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.
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).
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 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).
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.