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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
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
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