The Gut Microbiota – a Fundamental Mediator of Metabolism The complex ecosystem comprising trillions of microorganisms (bacteria, yeast, protozoa, and viruses) housed in the gut are known collectively as the gut microbiota. The collection of all gut microbial genes (the gut microbiome) are more than one order of magnitude higher than that of genes in the human genome. The majority of these microbes are commensal or mutualistic and reside in the digestive tract (especially the distal colon), but they are also present on our skin and elsewhere.Our co-existing microorganisms play a central role in human physiology. They are driven by the symbiotic exchange of metabolic products between host and microbe, and we are dependent on each other for numerous biological functions (e.g. nutrient absorption). It is now acknowledged that the gut microbiome plays a direct role in mediating communication between the different organ systems. There are clear links between the microbiome and its influence on host metabolism, with profound implications for human health given the prevalence of obesity and metabolic syndrome in Western societies. The Interface between Diet, the Gut Microbiome, and Metabolic Health Part 1 Cutting-edge techniques in microbiome research have revealed that environmental factors such as diet and lifestyle have more of an impact on shaping our gut microbiome than genetics. Dietary fiber is a polymer of carbohydrates (oligosaccharides), and humans lack the enzymes to break down the glycosidic bonds. When we consume fiber, it passes through our digestive tract mostly undigested. When it reaches the colon, fiber gets metabolized through a process called fermentation whereby several carbon compounds are generated, principally the short chain fatty acids (SCFAs) butyrate, propionate, and acetate. Butyrate has been shown to be of particular importance. These SCFAs bind to receptors on various organ sites and elicit signaling cascades that promote a myriad of downstream effects. When SCFAs bind to receptors on the intestinal brush border, peptides such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), which have appetite suppressing (anorexigenic) effects, are activated. Butyrate can bind to G-protein coupled receptors (GPCRs) on adipocyte (fat cell) membranes causing decreased fat accumulation, stimulation of lipolysis and beta-oxidation (so it promotes the release of fat from the fat cells and the oxidation of that fat). It also decreases insulin signaling, which further enhances fatty acid release and oxidation (colloquially known as “fat burning”). Insulin is a critical hormone, but too much is not good. Insulin inhibits lipolysis and beta-oxidation, causing fat accumulation. It also increases the transcription of enzymes involved in fat synthesis (lipogenesis) and decreases genes known to be involved in longevity. Takeaway Dietary fiber is the indigestible part of food-derived plant matter to which we lack the digestive enzymes to break down ourselves. Instead, the gut microbiome breaks it down and converts it into compounds such as SCFAs, which are cell signaling molecules that act on several different organ systems. SCFAs increase hormones that promote satiety such as PYY, GLP-1, and CCK. Butyrate in particular has many beneficial effects. It serves as a primary fuel source of our colon cells and for helping to maintain the integrity of the gut in many ways. It also stimulates fat loss and improves metabolic health through several mechanisms. The Interface Between Diet, Gut Microbiome, and Metabolic Health Part 2 SCFAs can inhibit a protein inside enterocytes called Fiaf. Fiaf’s normal function is to inhibit lipoprotein lipase (LPL). So, the inhibition of Fiaf releases inhibition on LPL. This, in turn, promotes decreased fat accumulation. SCFAs also act on the adipose tissue to increase beta adrenergic signaling, which further increases fatty acid degradation to be released into the blood and oxidized. Additionally, SCFAs decrease adipose tissue inflammation and enhance the conversion of white adipose tissue (WAT) to brown adipose tissue (BAT), which has more of a propensity to burn fat and thermogenic effect. Furthermore, SCFAs also trigger the release of leptin from the adipose tissue, a hormone involved in satiety. Further, these compounds also act on the liver, skeletal muscle, and colonocytes. Butyrate in particular serves as a fuel for colonocytes, reduces inflammation in the colon and helps to maintain the integrity of the tight junction structures as well as the pH in the lumen. It also promotes cell cycle arrest and apoptosis, thereby reducing colon polyps that could develop into colon cancer. A paucity of SCFAs (by not getting enough through diet or by antibiotic depletion) contributes to disruption of microbial homeostasis. Pathogenic microbes, such as E. coli and Salmonella, are then given a more hospitable and opportunistic environment to outcompete commensal microbes that characterize a healthy gut flora. Microbial homeostasis is, in part, maintained by activation of receptors for SCFAs (such as PPAR-y). Obesity and metabolic disorders such as type 2 diabetes are associated with lower microbial diversity and specific types of microbes. The capacity to harvest more calories from the diet is increased in obese individuals. Compared to lean mice and humans, obese individuals have an increased relative abundance of Firmicutes, and reduced abundance of Bacteroidetes. Metagenomic analyses demonstrate that individuals with reduced microbial diversity have higher levels of systemic inflammation, insulin resistance, dyslipidemia, and adiposity. Conversely, other genera including Akkermansia, Bifidobacterium, Lactobacillus, and Faecalibacterium have been demonstrated to be associated with higher microbial gene count and lean individuals with better overall metabolic health. Takeaway Obesity and metabolic disorders such as T2DM are associated with specific microbial signatures that correlate with insulin resistance, systemic inflammation, excess fat accumulation, and aberrant fat metabolism. Interestingly, when you swap the gut microbiome of two rodents–let’s say one that is obese with metabolic syndrome and one that is lean and metabolically healthy–it changes their phenotype to that of the one they were swapped for. So, the lean mouse becomes obese and insulin resistant while the obese mouse becomes lean and metabolically healthier. This suggests that the gut microbiome may have a direct causal role in our metabolic health. The Influence of the Gut Microbiota on Metabolism Through Regulation of Gut Hormones As highlighted previously, the gut microbiome contributes
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