Gut microbiota and energy homeostasis: How hidden organs affect metabolism

3. Gut Microbiota The human gut microbiota is rich and diverse, with the small intestine containing approximately 10¹⁴¹⁰ species of bacteria, which is 10¹⁰ times the number of human eukaryotic cells. The gastrointestinal tract is the primary habitat for the microbial community and the most important site for interaction between microorganisms and the host. The ecosystem of various symbiotic microorganisms within it is called the gut microbiota. Studies have shown that approximately 90% of the gut microbiota in healthy individuals belongs to the phyla Bacteroidetes (Gram-negative bacteria) and Firmicutes (Gram-positive bacteria), while the abundance of phyla such as Proteobacteria, Actinobacteria, Acidobacteria, and Verrucous Microbes is relatively low. Furthermore, the gut microbiota, as a "hidden organ" of the human body, plays an indispensable role in the host's life cycle: promoting the absorption and metabolism of nutrients that the host cannot digest; forming the intestinal barrier and protecting the mucosa; participating in the immune system and resisting pathogen invasion; maintaining homeostasis and preventing disease. Specific bacterial categories or bacterial metabolic activities may have beneficial or harmful effects on the development and progression of obesity. Studies have shown that the gut microbiota composition of leaner individuals differs significantly from that of obese individuals, with obese individuals potentially possessing bacterial communities that more effectively absorb or store energy from nutrients. Research has found that the relative proportion of Bacteroides is significantly lower in obese individuals compared to normal-weight individuals, while the proportion of Firmicutes increases. Firmicutes can convert polysaccharides into absorbable monosaccharides and short-chain fatty acids, generating more absorbable energy, leading to increased body weight and obesity. Gut microbiota can regulate adipose tissue (fat) storage; adult germ-free mice that acquired a normal gut microbiota from conventionally fed mice showed a 60% increase in fat content and insulin resistance despite lower food intake. Another study also indicated that if germ-free mice colonized with an obese microbiota, their increase in body fat was much greater than that of mice colonized with a lean microbiota. Therefore, an important mechanism explaining the difference in body fat between normal and germ-free mice is that gut microbial fermentation increases energy harvesting from food. The gut microbiota may influence obesity by affecting calorie absorption, and obesity may, in turn, affect the composition of the gut microbiota. 4. Microbial metabolites Microorganisms can also influence the host's neurophysiological changes by producing chemical substances that bind to receptors inside and outside the intestine through metabolism. The products and metabolites of the gut microbiota can also act on distal organs and affect obesity-related pathophysiological processes: LPS and SCFA act on adipose tissue, LPS, bile acids, SCFA, ethanol and choline act on the liver, and the active substances produced by the microbiota act on the brain through the gut-brain axis. The microbiome can synthesize, regulate and degrade many small molecules, especially metabolize dietary components that the host cannot metabolize, such as complex carbohydrates, thereby complementing the host's metabolic function and helping to synthesize primary metabolites and regulate secondary metabolites that affect the host's physiology in a variety of ways. Several key gut microbial metabolites are beneficial to neuronal regulation, immune cell development, nutrient digestion and intestinal epithelial homeostasis. (1) Short-chain fatty acids: SCFAs are produced by the fermentation of dietary fiber by intestinal microorganisms in the large intestine. They mainly include acetate, propionate and butyrate, which are important metabolites of partially digestible and indigestible carbohydrates (i.e. dietary fiber) fermented by anaerobic symbiotic microbiota. In a rat model of transient focal cerebral ischemia, intraperitoneal injection of sodium butyrate attenuated disruption of the blood-brain barrier (BBB). In animal models, SCFAs can improve neurodevelopment and cognitive function in animals with neurodegenerative diseases. SCFAs not only serve as an energy source for epithelial cells but also maintain the epithelial barrier, protect mucosal immunity, and influence the biological function of regulatory T cells. Other microbial-derived molecules, such as neuroactivating molecules, 5-HT, melatonin, histamine, and acetylcholine, also play roles in the gut-brain axis. Another important basis for SCFAs' involvement in gut-brain axis regulation is their ability to cross the blood-brain barrier. Short-chain fatty acids in the bloodstream, such as butyrate and propionic acid, can be transported long distances across the blood-brain barrier via monocarboxylate transporters (MCTs) into the central nervous system. Once in the central nervous system, they can continue to be transported to glial cells and neurons via MCTs. (2) Microbial metabolites of tryptophan: Bacteria in the gut can metabolize tryptophan into active products. For example, Escherichia coli uses tryptophan to synthesize indole. Indole, as a "quorum sensing" signal, can regulate the virulence of E. coli and other bacteria and the formation of biofilms, and has typical beneficial effects on the gut. The products of microbial metabolism of tryptophan can also regulate the inflammatory response of the gut and the central nervous system. The metabolites of gut microbiota can also enter the bloodstream and act on the whole body, but their potential effects on the host are not yet clear. However, the activation of pathogen-associated molecular patterns and danger signal-associated molecular patterns plays an important role in the stimulation of the CNS by gut microbiota. These mainly include lipopolysaccharide and peptidoglycan, which can activate Toll-like receptor 4 (TLR4) and NOD1 or NOD2 in the nucleotide-binding oligomer domain-like receptor (NLRs) family, respectively. (3) Lipopolysaccharide: In obese patients, increased intestinal mucosal permeability can lead to endotoxin lipopolysaccharide entering the host blood or tissues through the intestinal mucosal barrier, causing endotoxemia. Altered intestinal epithelial permeability has also been observed in patients with irritable bowel syndrome, autism, and schizophrenia. Conversely, the gut microbiota plays a crucial protective role in intestinal barrier function. Overactivity of the HPA axis can lead to gut microbiota dysbiosis by altering intestinal permeability and activating intestinal immunity. Corticotropin-releasing hormone (CRH), with the participation of mast cells, acts on the enteric nerve plexus, reducing the expression of tight junction proteins in the intestinal mucosal epithelium, thereby disrupting the intestinal mucosal barrier. When intestinal permeability is altered, lipopolysaccharide can be recognized by Toll-like receptors (TLRs) on the surface of immune cells, triggering the secretion of pro-inflammatory factors and subsequently causing an inflammatory response. Inflammation and pathogen infection are the pathological basis for various psychosomatic diseases, leading to lesions in various systems or internal organs innervated by the autonomic nervous system.