Microbial metabolism and lipid regulation: bile acids, choline, and gut microbiota-mediated inflammation

(4) Choline: Choline is an important component of cell membranes, mainly obtained through food, but can also be synthesized by the body. Choline-like substances entering the body are metabolized by microbial enzyme complexes (CutC/D, CntA/B, YeaW/X) to produce the primary bacterial metabolite trimethylamine. Trimethylamine is further metabolized in the liver by flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine N-oxide (TMAO). Excessive TMAO in the blood increases foam cells and inhibits reverse cholesterol transport, leading to atherosclerotic lesions. Recent studies have found that the TMAO metabolic pathway is involved in energy metabolism in obese mice and obese individuals, and FMO3 has been found in white adipose tissue, showing a positive correlation with body mass index and waist-to-hip ratio. A two-month choline-based dietary intervention trial involving 15 healthy individuals found that gut microbiota was associated with fatty liver before the low-choline dietary intervention. (5) Bile acids: Bile acids are synthesized from cholesterol in the liver via cytochrome P450 oxidation. The bioconversion of bile acids into unbound forms by gut microbiota is central to gastrointestinal metabolic homeostasis. Currently known gut microbiota associated with bile acid uncoupling include Bacteroides, Clostridium, Lactobacillus, Bifidobacterium, and Listeria. Bile acids bioconverted by gut microbiota activate bile acid receptors in the host liver, intestines, and peripheral tissues, primarily binding to the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5), affecting glucose and lipid homeostasis and energy metabolism. Studies have shown that FXR and TGR5 are influenced by gut microbiota, with TGR5 being the primary bile acid receptor. An antibiotic-associated gut microbiota intervention trial found that after one week of vancomycin intervention, a decrease in Gram-positive gut bacteria led to changes in bile acid composition and increased peripheral insulin sensitivity in the subjects. III. Gut Microbiota and Obesity 1. Gut Microbiota and Energy Metabolism Obesity is essentially an imbalance in the body's energy metabolism, leading to excessive calories being stored as fat, thus causing obesity. Gut bacteria are not only essential for food digestion but also participate in many aspects of the body's energy production, conversion, storage, and utilization. They influence the body's energy metabolism by regulating the expression of gut hormones and altering how tissues utilize energy. Studies have found that even mice with a genetic predisposition to obesity can maintain a lean physique under sterile conditions, while germ-free mice inoculated with feces from obese patients and obese mice exhibit increased appetite and a tendency towards obesity. Other studies have found that germ-free mice receiving feces from asymmetrically obese twin mice showed significant differences in food intake, fat accumulation, weight gain, and the content of SCFAs in feces. Furthermore, the levels of propionate and butyrate in the cecum of lean mice were significantly higher than in obese mice. This suggests that the influence of gut microbiota on energy metabolism is not necessarily directly caused by the microbiota itself but may also be achieved through the inhibition of fat accumulation by its metabolites. The mechanisms by which gut microbiota affects host energy storage may include the following two aspects: (1) Gut microbiota breaks down polysaccharides that the human body cannot digest into small molecules such as short-chain fatty acids, mainly including acetic acid, propionic acid, and butyric acid, providing the host with extra energy and promoting fat synthesis and storage. In particular, acetic acid can activate the parasympathetic nervous system and stimulate the production of gastrointestinal stimulant, leading to overeating and obesity. (2) Gut microbiota also plays a role in regulating host lipid metabolism, especially affecting triglyceride levels. Bile salt hydrolysates produced by gut microbiota metabolism convert bound bile acids into secondary free bile acids, which regulate liver and systemic lipid metabolism through G protein-coupled receptors. Therefore, when gut microbiota is imbalanced, it can lead to bile acid secretion disorders, abnormal fat absorption, and excessive energy intake. In addition, intestinal epithelial cells can produce a lipoprotein lipase inhibitor-fasting-induced adipose factor (Fiaf). Gut microbiota can promote lipoprotein lipase expression by inhibiting Fiaf gene expression, thereby promoting the storage of triglycerides in adipocytes. 2. Gut Microbiota-Mediated Inflammatory Response. Obesity is a disease accompanied by chronic low-grade inflammation. Unlike traditional inflammation, it does not present with symptoms such as redness, heat, swelling, or pain. It is a non-specific, systemic, low-level chronic inflammation induced by various inflammatory factors. Studies have shown that the quantity and diversity of gut microbiota are significantly reduced in obese individuals, while bacteria that cause mild inflammation in the digestive tract and even the entire body are dominant, leading to exacerbated weight gain. Therefore, gut microbiota-mediated chronic inflammation is another important cause of obesity. When the gut microbiota is imbalanced, the proportion of Gram-negative bacteria increases, leading to increased production of lipopolysaccharides (LPS). LPS can cross the intestinal wall and enter the systemic circulation, causing toxinemia and playing an important role in the development of obesity and related chronic diseases. LPS is the main active substance responsible for the biological effects of endotoxins. It forms an immune complex with its corresponding receptor CD14 and is recognized by the TLR4 receptor on the surface of immune cells. Through a series of signal transductions, it stimulates the expression of various inflammatory factors, forming the LPS-LBP-CD14/TLR4 signal transduction pathway. This activates the TLR4-MyD88-NFkb signaling pathway and can induce the expression of inflammatory factors such as IL-1, TNF-α, and IL-6 through signal transduction, resulting in non-specific chronic low-grade inflammation, which in turn leads to obesity. At the same time, these inflammatory factors can enter important metabolic tissues, such as adipose tissue, liver tissue, and muscle tissue, causing abnormal function in these metabolically active tissues and forming a vicious cycle.