The Therapeutic Effect of SCFA-Mediated Regulation of the Intestinal Environment on Obesity

Abstract

Intestinal environment disorder is a potential pathological mechanism of obesity. There is increasing evidence that disorders in the homeostasis of the intestinal environment can affect various metabolic organs, such as fat and liver, and lead to metabolic diseases. However, there are few therapeutic approaches for obesity targeting the intestinal environment. In this review, on the one hand, we discuss how intestinal microbial metabolites SCFA regulate intestinal function to improve obesity and the possible mechanisms and pathways related to obesity-related pathological processes (depending on SCFA-related receptors such as GPCRs, MCT and SMCT, and through epigenetic processes). On the other hand, we discuss dietary management strategies to enrich SCFA-producing bacteria and target specific SCFA-producing bacteria and whether fecal bacteria transplantation therapy to restore the composition of the gut microbiota to regulate SCFA can help prevent or improve obesity. Finally, we believe that it will be of great significance to establish a working model of gut- SCFA- metabolic disease development in the future for the improvement this human health concern.

Keywords: SCFA; gut microbiota; intestinal environment; metabolism; obesity.

Figure 1

Gut microbiome disorders in obese patients are caused by intestinal environment disorders, which have the following characteristics: (1) Intestinal leakage and low levels of LPS in the blood may activate signal transduction in various TLR4-expressing cells, leading to the occurrence of fat inflammation and lipid accumulation. (2) Intestinal immune function decreased, and levels of proinflammatory Th1 cells, total macrophages, dendritic cells and NK cells increased, exacerbating inflammation. (3) The abundance of SCFA-producing bacteria decreased, leading to a decrease in the intestinal absorption capacity of SCFA and an increase in fecal SCFA concentration. Increased nutrient intake is associated with increased levels of gastrointestinal leakage, and through passive ingestion, increased serum SCFA concentration.

Figure 2

Activation of SCFA-associated receptors in early life intestinal response mechanisms to prevent metabolic diseases in adulthood: by regulating the intestinal flora matrix, increased maternal SCFA flows into the embryo to activate embryonic sympathetic nerve receptor GPR41 and intestinal epithelium and pancreas GPR43, promotes the development of the baby's nerve and bowel, improves embryo glucolipid metabolism, and improves the fetal malnutrition caused by maternal metabolic disorders, preventing metabolic diseases in adulthood.

Figure 3

Activation depends on SCFA-associated receptors to maintain intestinal function and alleviate metabolic disorders: (1) Extracellular, SCFA-sensing G-protein-coupled receptors (GPCRs) are activated to recruit and bind downstream effector proteins (e.g., G proteins, β-arrestin, etc.), which then function in vivo through the cAMP signaling pathway, ERK signaling pathway 1/2, and calcium ion signaling pathway. (2) The activation of GPR43 and GPR41 receptors on intestinal endocrine cells is closely related to the regulation of metabolic disorders. After activation, GLP-1 can be stimulated, the secretion of PPY maintains glucose homeostasis, and the activation of SCFA transporters MCT and SMCT can promote the entry of SCFA into intestinal epithelial cells and regulate genes related to fat metabolism. Activation of these SCFA-dependent receptors is particularly important for fat storage, oxidation, inflammation, and thermogenesis.

Figure 4

SCFA can also inhibit obesity by inhibiting the HDAC receptor-independent pathway: after inhibiting HDAC, SCFA play a core role in PPAR-regulated lipid oxidation in the intestinal epithelium and can regulate a variety of genes that respond to microflora regulation of metabolism to improve lipid accumulation in intestinal epithelial cells. Moreover, inhibition of HADA has been found to play a beneficial role in lipid metabolism in the liver, in addition to the regulation of Tregs in immune cells. Inhibition of inflammation is also closely related to the occurrence and development of obesity.

Figure 5

Methods and approaches to improve obesity-related metabolic diseases by regulating the intestinal environment through SCFA: Dietary therapy (direct supplementation of SCFA, dietary fiber and prebiotics) and microbiological therapy (fecal bacteria transplantation) concentrate/target SCFA-producing bacteria, increase SCFA production, repair intestinal barrier damage, reduce inflammation in intestinal and periintestinal tissues, enhance lipolysis, and improve glucose homeostasis. This approach results in inhibition of the occurrence of obesity and related metabolic diseases.

Figure 6

A. muciniphila promotes SCFA metabolism and improves the intestinal environment to improve metabolic abnormalities: (1) A. muciniphila can increase the production of SCFA (such as propionate and acetate) by degrading mucin, increasing the abundance of Bacteroidetes and degrading HMO. (2) Promoting intestinal epithelial cell proliferation by supporting mucus-secreting goblet cell differentiation, promoting the maturation of Wnt3- and defensin-secreting Paneth cells in a GPR43/41-dependent manner. (3) Promoting the secretion of GLP-1 and PYY in a GPR43/41-dependent manner. (4) Inducing Fiaf expression and inhibiting LDL production. (5) Inhibiting LPS production and inflammation.