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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