy (379, 380). Exercise (surprise, surprise) reduces muscle ceramide content, restoring insulin sensitivity (381). Testosterone The testis barrier basically works exactly the same as the gut barrier, including 1) being susceptible to increased permeability to LPS and inflammatory damage, 2) the enhanced expression of tight junction proteins and improvement of barrier function by bacterial fermentation products such as butyrate, and 3) modulation of all of this by the gut microbiome (382, 383). LPS administration in healthy subjects inhibits testosterone production directly in the Leydig cells of the testes (384, 385). Germ free mice (which do not have bacteria to produce SCFAs) show increased blood-testis-barrier permeability and lower testosterone production, which is fixed with probiotic administration (386), 387, 388). Obesity and metabolic syndrome are associated with lower testosterone levels, along with the low-grade inflammatory state (389, 390). A close relationship exists between the development of a pro-inflammatory state and the decline in testosterone levels, and these are thought to be very much causally linked (391, 392). Finally, heavy endurance exercise training (like marathons and such) is consistently associated with persistent low-grade systemic inflammation together with reduced free and total testosterone levels (393, 394). You are no doubt familiar with the positive effects of testosterone on muscle, so we won’t get into that, but I will just note that testosterone inhibits the LPS/TLR-4/TNF-alpha inflammatory, anti-anabolic/pro-catabolic pathways (395). LPS and Catabolic Pathways This is simplified a bit, once again, but LPS induced increases in catabolism basically proceed as follows: LPS/TLR-4/TNF-a/ROS INCREASES NF-kB/Atrogenes/Muscle Breakdown LPS/Cortisol/Myostatin DECREASES Akt INHIBITION OF FoxO/Atrogenes/Muscle Breakdown LPS/TLR-4/TNF-a/ROS/NF-kB<->Myostatin<->ROS<->NFKb and FoxO/Atrogenes/Muscle Breakdown Just like with inhibition of anabolic signaling, LPS escapes the gut, increasing inflammatory cytokines like TNF-alpha and reactive oxygen species throughout the body. This elevates NF-kB, which then triggers atrophy promoting genes (atrogenes) that subsequently induce the physical breaking down of proteins in muscle tissue. LPS also amplifies cortisol release, which increases myostatin, which inhibits Akt. This takes the breaks off of FoxO activated atrogene expression which, again, subsequently induces the physical breaking down of proteins in muscle tissue (396). There is also a feed forward myostatin/TNF-alpha/ROS/NF-kB loop, where they all increase each other, which results in activation of both NF-kB and FoxO (397, 398). NF-kB and FoxO, together, account for 95% of muscle fiber atrophy, so let’s take a look at some data on those two (399). NF-kappaB Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), along with FoxO, is one of the two primary atrogene activating pathways at the end of the LPS induced catabolic chain (400). It is induced by reactive oxygen species generated by TNF-alpha, and blocking ROS production prevents its activation by LPS administration (401, 402). Blocking TLR-4, upstream of TNF-alpha, also inhibits NF-kB (403). NF-kB is implicated in various models of atrophy (404, 405). It is significantly elevated, along with TNF-alpha, in myocytes from obese type-2 diabetics (406). Insulin resistant subjects display higher elevations in NF-kB in response to LPS than normal glucose tolerant ones (407). The resistance to the anabolic effects of exercise seen in aging is also associated a rise in NF-κB activity (408). Interestingly, the increases seen with aging, and the associated inflammation, is normalized with lifetime calorie restriction (known to be anti-inflammatory) in animal models (409, 410). Though, it increases catabolism in both slow-twitch and fast-twitch muscle fibers, NF-kB is more highly expressed in slow-twitch fibers (411, 412). It is particularly noted in disuse atrophy, so hopefully you already have that part of it covered with exercise (413, 414). It also inhibits Akt, perhaps via myostatin, which would ultimately also induce catabolic FoxO, which we will talk about next (415). Thus, its indirect negative effects of NF-kB on muscle may be even more important than the direct ones. FoxO The Forkhead Box O (FoxO) family is the second major atrogene activating pathway at the end of the LPS induced catabolic chain. It is induced by cortisol and myostatin, and it results primarily in atrophy of fast-twitch fibers (416). It is stimulated by ROS, likely through myostatin (417). FoxO is negatively regulated by Akt, as we mentioned previously (418, 419). When Akt’s inhibition of FoxO is removed, atrogenes are induced and loss of muscle mass follows (420, 421). It is inhibited by both insulin and IGF-1 signaling via Akt (422, 423). FoxO is likely the more important catabolic pathway vs. NF-kB, both because of the preferential fast-twitch degradation and because activation occurs in more common atrophy promoting situations due to the nexus with the ubiquitous Akt. Blockade of FoxO also prevents muscle atrophy from glucocorticoids, which leads us to our next segment (424). Cortisol Cortisol strongly activates both anti-anabolic (via inhibition of insulin signaling) and catabolic (via myostatin and FoxO) pathways, but we are putting it in the catabolic section. Being a stress hormone, it is triggered by not just perceived emotional stress, but energetic stress, such as with starvation, or for our purposes, the metabolic stress of the LPS induced inflammatory response (425). Before we get into the negative effects of gut dysbiosis on cortisol in relation to muscle, it should be mentioned that there exists a bidirectional communication system between the gastrointestinal tract and the brain (426, 427). A full treatment of the Gut-Microbiota-Brain axis is well beyond our scope, but in addition to dysbiosis and inflammation messing up the stress axis, stress and anxiety are signaled from the brain to the gut and mess it up, as well (428, 429). In other words, it is a feed-forward vicious cycle. Getting back to LPS and cortisol… As a systemic immunological stressor, LPS invokes a prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis via cytokines such as TNF-alpha, ultimately increasing cortisol release from the adrenals (430, 431). Cortisol is anti-inflammatory, and synthetic glucocorticoids are well known as being useful for this purpose (432). This anti-inflammatory activity, from an evolutionary perspective, likely serves as a mitigating factor in fever/ROS induced cellular toxicity (433, 434). Indeed, impairment of the HPA axis results in greatly increased lethality from LPS/endotoxic shock (435). Getting to cortisol and muscle, the purpose of cortisol with cellular stress such as from the LPS inflammatory cascade is to rapidly mobilize carbohydrate, fat, and protein stores to provide energy for the fight (436). With inflammation, protein is particularly in demand, as it is necessary for synthesis of acute phase reactants, which are a group of proteins that modulate the immune response (437). Thus, muscle protein synthesis is suppressed while breakdown is activated to provide said protein (438). This response also increases gluconeogenesis from amino acids preferentially over fatty acid oxidation as fuel to quickly provide ATP for increased energetic demands (439). We’ve basically mentioned all of that before, but it is worth repeating, as it is the “Why” on something meant to protect you going so terribly wrong. Cortisol quickly initiates muscle fiber atrophy, as IGF-1 and insulin signaling are blunted while myostatin is increased (440, 441, 442). This is mediated, downstream, through the Akt/mTOR and Akt/FoxO pathways, respectively (443, 444). Even worse, this atrophy is preferential toward high energy demanding fast-twitch fibers (445, 446). Glucocorticoids also initiate NF-κB activation, likely through the myostatin-ROS pathway mentioned earlier (447). In addition to insulin resistance through Akt/mTOR inhibition, glucocorticoids also reduce the activity of GLP-1, which we will talk about in a bit (448) Lactobacillus has been found to block restraint stress induced increases in LPS and cortisol (449). Interestingly, though cortisol inhibits mTOR’s anabolic activity, mTOR modulates glucocorticoid receptor function, counteracting its catabolic effects (450). So, more good news on BCAAs. Myostatin Myostatin is the major mediator in cortisol’s negative effects on muscle size, so we will give it its own little mini-section. It is upregulated by glucocorticoid administration and stress (451, 452). This stimulates muscle atrophy through a cascade of signals that includes activation of FoxO and NF-kB (453, 454, 455). Myostatin overexpression results in an atrophic phenotype with fast-twitch fibers being most sensitive (456). Myostatin also inhibits Akt, thus insulin and IGF-1 anabolic signaling through mTOR (457, 458, 459). Part 5 finale on Thursday, June 28th
  3. Inside the Gut Short Chain Fatty Acids (SCFAs) Along with outcompeting the LPS producing bacteria that trigger inflammation, one of the primary and most basic ways by which probiotic bacteria work their magic is by fermenting prebiotics to produce SCFAs (primarily acetate, butyrate, and propionate). So, we are going to talk a bit about those, now. SCFAs primarily work through three mechanisms: 1) Decreasing inflammation and permeability in the gut 2) Activation of free fatty acid receptors, FFAR2 and FFAR3, in the gut 3) Inhibition of Histone De-Acetylase (HDAC) in skeletal muscle We will talk about the first one, now, as it occurs wholly inside the gut (though, it ultimately prevents bad things outside of it). The second one begins in the gut, but mostly does its work outside, so we will cover it a bit here, then get deeper into it and number 3, later, in the section on all of the stuff outside of the gut. I should probably further emphasize that the Gut-Microbiota-Muscle axis is not straight-forward linear and compartmentalized. There is inside and out, as well as back and forth, communication. There are also overlapping functions and pathways. LPS/inflammation increases gut barrier breakdown, thus its own leakage into the body, and SCFAs/butyrate directly reduce inflammation in addition to reducing LPS/inflammatory leakage by strengthening barrier function… in addition to directly attacking problems caused by inflammation related pathways in skeletal muscle. Anyway, back to SCFAs. Both acetate and propionate reduce inflammatory pathways of lipopolysaccharide like TNF-alpha and NF-kB (238, 239). However, butyrate is significantly more potent (240, 241). Butyrate also plays the most critical role in maintaining colonic health via modulation of intestinal cell growth and differentiation (242). It is the primary fuel source for enterocytes, being responsible for up to about 70% of their energy use (243, 244). Butyrate also dose-dependently reduces LPS impairment of tight junction permeability and intestinal barrier integrity. We’ll get into this more in muscle, but one mechanism by which it increases tight junction proteins is by preventing LPS induced inhibition of the anabolic Akt/mTOR mediated protein synthetic pathway (245). Butyrate also dose-dependently increases mucin protein contents of the mucosal layer of the intestine (246). The mucosal layer is the first line of defense against noxious substances and pathogens (247, 248). In addition to being food for some of the best bacteria, mucin improves adherence of probiotics to the mucosal layer of the intestine, thus mucins are perhaps the most important aspects of their viability and colonization (249, 250). Butyrate also improves intestinal barrier function via activation of AMPK (251). Sodium butyrate has been specifically found to be an AMPK agonist (252). And, butyrate increase tight junction assembly, thus improving barrier function, specifically through AMPK (253, 254). This seems like as good of a place as any to add a bit more about AMPK, really quickly, as it is one of the major targets in all of this inside the gut. AMPK AMPK is a primary signaler in the maintenance of tight junction integrity and intestinal barrier function. It is one of the most important pathways in preventing the “leaky gut” we have spoken of earlier in regard to LPS and other inflammatory and infectious molecules escaping into the body to wreak havoc (255, 256). As we’ve mentioned, modern food processing and the Western diet is a particularly egregious malefactor in all of this (257). In addition to its involvement in barrier function, AMPK activation is extremely positive for the great bacteria that we can’t get commercially. Metformin increased Akkermansia 18-fold through AMPK activation. Also, against a high-fat diet, it restored Bacteroides levels and normalized microbiota constituent ratios to that of lean subjects (258, 259, 260). It inhibited LPS induced inflammation and gut permeability increases, while improving glucose uptake and insulin sensitivity (259). Akkermansia increases are likely at least partially due to greatly elevated production of its favorite food, mucin, which is stimulated by AMPK. Its activation also reduces insulin resistance and adipose tissue inflammation in a high-fat diet (260). Free Fatty Acid Receptors Activation of FFAR2 by SCFAs suppresses insulin signaling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of lipids and glucose in other tissues such as muscle (S2). Propionate and butyrate also both activate intestinal gluconeogenesis. Butyrate does so through AMPK, while propionate works through a gut-brain neural circuit involving FFAR3 (261). This glucose then triggers a signal to the brain which normalizes whole body glucose homeostasis (262). In a fasting state, as much as 62% of infused propionate is converted to glucose in the intestine, accounting for 69% of total glucose production (263). This is especially applicable to lower carb diets. Basically, it makes your brain think you are plenty fed with carbs/glucose. When the brain thinks the body is well-fed, energy intensive protein synthesis is supported. It also reduces peripheral gluconeogenesis, sparing amino acids for use in muscle tissue, while improving insulin sensitivity via reduced output of glucose from the liver (262). Short chain fatty acids, especially butyrate, are also direct precursors for ketone formation, obviously handy for ketogenic diets (264, 265). Activation of FFAR2/3 by SCFAs also stimulates the release of the incretin hormone, glucagon-like peptide-1 (GLP-1), enhancing anabolic and anti-catabolic insulin signaling pathways in muscle (266, 267). We will discuss this more, later. Protein Absorption and Efficiency The earliest studies on pro- and prebiotics were done to replace antibiotics for increasing digestion/feed efficiency in livestock. They result in the production of more meat (i.e. muscle mass), in general, and more meat per unit of food given. So, let’s take a look at the mechanisms on how this works, and how it will work for you. As we have briefly discussed, probiotics and prebiotics, via short chain fatty acids, increase the proliferation of intestinal epithelial cells, as well as increasing villus height and crypt depth, expanding total surface area for nutrient absorption. Likewise, increases in the quantity and quality of goblet cells increases mucin, helping to maintain optimal health and function of the intestine. Ultimately, this increases total nutrient digestibility in the intestinal tract (268). SCFAs, and other organic acids such as lactic acid (produced by lactobacillus, thus the name), reduce pH, increasing bioavailability of protein (269). They also enhance the release of digestive proteases, increasing absorption of small peptides and amino acids by enterocytes. (270). Only 80–90% of protein is actually digested and made available as amino acids in the small intestine, and we obviously want it on the high end (271). This inefficiency results in the entry of a good chunk of undigested protein into the large intestine, which we will discuss more in a moment. Once proteins have been digested and absorbed, we get to yet another area where probiotics and prebiotics, via SCFA acids, are useful – namely, in protein sparing. The gut has one of the highest rates of cellular and protein turnover of any tissue in the body. If cellular needs are not met by diet and supplementation, skeletal muscle proteolysis results, with amino acids being funneled from the periphery to the gut (272The liver and the gut account for 20 to 35% of whole-body protein turnover and energy expenditure, and your big brain gets a crack at those before your muscles, as well (273). Up to 50% of dietary amino acids are oxidized in first pass in the gut, with anabolic BCAAs being amongst the most favored (274). Some of this is inevitable, as these amino acids go toward protein structures in the intestines, such as digestive enzymes, mucins, and the physical makeup of the intestinal cells, themselves. But, they are also heavily used for fuel if their favorite food, SCFAs (especially butyrate), are not available (275, 276) . Dietary amino acids are preferred over glucose as intestinal metabolic fuel, and the systemic availability of dietary amino acids is ultimately one of the biggest determinants of the growth rate of lean body tissues such as muscle (277). And, indeed, both probiotics and prebiotics have been shown to enhance the entry of dietary amino acids into systemic circulation. While the increase in digestion and absorption is modest at around 5%, plasma levels are increased by as much as 30% by the protein sparing effect of SCFAs (278, 279). Given the figure of 50% of amino acids being oxidized in first pass in non-pre/probiotic subjects, for a 200lb person on the standard 1g/lb of bodyweight protein intake, we are talking about the equivalent of an extra 30g of protein per day making it to systemic circulation to be available to your muscles! And, there is more. As we mentioned above, 10-20% of protein is unabsorbed in the small intestine and moves on to the large intestine (with plant proteins being more poorly absorbed than animal ones), which leads us to nitrogen/amino acid recycling by the gut microbiota (280, 281). This recycling is not only of the undigested protein, but also amino acids which have entered the ammonia/urea cycle, generally after having been oxidized for fuel, particularly for the metabolic needs of skeletal muscle (282, 283). Glutamine and the BCAAs are favorites, here (284 , 285). Nitrogen/amino acid salvage and recycling by the gut back into the body amino acid pool is quite substantial, being equal to approximately one-half of total dietary intake (286). The gut microbiota’s recycling of ammonia and urea back into amino acids, especially from glutamine, BCAAs, and EAAs has been found to be on the order of 300+mg/kg/day (287, 288). For our 200lb man, this would be another 27 grams of protein per day reclaimed by the healthy and efficient gut to go toward muscle building. Other studies have found in the 15-30g/day range, but this was with smaller people and smaller intakes than bodybuilding and fitness types (289). Lactobacillus have the best research in this regard, though it is an area absolutely begging for more research (290, 291). This nitrogen recycling seems to be of particular importance in the overnight fasting period when food/protein is not being consumed (292). Basically, it helps you stay anabolic 24-7. All in all, this is massive!! Pun intended. Between greater peripheral delivery of amino acids and nitrogen/AA recycling, we are talking as much as 60g of protein a day, for a 200lb person consuming the typical 1g/lb of bodyweight. This is 2 meals worth of extra protein available to promote muscle growth. Finally, data in animals have shown direct correlations of microbial make-up with superior growth and feed efficiency. There is no such data on humans, as they are not grown for food, yet. Families and genera of butyrate producing genera and species including the aforementioned Bacteroides, Roseburia, and Faecalibacterium prausnitzii were all highly represented on the superior growth and feed efficiency side, as you might expect from what we have learned so far (293, 294, 295, 296, 297). Part 4 on Tuesday, June 26th
  4. Bacteria Bifidobacteria and Lactobacillus are by far the most common and well-known probiotic bacteria. They are commercially available and quite affordable. We can also readily manipulate levels of the good bacteria that are not commercially available such as Bacteroides species, Roseburia species, Akkermansia muciniphilia, and Facealbacterium prausnitzii via diet and supplementation of ingredients that ARE available. More on that later. Bifidobacteria Bifidobacteria are significantly lower in type-II diabetics and have been consistently shown to combat the cycle of LPS inflammation, leaky gut, and insulin resistance (49, 50, 51). They are reinforcing on intestinal epithelial cells and mucosa, improving the physical barrier of the intestine, preventing translocation of pathogenic bacteria and LPS from intestine to body tissue (52, 53). They limit pro-inflammatory signals and increase tight junction proteins supporting mucosal recovery, ultimately restoring normal intestinal permeability and preserving gut barrier function in the face of inflammation (54, 55). Bifidobacteria administration quells general colonic inflammation, particularly from LPS and its downstream signal, TNF-alpha (56, 57, 58). In reducing LPS levels, inflammation induced insulin resistance is reversed in the face of a high-fat diet (59, 60, 61). They shift the composition of the microbiota toward that of a lean phenotype, reducing inflammatory activity and insulin resistance while lowering body fat (62, 63). Bifidobacteria are also extremely important for cross-feeding. This is where one bacterial strain produces metabolites that other species and strains can use for fuel (64, 65). This is particularly important for the bacteria that are not commercially available, which we will discuss in detail in a bit. Bifidobacteria produce acetate and oligosaccharides which are then consumed by these acetate utilizing, butyrate and propionate producing bacteria (66). Faecalibacterium prausnitzii is almost fully dependent on acetate. It converts it to butyrate with 85% efficiency, and its growth is enhanced by co-culture with Bifidobacteria (67, 68). Roseburia is also an acetate user, and it is generally required for its growth (69, 70). Combined with bifidobacteria, Roseburia was able to grow in pure complex carbohydrate cultures, which it cannot metabolize on its own, owing to cross-feeding (71). Cross-feeding with Bifidobacterium also modulates the positive effects of prebiotic oligosaccharides on growth of Roseburia and F. prausnitzii by making acetate available (72). And, butyrate production increases mucins, which are fed on by Bacteroides and Akkermansia, two more great, but commercially unavailable bacteria. Lactobacillus Lactobacillus consistently increases tight junction protein formation and improves intestinal barrier function, ultimately inhibiting systemic inflammation from LPS and its downstream pathways (73, 74, 75, 76, 77, 78). They also increase the levels of butyrate and the other short-chain fatty acids (79, 80). Lactobacillus raises levels of Bacteroides, a propionate producer, and another one of the types of great bacteria that we cannot get commercially (81). They promote favorable intestine morphology, improving parameters such as villus height, crypt depth, mucin expression, and the quantity of goblet cells, all things favoring digestive function and efficiency (82). Lactobacillus decrease LPS, systemically, as well as downstream inflammatory markers including TNF-alpha , IL-6, and COX-2, (83, 84, 85, 86). Relatedly, they also reduce expression of TLR-4, which is basically the “LPS receptor” (87, 88). They have also shown improvements of inflammatory colitis, which is essentially an extreme version of a “leaky gut” (89, 90). The reduction in inflammatory responses downstream of the LPS signaling pathway is a consistent finding in studies with Lactobacillus, including decreased adipose tissue inflammation, further evidence of preventing LPS actions outside of the gut (91, 92, 93, 94). In combating these inflammatory pathways, Lactobacillus lower oxidative stress levels, ultimately improving insulin sensitivity (95, 96, 97). They also increase the insulin sensitizing peptide adiponectin (98, 99, 100). Finally, they specifically improve insulin sensitivity against Western-style, obesity promoting diets (101, 102, 103). In even more direct findings on probiotics and body composition improvements, Lactobacillus have been found to protect the testes from oxidative stress, increasing testosterone levels (104, 105). In fact, testosterone levels were 4-8 times higher in aging mice (a model of chronic, low-level inflammation), given Lactobacillus (106). They have been found to increases growth hormone levels and reduce the expression of atrophy inducing genes (107, 108). They increased weight with the same body fat, meaning more lean mass (109). Lactobacillus dose-dependently increased grip strength, muscle fiber number, and endurance swimming while decreasing muscle tissue breakdown (110). They inhibited increased levels of cortisol in response to stress (111). Finally, Lactobacillus feeding stimulates IGF-1 and decreases myostatin (112, 113, 114). Bacillus, another genus of commercial probiotic, increased goblet cell number, villus length, and mucin synthesis in the intestine (115). This would be expected to improve intestinal mucosal cell proliferation and, ultimately, efficiency of nutrient digestion and absorption (116). And, indeed, improved growth performance and enhanced protein utilization has been found with Bacillus (117). Probiotic Combinations You may have noticed that almost no probiotic formulas contain just a single species of bacteria, nowadays. And, if you did not, I will just say that it is for a good reason. They work better in combination. First of all, microbial diversity seems to be good, in and of, itself. Essentially, a diverse gut is a healthy gut (118). Obesity has been associated with a lack of microbial diversity and, as you might expect, lean subjects have greater microbial diversity in the gut (119, 120, 121). Insulin sensitivity is also improved along with diversity increases (122). Finally, in the interesting but not terribly shocking category, exercise increases microbial diversity (123, 124). Combinations also work to specifically create an environment where probiotic bacteria can thrive, thus enhancing their ultimate performance (125). Compared to individual strains alone, combinations greatly increase adhesion to intestinal mucus, which is necessary for most survival, growth, and activity (126, 127). Conversely, they inhibit adhesion and growth of pathogenic bacteria better when in combination (128, 129). However, you do not want to just throw every single commercially available species and strain into a product as so many companies do. They need to be rationally combined. If not, they can interfere with each other’s actions and compete for space and resources (130, 131, 132). But, perhaps the most interesting benefit of probiotic combinations is through the afore-mentioned cross-feeding of the commercially unavailable bacteria we are about to discuss, right now. The Best Probiotics That Money Can’t Buy Unfortunately, several species of bacteria with some of the very best data are not available commercially, due to regulatory issues and well as practical challenges such as stability and viability of the bacteria themselves. Several groups are working on these, but it will happen later rather than sooner, at best. Fortunately, there are a myriad of ways to specifically target and increase these strains using methods that ARE available. So, let’s take a look at these novel wonder-bacteria. Bacteroides Species Bacteroides are butyrate and propionate producing. Levels were 6-fold higher in lean vs. obese subjects, as well as being reduced in obese patients, in general, compared to control populations (133, 134, 135, 136). Levels in Type-2 diabetics were only half that of subjects with normal glucose tolerance (137). Among various species in the Bacteroides genus, B. uniformis reduced bodyweight gain, triglycerides, and adipocyte volume while improving insulin and leptin sensitivity. It also lowered LPS and other inflammatory signals (138). B. fragilis releases a symbiotic immunomodulatory anti-inflammatory factor called Polysacharride A – kind of an anti-LPS (139, 140). This has been shown not just to prevent but to cure experimental colitis, an extreme version of a leaky, inflammatory gut (141). It has also been shown to prevent demyelination of neurons in the central nervous system, indicative of protection against inflammation well outside of the gut (142). Faecalibacterium prausnitzii Faecalibacterium prausnitzii are butyrate producing and considered a physiological sensor and marker of human health (143). It does not get much more important than that. It is lower in the obese and type-2 diabetics (144, 145, 146). Conversely, it is higher in normal glucose tolerance vs. pre-diabetic subjects (147). Faecalibacterium prausnitzii is also negatively correlated with inflammatory markers and sharply decreased in inflammatory bowel diseases (148, 149). It is greatly reduced in ulcerative colitis and less abundant in Crohn’s disease (150, 151). As would be expected from the above, it improves intestinal barrier function (152). Akkermansia muciniphilia Akkermansia muciniphilia is mucin degrading, meaning it feeds on mucins (153). It is also decreased in obesity and type-2 diabetes. Its administration reduced fat mass, adipose tissue inflammation, and enhances insulin sensitivity. Along with this, improved gut barrier function and increased intestinal endocannabinoid levels were seen (154). This species is also inversely related to fasting glucose, waist-to-hip ratio, subcutaneous adipocyte diameter, plasma triglyceride levels, visceral adipose tissue mass, and insulin resistance (155). Along with enhanced glucose tolerance, it reduced adipose tissue inflammation (156). Akkermansia levels are higher in normal glucose tolerance vs. pre-diabetic subjects (157). It decreases inflammatory cytokine production and protected intestinal barrier function in experimental colitis (158). Finally, its levels are reduced in ulcerative colitis (159). Roseburia Species Roseburia species are butyrate producing (160). An increase in this species is associated with decreased body weight, fat mass, insulin sensitivity, and triglycerides -- independent of calorie intake (161). Increased Roseburia correlated with reduced body weight, improved profile of lipid and obesity related gene expression, along with a normalized inflammatory status (162). It is also lower in type-2 diabetes (163). Levels are increased by a Mediterranean diet, as is insulin sensitivity (164). Finally, its levels display an inverse correlation with disease activity in ulcerative colitis (165). High protein/low carbohydrate diets, which are so effective and popular, reduce Roseburia and SCFA levels, making pro- and prebiotics particularly useful with these (166, 167). Prebiotics Prebiotics are the food for our probiotic bacteria, and they are also the substrates that get transformed into super beneficial short-chain fatty acids like butyrate, so we will look at some data on those as well. Prebiotics have come a long way since oat bran and psyllium husks. Beginning with inulin, a huge array of oligosaccharide and glycan type compounds have been found to be fermented and fed on by intestinal bacteria. These newer prebiotics tend to be basically tasteless and dissolve effortlessly, which is quite handy. With the importance of microbial diversity for optimal gut and body health, we want a number of different prebiotics for them to feed on. Likewise, we want to choose the ones that best increase the bacteria we want to increase, rather than just randomly feeding all of them. Let’s briefly look at some data on the positive effects various prebiotics. Increased Good Bacteria and SCFAs Prebiotics, by definition, increase beneficial bacteria, with data being most focused on Lactobacillus and Bifidobacterium, as they were the earliest studied and most common. Bifidogenic potential was the primary measurement for prebiotic activity until about 10 years ago. Lactobacilli are promoted by a wide range of fibers and oligosaccharides (168, 169, 170). They can also ferment sugars, such a sucrose, fructose, and glucose (171). They are stimulated even by flour (172). So, one doesn’t have to put that much effort into getting them to grow. As you would expect from their growth being how prebiotics were defined, Bifidobacteria also grow quite well on a wide range of commercial prebiotics, with 5-10 fold increases in some subjects being noted (173, 174, 175, 176). The much more interesting prebiotic data is the increases found in levels of the aforementioned commercially unavailable butyrate and propionate producing bacteria via the aforementioned cross-feeding. As we have mentioned, and as you will really see later, butyrate production is probably the single most important way that probiotics and prebiotics ultimately work their magic. And, indeed, prebiotics have been found to not only raise Bifidobacterium counts, but do so concomitant with increased Akkermansia and F. prausnitzii (177, 178, 179). They also promote increases in Bacteroides (180, 181, 182, 183). Other studies have found elevated Roseburia, F. prausnitzii, and Bacteroides together with greater butyrate levels, with total SCFA increases as high as 2-3 fold (184, 185, 186, 187). Other prebiotic studies have shown increased propionate production along with Roseburia levels (188, 189). They have also been found to increase butyrate and propionate to go along with raised bifidobacteria and acetate levels – again, suggestive of cross-feeding to butyrate and propionate producing bacteria (190, 191, 192, 193). Mucins Prebiotics administration has shown 2-4 fold mucin elevations, which would create a positive environment for mucin feeders such as Akkermansia, Roseburia, and Bacteroides (194). Another found prebiotic augmentation of mucin production of 6-fold, leading to large elevations in Akkermansia, Roseburia, and propionate (195). Akkermansia is the most well characterized mucin consumer (196, 197). Verrucomicrobia, of which Akkermansia is the primary genus, was increased from .03% to 5.25% by mucin (198). That is a 175-fold increase, if you are counting. Multiple species of Bacteroides are also mucin degrading specialist, as well (198, 199, 200, 201, 202). A species of Roseburia, R. intestinalis also colonizes the mucosal layer and feeds on mucins (203). With these bacteria colonizing the mucus and being close to the epithelium, particularly with the butyrate producers, bioavailability for epithelial cell regeneration and barrier function is enhanced, so they are especially important and effective. Gut Permeability and Inflammation Prebiotics augment intestinal protein junction assembly, decreasing intestinal permeability and preventing loss of gut barrier function (204). Oligosaccharides also directly displayed a microbiota independent increase in tight junction assembly and improved barrier function (205). Prebiotics decrease LPS and increase epithelial cell proliferation (206, 207). They decrease downstream inflammatory markers triggered by LPS (208, 209). Increases in tight junction proteins and improved barrier function inhibited systemic inflammation in adipose tissue (210). Finally, prebiotics protect against stress induced LPS inflammation and activity (211, 212). Insulin Sensitivity and Protein Sparing Along with decreased LPS and inflammation, prebiotics reduced plasma glucose (213). They improved glucose tolerance by reducing oxidative stress and low-grade inflammation (214). Prebiotic inhibition of LPS target Toll-like Receptor 4 (TLR4), and downstream inflammatory affecter TNF-alpha, improved insulin sensitivity (215, 216). They also improve post-prandial blood glucose and insulin levels as well as improving glucose uptake in insulin resistant cells (217, 218, 219). In addition, by supplying SCFAs, the preferred fuel of the enterocyte, prebiotics reduce protein fermentation in the gut (220, 221, 222). This spares amino acids for more useful purposes like building muscle as well as preventing formation of toxic breakdown products (223). We will talk a good bit more about protein sparing, later. Polyphenols as Prebiotics Less well known than with typical prebiotics, polyphenols are also fermented by the gut microbiota. Polyphenols are generally prebiotic for good bacteria (Bifidobacterium, Akkermansia, Bacteroides, and Roseburia), and antibacterial for less favorable and pathogenic ones (224, 225, 226). Fruit/berry based polyphenols seem to be particularly favorable toward Bacteroides and Akkermansia growth compared to other polyphenol sources (227, 228, 229). Lactobacillus lack glycan degrading enzymes, thus do not grow on them particularly well compared to the others, so they are especially targeted to butyrate producers (230). Fermentation of herbs and such containing polyphenols also transforms them, resulting in much higher concentrations of active compounds compared to unfermented (231). This same fermentation is done in the body, but it is highly dependent upon the microbial make-up of the individual’s gut, so it can vary widely from person to person (232, 233). As an example, a fermented herb preparation inhibited LPS mediated inflammatory damage, while the unfermented one was ineffective (234, 235). The same was true for insulin sensitivity (236, 237). So, not only do polyphenols increase good bacteria, but the good bacteria make the polyphenols work better. The prebiotic effect plus the transformation into more active compounds is why polyphenols so consistently show a myriad of great benefits despite supposedly being so poorly bioavailable. Mechanisms of Action With the background information and general overview out of the way, we will now get deeper into the mechanisms of how this affects muscle mass. There are a lot of interacting pathways and systems here, though much of it comes down to inflammation and butyrate, both inside of the gut and outside. First, we will talk about fixing the gut, itself, both the inflammatory signaling (LPS et al) as well as the intestinal barrier that prevents them from escaping. Within the gut, we will also discuss protein sparing and absorption/utilization improvements from a healthy microbiota and gut. Then, we will talk about anabolic and anti-catabolic pathways outside the gut. Part 3 on Thursday, June 21st
  5. So, it turns out that artificial sweeteners are really bad for the composition of the gut microbiome. Physiol Behav. 2016 Oct 1;164(Pt B):488-493. doi: 10.1016/j.physbeh.2016.04.029. Epub 2016 Apr 15. Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance? Nettleton JE(1), Reimer RA(2), Shearer J(3). Disruption in the gut microbiota is now recognized as an active contributor towards the development of obesity and insulin resistance. This review considers one class of dietary additives known to influence the gut microbiota that may predispose susceptible individuals to insulin resistance - the regular, long-term consumption of low-dose, low calorie sweeteners. While the data are controversial, mounting evidence suggests that low calorie sweeteners should not be dismissed as inert in the gut environment. Sucralose, aspartame and saccharin, all widely used to reduce energy content in foods and beverages to promote satiety and encourage weight loss, have been shown to disrupt the balance and diversity of gut microbiota. Fecal transplant experiments, wherein microbiota from low calorie sweetener consuming hosts are transferred into germ-free mice, show that this disruption is transferable and results in impaired glucose tolerance, a well-known risk factor towards the development of a number of metabolic disease states. As our understanding of the importance of the gut microbiota in metabolic health continues to grow, it will be increasingly important to consider the impact of all dietary components, including low calorie sweeteners, on gut microbiota and metabolic health. Copyright © 2016 Elsevier Inc. All rights reserved. DOI: 10.1016/j.physbeh.2016.04.029 PMID: 27090230 [Indexed for MEDLINE] Nature. 2014 Oct 9;514(7521):181-6. doi: 10.1038/nature13793. Epub 2014 Sep 17. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Suez J(1), Korem T(2), Zeevi D(2), Zilberman-Schapira G(3), Thaiss CA(1), Maza O(1), Israeli D(4), Zmora N(5), Gilad S(6), Weinberger A(7), Kuperman Y(8), Harmelin A(8), Kolodkin-Gal I(9), Shapiro H(1), Halpern Z(10), Segal E(7), Elinav E(1). Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage. DOI: 10.1038/nature13793 PMID: 25231862 [Indexed for MEDLINE] Front Physiol. 2017 Jul 24;8:487. doi: 10.3389/fphys.2017.00487. eCollection 2017. Gut Microbiome Response to Sucralose and Its Potential Role in Inducing Liver Inflammation in Mice. Bian X(1), Chi L(2), Gao B(1), Tu P(2), Ru H(3), Lu K(2). Sucralose is the most widely used artificial sweetener, and its health effects have been highly debated over the years. In particular, previous studies have shown that sucralose consumption can alter the gut microbiota. The gut microbiome plays a key role in processes related to host health, such as food digestion and fermentation, immune cell development, and enteric nervous system regulation. Inflammation is one of the most common effects associated with gut microbiome dysbiosis, which has been linked to a series of human diseases, such as diabetes and obesity. The aim of this study was to investigate the structural and functional effects of sucralose on the gut microbiota and associated inflammation in the host. In this study, C57BL/6 male mice received sucralose in their drinking water for 6 months. The difference in gut microbiota composition and metabolites between control and sucralose-treated mice was determined using 16S rRNA gene sequencing, functional gene enrichment analysis and metabolomics. Inflammatory gene expression in tissues was analyzed by RT-PCR. Alterations in bacterial genera showed that sucralose affects the gut microbiota and its developmental dynamics. Enrichment of bacterial pro-inflammatory genes and disruption in fecal metabolites suggest that 6-month sucralose consumption at the human acceptable daily intake (ADI) may increase the risk of developing tissue inflammation by disrupting the gut microbiota, which is supported by elevated pro-inflammatory gene expression in the liver of sucralose-treated mice. Our results highlight the role of sucralose-gut microbiome interaction in regulating host health-related processes, particularly chronic inflammation. DOI: 10.3389/fphys.2017.00487 PMCID: PMC5522834 PMID: 28790923
  6. Probiotics, the Gut, and Muscle Mass Currently, probiotics are mostly thought of and used in relation to a healthy digestive system (reducing upset stomach, gas and bloating, diarrhea, and IBS type symptoms) and to a lesser extent, the immune system (coughs, colds, and general sinus and respiratory health). While they certainly are indeed useful for such applications, the ramifications of an unhealthy gut and microbiota go far, far beyond that. The gut and its microbiome are essentially a massive endocrine organ, controlling and influencing basically your entire body and brain. And, given that all of the trillions of bacteria that call it home originally came from outside your body – and entered without your express written consent – it is by far the most important organ in which we can take steps to manipulate and regain control. “You are what you eat” is more accurate than we ever realized. We will first look at some basic science on how this all works. Then, we will look at studies that have shown alterations in the microbiotic make-up of the gut, and the correlations they display in metabolic health, disease, and fitness. We will particularly focus on the adverse effects of dysbiosis in regard to muscle mass, including diminished protein absorption, testosterone levels, and insulin signaling in the skeletal muscle which results in downregulation of anabolic pathways and upregulation of catabolic ones, ultimately resulting in poor nutrient partitioning that favors accumulation of fat over muscle. It is a massive subject, far too much to discuss in complete depth, here, so we’ll do our best to keep it as short and sweet as possible while still giving you enough background in this field to understand the shocking reality, scope, and importance of this microscopic invasion. Then, we will get down to business and into the specifics of the science of making yourself king of your own biological castle, again, with special emphasis on a lean, muscular body. The Basics The Western lifestyle, including diet and lack of exercise, as well as artificial sweeteners, antibiotics, and alcohol (and, in all likelihood, genetics, though the data just isn’t quite there, yet) leads to an imbalance of the bacterial composition of the gut (1, 2). This results in the excess production and release of inflammatory signals, such as Lipopolysaccharide and TNF-alpha, which subsequently escape the gut and enter the rest of your body, causing havoc (3). Gut dysbiosis also negatively alters production of short-chain fatty acids, with butyrate being most important. This ultimately negatively affects anabolic and anti-catabolic signaling of insulin and other growth factors and pathways, as well as testosterone production. Lipopolysaccharide (LPS) and its downstream inflammatory and redox sensitive pathways will compose the bulk of our focus. LPS, also known as endotoxin, is the major component of the outer membrane of Gram-negative bacteria. These are the ones behind pathogenic bacterial infections like E coli and Salmonella, as well as the bad bacteria of gut dysbiosis that chronically or semi-chronically reside inside you. LPS binds to Toll Like Receptor-4 (TLR-4) and produces a potent immune response in mammals (4). TLR-4 belongs to the pattern recognition family of receptors which recognize pathogen-associated molecular patterns that are expressed on infectious agents (5). This triggers inflammatory cytokines like TNF-alpha, which then trigger reactive oxygen species. Within the gut, this leads to the general digestive issues and inflammatory bowel disorders like IBS and colitis that you have commonly known probiotics as being used to alleviate (6). While fixing digestive disorders will come along for the ride, our primary focus is going to be on body composition and metabolic health. In other words, we want to make you more muscular, stronger, and leaner. However, there really is so much more to it than that, as a few quotes from the literature aptly demonstrate: “Changes in the composition of the gut microbiota (dysbiosis) may be associated with several clinical conditions, including obesity and metabolic diseases, autoimmune diseases and allergy, acute and chronic intestinal inflammation, irritable bowel syndrome (IBS)…” (7) “In this milieu… disturbance of the gut microbiota balance and the intestinal barrier permeability is a potential triggering factor for systemic inflammation in the onset and progression of obesity, type 2 diabetes and metabolic syndrome.” (8) “Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome… Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.” (9) As you can see, alterations in the microbiota can affect basically everything, but the good news is that it is also ripe for positive manipulation. Getting back to the gut and body composition, the aforementioned Lipopolysaccharide (LPS), in combination with the Western diet, disrupts the endocannabinoid system, ultimately leading to an increase in intestinal motility (speed of food going through) in the proximal parts of the intestine (10, 11). This leads to less efficient absorption of nutrients, of which protein and nitrogen are of particular concern. It also reduces nutritive feedback signals that tell the brain you are well fed, thus able to ramp up energy intensive protein synthesis (12, 13). LPS and inflammation also damages the endothelia and microvilli of the gut, further hampering digestion and absorption of nutrients, again with protein and amino acids being of particular concern (14, 15, 16 , 17). It gets much worse from there. Along with this inflammatory state is a disruption in the intestinal barrier. Intestinal permeability is increased, and these inflammatory agents spill out systemically. This is often called a “leaky gut”. This results in a chronic, low-level inflammatory state in the entire body. The biggest culprit here is, once again, LPS (18). LPS interacts with the cannabinoid system in the body and brain, just as in the intestine. In the fat tissue, this leads to activation of PPAR-gamma, and an upregulation of triglyceride synthesis, fat cell formation, and fat storage (19) More important is its activation on TLR-4 which, along with other downstream inflammatory signals (TNF-alpha, interleukins, NF-kB), promotes insulin insensitivity in skeletal muscle, reducing it anabolic and anti-catabolic effects (20, 21). There is also a blood-testis barrier directly analogous to the gut barrier, with equally negative results on testosterone production from these inflammatory invaders (22, 23). This is really bad news in combination with the PPAR-gamma activation in fat cells as it drives nutrient partitioning toward accumulation of fat over muscle. At this point, your phenotype is getting wrecked. You have “skinny fat” or, if blessed with being naturally lean, “hargainer” physiology. Obviously, this is not at all what you want. And, it is just a bunch of microscopic bacteria that call your gut “home” causing all of this devastation. This is the Gut-Microbiota-Muscle axis gone wrong (24, 25, 26). General Data Unless you are quite lean and have an extremely good diet, this is likely affecting you and your muscular gains to at least some extent. Inflammation precedes insulin sensitivity decreases, and the negative effects of such on anabolic and catabolic processes. And, alterations of the microbiota happen even more before that, with all of it happening before significant body fat accrual (27). In other words, it often happens before you have any reason to be aware of it. These changes are extremely rapid. They can occur in a matter of days. Your body simply isn’t built for modern, processed foods (28). They are an attack. In a human colon simulator, the composition of the microbiota was significantly altered within 24 hours by conditions simulating a Western meal (29). In another human study, changes were noted over 4 days, with the earliest changes beginning on day one (30). High-fat feeding for just 3-4 days increased inflammation and reduced insulin sensitivity in mice (31, 32). On the human side, a high fat diet in young, healthy men resulted in an altered inflammatory response within a week. (33). Another study in healthy males found a 3-day hypercaloric and high-fat diet induced decreased insulin sensitivity (34). Perhaps most frighteningly, in a study of a human microbiome transferred into mice, over multiple generations of a low fiber diet some species of bacteria actually became EXTINCT (35). The Western diet is now well into its 4th and 5th generations in the US. And, all of these little attacks are cumulative, so they build up over time (36, 37). Aging, itself, and the deterioration of muscle mass and everything else that comes with it, is basically a whole-body, low-grade inflammatory state (38). Likewise, even in the relatively young, chronic inflammation will epigenetically make your cells “old”, including muscle cells (39). This is known as “inflamm-aging” (40). Basically, unless you are under 30, quite lean, and have a Paleo diet with fruits and veggies, not just low-moderate carbs, you likely have some degree of inflammation induced decreases in muscular insulin sensitivity and protein utilization, thus less than ideal anabolic and anti-catabolic signaling. More powerful evidence of the profound effect of the microbiota on metabolic parameters and the phenotype come from studies on “fecal transfer”. And, yes, that is exactly what it sounds like – transferring poop from one subject’s intestine to another’s. In twins, transfer of an obese microbiota to lean mice was accompanied by an increase in bodyweight, fat mass, and a dysbiotic alteration of the microbiota to reflect that of the obese model (41). A similar transfer replicated the obese phenotype with increased weight gain, lipogenesis, adipogenesis, as well as inflammation and hyperglycemia in formerly lean, healthy subjects (42, 43). On the other side of the coin, transferring the intestinal microbiota from lean donors increases insulin sensitivity in individuals with Metabolic Syndrome, as well as reversing obesity and gastrointestinal issues (44). It also reduced markers of Metabolic Syndrome, inflammation, and oxidative stress in animals challenged with high-fructose diets (45). Other studies have found corrections of high fat diet induced inflammatory status and insulin resistance, accompanied by altered microbiota composition to reflect that of the healthy donor (46, 47). In the most direct findings, transfer of the microbiota from a genetically obese lineage of pig into germ free mice resulted in higher body fat mass, higher slow-twitch fiber proportion, and decreased muscle fiber size and fast-twitch fiber percentage, with the gut microbiota composition of colonized mice sharing high similarity with their donor pigs (48). The microbiome is basically trillions of little biological nanobots going to work on you, for good or bad. Obviously, while it highlights the science, doing a fecal transfer is not terribly practical, appetizing, or readily available -- unless maybe you work for Bill Phillips. Fortunately, we can fix all of this with less intrusive methods. Part 2 on Tuesday, June 19th
  7. Irisin -- Is it a myth?

    It still has some interesting data stuff, though also some conflicting. Brain Plast. 2015;1(1):55-61. doi: 10.3233/BPL-150019. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Wrann CD(1). Author information: (1)Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Exercise can improve cognitive function and the outcome of neurodegenerative diseases, like Alzheimer's disease. This effect has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Recently, we have reported a PGC-1α-FNDC5/irisin pathway, which is activated by exercise in the hippocampus in mice and induces a neuroprotective gene program, including Bdnf. This review will focus on FNDC5 and its secreted form "irisin", a newly discovered myokine, and their role in the nervous system and its therapeutic potential. In addition, we will briefly discuss the role of other exercise-induced myokines on positive brain effects. DOI: 10.3233/BPL-150019 PMCID: PMC5419585 PMID: 28480165 Med Hypotheses. 2016 May;90:23-8. doi: 10.1016/j.mehy.2016.02.020. Epub 2016 Mar 2. FNDC5/irisin, a molecular target for boosting reward-related learning and motivation. Zsuga J(1), Tajti G(2), Papp C(2), Juhasz B(3), Gesztelyi R(4). Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.mehy.2016.02.020 PMID: 27063080 [Indexed for MEDLINE]
  8. In addition to the archives themselves, the chinese Baidu bot guests in the "Online Users" tab lead to some great threads.
  9. Pretty interesting shit. Am J Med Genet B Neuropsychiatr Genet. 2018 Mar;177(2):181-198. doi: 10.1002/ajmg.b.32599. Epub 2017 Sep 13. The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research. Schuch JB(1), Genro JP(2), Bastos CR(3), Ghisleni G(3), Tovo-Rodrigues L(4). The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders. © 2017 Wiley Periodicals, Inc. DOI: 10.1002/ajmg.b.32599 PMID: 28902457 Neurosci Bull. 2015 Feb;31(1):141-59. doi: 10.1007/s12264-014-1495-3. Epub 2015 Feb 6. Genetics and epigenetics of circadian rhythms and their potential roles in neuropsychiatric disorders. Liu C(1), Chung M. Author information: (1)State Key Laboratory of Medical Genetics of China, Changsha, 410078, China, liucy@uic.edu. Circadian rhythm alterations have been implicated in multiple neuropsychiatric disorders, particularly those of sleep, addiction, anxiety, and mood. Circadian rhythms are known to be maintained by a set of classic clock genes that form complex mutual and self-regulatory loops. While many other genes showing rhythmic expression have been identified by genome-wide studies, their roles in circadian regulation remain largely unknown. In attempts to directly connect circadian rhythms with neuropsychiatric disorders, genetic studies have identified gene mutations associated with several rare sleep disorders or sleep-related traits. Other than that, genetic studies of circadian genes in psychiatric disorders have had limited success. As an important mediator of environmental factors and regulators of circadian rhythms, the epigenetic system may hold the key to the etiology or pathology of psychiatric disorders, their subtypes or endophenotypes. Epigenomic regulation of the circadian system and the related changes have not been thoroughly explored in the context of neuropsychiatric disorders. We argue for systematic investigation of the circadian system, particularly epigenetic regulation, and its involvement in neuropsychiatric disorders to improve our understanding of human behavior and disease etiology. DOI: 10.1007/s12264-014-1495-3 PMCID: PMC4821655 PMID: 25652815
  10. Elife. 2016 Jun 2;5. pii: e15092. doi: 10.7554/eLife.15092. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Sleiman SF(1), Henry J(2)(3)(4)(5), Al-Haddad R(1), El Hayek L(1), Abou Haidar E(1), Stringer T(2)(3)(4)(5), Ulja D(2)(3)(4)(5), Karuppagounder SS(6)(7), Holson EB(8)(9), Ratan RR(6)(7), Ninan I(2)(3)(4)(5), Chao MV(2)(3)(4)(5). Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF. DOI: 10.7554/eLife.15092 PMCID: PMC4915811 PMID: 27253067 J Neurochem. 2016 Dec;139(5):769-781. doi: 10.1111/jnc.13868. Epub 2016 Nov 14. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. Marosi K(1), Kim SW(1), Moehl K(1), Scheibye-Knudsen M(2), Cheng A(1), Cutler R(1), Camandola S(1), Mattson MP(1)(3). Author information: (1)Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA. (2)Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. (3)Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms remain unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD+ /NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain-derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-κB, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. DOI: 10.1111/jnc.13868 PMCID: PMC5123937 PMID: 27739595
  11. Anyone ever tried huffing vodka? The gut microbiota includes a community of bacteria that play an integral part in host health and biological processes. Pronounced and repeated findings have linked gut microbiome to stress, anxiety, and depression. Currently, however, there remains only a limited set of studies focusing on microbiota change in substance abuse, including alcohol use disorder. To date, no studies have investigated the impact of vapour alcohol administration on the gut microbiome. For research on gut microbiota and addiction to proceed, an understanding of how route of drug administration affects gut microbiota must first be established. Animal models of alcohol abuse have proven valuable for elucidating the biological processes involved in addiction and alcohol-related diseases. This is the first study to investigate the effect of vapour route of ethanol administration on gut microbiota in mice. Adult male C57BL/6J mice were exposed to 4 weeks of chronic intermittent vapourized ethanol (CIE, N=10) or air (Control, N=9). Faecal samples were collected at the end of exposure followed by 16S sequencing and bioinformatic analysis. Robust separation between CIE and Control was seen in the microbiome, as assessed by alpha (p<0.05) and beta (p<0.001) diversity, with a notable decrease in alpha diversity in CIE. These results demonstrate that CIE exposure markedly alters the gut microbiota in mice. Significant increases in genus Alistipes (p<0.001) and significant reductions in genra Clostridium IV and XIVb (p<0.001), Dorea (p<0.01), and Coprococcus (p<0.01) were seen between CIE mice and Control. These findings support the viability of the CIE method for studies investigating the microbiota-gut-brain axis and align with previous research showing similar microbiota alterations in inflammatory states during alcoholic hepatitis and psychological stress. https://www.ncbi.nlm.nih.gov/pubmed/?term=25803049
  12. After all of that, it was just a few dudes shitposting on facebook and twitter.
  13. In the last episode of The CKD Files, Derf and Dan Jr. had just returned home from the gym following their two hour glycogen depletion workout and had subsequently commenced preparations for the ensuing carb-up. Setting: Daytime in a living room DERF: Typical musclehead, 240+ lbs, sub 6% bodyfat, head shaved to hide the consequences of years of 5-alpha reductase activity, rummages through a tackle box full of pills, vials, and syringes. DAN JR: who couldn't grow on a gram of tren a day, sits, rolling a joint. DERF Dude, I'm low on gear. DAN JR. Yeah, me too. We should go back by the gym and see BigWill after we smoke this. He takes a puff and hands it to Derf, who does the same. DERF I'm gonna need to eat first. DAN JR. (annoyed) Did you take your shot already?? He nods, a bit woozy. Dan just shakes his head, grabsa syringe, and stands up. Derf passes out. Dan heads to the kitchen and returns with a bottle of glucose. He draws some into the syringe and injects it into one of the giant veins on Derf's arm. He comes to. DERF Thanks, dude. Let's hit McDonald's. DAN JR. (shakes his head) That's far too high in fat. Glycogen storage and amino acid uptake are optimal right now -- We need high Glycemic Index carbohydrates. A post workout drink of dextrose and whey is ideal. DERF Bullshit. I haven't had anything except whey and flaxfor the last two weeks. I want some food. DAN JR. Fine. But, we're not eating McDonald's -- we'll go toan all you can eat place. Dan takes out a syringe and injects himself in thethigh. DERF Nubain? DAN JR. Insulin. Derf nods. Dan pulls out another. DERF Nubain? DAN JR. GH. He injects it and pulls out another. DERF Nubain? DAN JR. Yep. Setting: Daytime at all All-You-Can-Eat Restaurant They walk into the restaurant, anxious to begin refilling of glycogen stores and raising leptin levels. There are a couple of people in line in front of them, so they step back. They stand there for a moment, already impatient, when an OBESE WOMAN waddles up and cuts in front of them in line. They give each other a "What the fuck?!" look, then stare at her back, in a rage fueled by low blood sugar, serotonin depletion, and supraphysiological androgen levels. DAN JR. Did that chubby bitch just cut in front of us? DERF Yeah. DAN JR. Does she think we're just standing here to greet people as they walk in the door? Derf shrugs. DAN JR. She doesn't need to be getting seconds anyway. DERF Nope. DAN JR. How much do you think she weighs? DERF Three hundred? DAN JR. I'm thinking maybe as much as four bills. But it's pretty hard to tell when they get that big... I'd say she's definitely pushing at least three and somechange... You'd think they'd have some kind of width limit to eat at all-you-can-eatrestaurants. You know? DERF (laughs) Like the height requirements for rollercoasters? DAN JR. Yeah. They should have a sign when you first walk in the door with a guy holding his arms out that says: Dan holds his arms out really wide. DAN JR. "You must not be this wide to eat at this restaurant." -- 'Cause if you are, you damn sure don't need to be eating at an all-you-can-eat restaurant. DERF She needs some EC. DAN JR. Fuck EC, she needs DNP and some meth. DERF Maybe she just has low leptin levels. DAN JR. Yeah, and maybe she swallowed a guy who swallowed a fly, but I fucking seriously doubt it. It takes a concerted effort to get that fat. You don't go to sleep one night looking like a normal human being and wake up the next day with 54% bodyfat. That doesn't happen. It takes years of determination and willpower. To look like that, there can be no skipping meals, no going to bed hungry, no exercise. Shit, just walking from the couch to the kitchen must burn more than a hundred calories when you weigh that much... I bet she keeps a crate of Krispy Kremes, in her fucking living room, so she can grab a box whenever the urge should strike... Low leptin levels my ass. I guarantee you that bitch gets three tiers of food on her tray. DERF (smiles) She's just got more to love, that's all. Derf walks up closer to her back. He pretends to spank her. DERF Big is beautiful. Ain't it baby. DAN JR. (shaking his head) Fat is not beautiful unless you're a sick, deviant motherfucker with a fetish for that shit. It just isn't aesthetically pleasing. The Obese Woman continues piling food on her tray. DAN JR. I mean, granted, culture and normal personal preferences play a role incertain aspects of what is considered beautiful at different times. For example: Hairstyles and fashion change -- certain trends are hip for a while, but fiveyears later are atrocious -- the 1980's come to mind. But some things are universally beautiful. And certain things are universally not beautiful in any way, shape, or form. DERF Like what? DAN JR. Things like Nicole Bass, and pimples, and warts, and melted flesh from third degree burns... And well-fed bitches like her. DERF You make a good argument. DAN JR. Don't kid yourself, Derf. I'm not finished. I haven't yet begun to ridicule. DERF Oh. DAN JR. You know it's gotta be unsanitary. I mean, can you imagine what kind ofbacteria and yeast and STD's and shit are spawning and fermenting betweeneach and every fucking chub roll on that immense body? DERF It's a sick thought. DAN JR. Of course, it is. And the other day I heard on Oprah something about "foodaholism". Like it's a fucking disease, like cancer. Like they can't help. Like it's not their fault. DERF I did read on MFW about a study linking obesity to a virus. DAN JR. Well, then the CDC needs to come out here and quarantine this bitch. DERF (laughing) If it was a virus, what do you think they'd call it. DAN JR. There's already a name for what she has. It's called "gluttony". The Obese Woman turns around with two trays full of food, each with plates piled one on top of the other like a pyramid. DAN JR . (as she walks by) How now, brown cow. She doesn't respond. Derf laughs, and they finally approach the windowto order their long-awaited food. The End. The following was a fictional skit. Any resemblance to actual people, be they from your local gym or alt.support.fat-acceptance, is purely coincidental.
  14. The following is an interview with TC Luoma. TC is the editor of TestosteroneMagazine, former editor of Muscle Media 2000, bodybuilding pioneer, and badass. THE LESBIAN PIMP How are you doing today, TC? TC LUOMA Man, I accidentally used too much Androsol this morning -- it's got me almost homicidal. I had to stop by a biker bar and kick some ass o­n my way out here. THE LESBIAN PIMP Really? TC LUOMA Oh yeah. This is powerful stuff. I can literally feel the increased protein synthesis - in fact, I've gained 29 grams of rock solid mass in the last 2 hours. THE LESBIAN PIMP Very impressive. Actually, you've made a number of impressive claims as far as results from different supplements over the years - it seems as though you should be vying for the Mr. O by now, yet looking at you, I can't really tell you work out. TC LUOMA Yeah, a lot of people say that. But, I'm 173 lbs at less than 13% bodyfat, so I just don't get it. And frankly, it pisses a T-dude off. In fact, if this Androsol wasn't wearing off, you'd be dead right now... just for bringing it up. THE LESBIAN PIMP I see. Why did Charles leave T-Mag? TC LUOMA I can't go into that too much, for legal reasons. THE LESBIAN PIMP Most of us assume that all of the hype and bullshit left him with a Biotest stank that he could no longer wash off of himself each night, even with Lava. And that has pumice, so it must have been really bad. TC LUOMA No. That's not it at all. It didn't have anything to do with Biotest. He-- (TC stops) Let's just say he saw something that made our business relationship uncomfortable. THE LESBIAN PIMP Like pissing in the Methoxy-7 or what?? TC LUOMA Like I said, I can't really say too much - so I'll just leave it at this: "Me, Tim, full body latex, and a tub of vanilla Grow." THE LESBIAN PIMP Fascinating. What was your relationship with Bill Phillips like? TC LUOMA (Getting teary eyed) I loved that man. Bill Phillips was a great man in the early years - when he still cared about the sport. But, then came the fame, then the drugs and the fitness bimbos... And after he started those physique transformation contests... he just turned into a completely different person. (TC breaks out crying) THE LESBIAN PIMP There. There. It's gonna be okay. TC LUOMA He made me eat out of a dog bowl. THE LESBIAN PIMP I see... Wait, he what?... Nevermind. (TC calms down a bit) So what does the "T" in "TC Luoma" stand for, TC? I assume it must be something pretty bad if it made you go through life just using your initials - 'cause "TC" really sounds pretty stupid itself. I bet it's a hermaphroditic name- that would explain a lot of the machismo - you know, like a coping mechanism for sharing your name with a girl. Is it Terry?... Tracey? (He bursts out crying again) TC LUOMA Bill used to call me that... Are you clean, Tracey? Are you wearing my favorite dress??... Who's ass is this, Tracey?! (he continues crying) It's your ass Bill -- It's your ass! (He's hysterical) Okay, I'll call you daddy -- please, just don't hit me again! THE LESBIAN PIMP Okay. I think that will just about do it. Thank you for coming by today, TC. We look forward to talking with you again soon. Obviously, this has been a fictional skit -- it is parody, co-written by The Lesbian Pimp and Par Deus, and is not intended to be taken at all seriously, nor is it intended to imply anything about the sexual inclinations of the real TC Luoma, Tim Patterson, or Bill Phillips.
  15. Okay, there is not going to be a true one master signal, as the body has a bunch of redundant systems, but BDNF may be the closest thing to it. It is increased by proper leptin and insulin signalling, decreased by cortisol, modulates the the positive neurotransmitter response and neurogenesis from exercise and anti-depressants, and it controls feeding and metabolic behavior.... Behav Neurosci. 2012 Aug;126(4):505-14. doi: 10.1037/a0028600. Epub 2012 Jun 11. A putative model of overeating and obesity based on brain-derived neurotrophic factor: direct and indirect effects. Ooi CL(1), Kennedy JL, Levitan RD. Author information: (1)Department of Psychiatry, University of Toronto, Ontario, Canada. Increased food intake is a major contributor to the obesity epidemic in all age groups. Elucidating brain systems that drive overeating and that might serve as targets for novel prevention and treatment interventions is thus a high priority for obesity research. The authors consider 2 major pathways by which decreased activity of brain-derived neurotrophic factor (BDNF) may confer vulnerability to overeating and weight gain in an obesogenic environment. The first "direct" pathway focuses on the specific role of BDNF as a mediator of food intake control at brain areas rich in BDNF receptors, including the hypothalamus and hindbrain. It is proposed that low BDNF activity limited to this direct pathway may best explain overeating and obesity outside the context of major neuropsychiatric disturbance. A second "indirect" pathway considers the broad neurotrophic effects of BDNF on key monoamine systems that mediate mood dysregulation, impulsivity, and executive dysfunction as well as feeding behavior per se. Disruption in this pathway may best explain overeating and obesity in the context of various neuropsychiatric disturbances including mood disorders, attention-deficit disorder, and/or binge eating disorders. An integrative model that considers these potential roles of BDNF in promoting obesity is presented. The implications of this model for the early prevention and treatment of obesity are also considered. DOI: 10.1037/a0028600 PMID: 22687148 [Indexed for MEDLINE] Trends Neurosci. 2013 Feb;36(2):83-90. doi: 10.1016/j.tins.2012.12.009. Epub 2013 Jan 18. BDNF and the central control of feeding: accidental bystander or essential player? Rios M(1). Author information: (1)Tufts University School of Medicine, Department of Neuroscience, Boston, MA 02111, USA. maribel.rios@tufts.edu A considerable body of evidence links diminished brain-derived neurotrophic factor (BDNF) signaling to energy balance dysregulation and severe obesity in humans and rodents. Because BDNF exhibits broad neurotrophic properties, the underpinnings of these effects and its true role in the central regulation of food intake remain topics of debate in the field. Here, I discuss recent evidence supporting a critical role for this neurotrophin in physiological mechanisms regulating nutrient intake and body weight in the mature brain. They include reports of functional interactions of BDNF with central anorexigenic and orexigenic signaling pathways and evidence of recognized appetite hormones exerting neurotrophic effects similar to those of BDNF. Copyright © 2013 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.tins.2012.12.009 PMCID: PMC3568936 PMID: 23333344 [Indexed for MEDLINE] Psychiatry Clin Neurosci. 2010 Oct;64(5):447-59. doi: 10.1111/j.1440-1819.2010.02135.x. Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. Kunugi H(1), Hori H, Adachi N, Numakawa T. Author information: (1)Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. hkunugi@ncnp.go.jp Although the pathophysiology of depressive disorder remains elusive, two hypothetical frameworks seem to be promising: the involvement of hypothalamic pituitary-adrenal (HPA) axis abnormalities and brain-derived neurotrophic factor (BDNF) in the pathogenesis and in the mechanism of action of antidepressant treatments. In this review, we focused on research based on these two frameworks in relation to depression and related conditions and tried to formulate an integrated theory of the disorder. Hormonal challenge tests, such as the dexamethasone/corticotropin-releasing hormone test, have revealed elevated HPA activity (hypercortisolism) in at least a portion of patients with depression, although growing evidence has suggested that abnormally low HPA axis (hypocortisolism) has also been implicated in a variety of stress-related conditions. Several lines of evidence from postmortem studies, animal studies, blood levels, and genetic studies have suggested that BDNF is involved in the pathogenesis of depression and in the mechanism of action of biological treatments for depression. Considerable evidence has suggested that stress reduces the expression of BDNF and that antidepressant treatments increase it. Moreover, the glucocorticoid receptor interacts with the specific receptor of BDNF, TrkB, and excessive glucocorticoid interferes with BDNF signaling. Altered BDNF function is involved in the structural changes and possibly impaired neurogenesis in the brain of depressed patients. Based on these findings, an integrated schema of the pathological and recovery processes of depression is illustrated. © 2010 The Authors. Psychiatry and Clinical Neurosciences © 2010 Japanese Society of Psychiatry and Neurology. DOI: 10.1111/j.1440-1819.2010.02135.x PMID: 20923424 [Indexed for MEDLINE] Med Hypotheses. 2016 May;90:23-8. doi: 10.1016/j.mehy.2016.02.020. Epub 2016 Mar 2. FNDC5/irisin, a molecular target for boosting reward-related learning and motivation. Zsuga J(1), Tajti G(2), Papp C(2), Juhasz B(3), Gesztelyi R(4). Author information: (1)Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. Electronic address: zsuga.judit@med.unideb.hu. (2)Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. (3)Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. (4)Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.mehy.2016.02.020 PMID: 27063080 [Indexed for MEDLINE]