Gut and obesity/metabolic disease: Focus on microbiota metabolites

Abstract

Obesity is often associated with the risk of chronic inflammation and other metabolic diseases, such as diabetes, cardiovascular disease, and cancer. The composition and activity of the gut microbiota play an important role in this process, affecting a range of physiological processes, such as nutrient absorption and energy metabolism. The active gut microbiota can produce a large number of physiologically active substances during the process of intestinal metabolism and reproduction, including short-chain/long-chain fatty acids, secondary bile acids, and tryptophan metabolites with beneficial effects on metabolism, as well as negative metabolites, including trimethylamine N-oxide, delta-valerobetaine, and imidazole propionate. How gut microbiota specifically affect and participate in metabolic and immune activities, especially the metabolites directly produced by gut microbiota, has attracted extensive attention. So far, some animal and human studies have shown that gut microbiota metabolites are correlated with host obesity, energy metabolism, and inflammation. Some pathways and mechanisms are slowly being discovered. Here, we will focus on the important metabolites of gut microbiota (beneficial and negative), and review their roles and mechanisms in obesity and related metabolic diseases, hoping to provide a new perspective for the treatment and remission of obesity and other metabolic diseases from the perspective of metabolites.

Keywords: gut microbiota; metabolic disease; metabolites; obesity.

FIGURE 1

The beneficial and negative metabolites produced by gut microbiota. The gut microbiota produces all kinds of beneficial or negative metabolites and directly affects the intestinal barrier and gut hormone (glucagon‐like peptide 1 [GLP‐1] and tyrosine tyrosine [PYY]) release. After entering circulation, those metabolites regulate satiety, insulin release, adipose tissue function, and systemic immunity, thus influencing obesity and energy metabolism.

FIGURE 2

Tryptophan metabolism. Most dietary tryptophan is metabolized to NAD+ in the liver. Part of tryptophan is synthesized into 5‐hydroxytryptamine (5‐HT). Approximately 5% of tryptophan is metabolized in the intestinal tract by the bacterial tryptophanase of the gut microbiota into a series of indole metabolites, such as indole‐3‐aldehyde (IAld), indole‐3‐acid‐acetic (IAA), indole‐3‐propionic acid (IPA), and indole‐3‐lactic acid (ILA).

FIGURE 3

Metabolites enhance satiety and inhibit eating. Through bile acid (BA) receptors (Takeda G‐protein‐coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]), short‐chain fatty acid (SCFA) receptors (GPR41/43), Toll‐like receptor (TLR) of intestinal cells, and enhanced Ca²⁺ entry, L cells can promote the release of intestinal hormones (glucagon‐like peptide 1 [GLP‐1]/tyrosine tyrosine [PYY]), activate hypothalamus proopiomelanocortin (POMC) and inhibit neuropeptide Y (NPY) to improve satiety. Meanwhile, BAs and SCFAs can cross the blood–brain barrier, and BAs enhance satiety through TGR5 receptors in the hypothalamus. SCFAs increase lactic acid and inhibit NPY. Otherwise, SCFAs promote the level of growth hormone, which can control energy homeostasis by stimulating lipolysis and protein retention.

FIGURE 4

Metabolites affect islet β cells and regulate insulin secretion. When glucose internalized in islet β cells is metabolized, it results in elevation of the adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio, closure of ATP‐sensitive potassium (KATP) channels, and opening of voltage‐dependent calcium channels (Ca²⁺ channels), causing secretion of insulin. First, short‐chain fatty acids (SCFAs) can improve or decrease glucose‐stimulated insulin secretion (GSIS). After Free fatty acid 2 (FFA2) activation, the Gαq/11 subunit activates phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5‐bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3), activating protein kinase C (PKC) and releasing calcium ions from endoplasmic reticulum (ER) storage, respectively, which can promote insulin release. FFA2 and FFA3 can also bind to Gα I/O subunits and inhibit adenylate cyclase (AC), thereby reducing the concentration of cyclic AMP (cAMP) and inhibiting protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC)‐mediated insulin release. Similarly, bile acids (BAs) activate the Takeda G‐protein‐coupled receptor 5 (TGR5) receptor to bind Gα s and promote insulin release through the PLC and cAMP pathways. BAs can also bind to farnesoid X receptor (FXR) receptors to promote Ca²⁺ release. Meanwhile, metabolites (SCFAs, BAs, and indole) promote the release of glucagon‐like peptide 1 (GLP‐1) by intestinal L cells, and its binding with GLP‐1R also promotes the release of insulin.

FIGURE 5

Metabolites affect adipose tissue function. Under the action of beneficial metabolites (short‐chain fatty acids [SCFAs], bile acids [BAs], long‐chain fatty acids [LCFAs]), adipose tissue promotes adipose thermogenesis and browning through uncoupling protein 1 (UCP‐1)/peroxisome proliferator‐activated receptor gamma‐coactivator 1α (PGC‐1α)/T3, promotes adipose decomposition through growth hormones produced by metabolites in the brain to balance energy metabolism in adipose tissue. In contrast, metabolites (trimethylamine N‐oxide [TMAO] and delta‐valerobetaine [VB]) inhibit browning and thermogenesis of adipose tissue, reduce lipid decomposition by reducing carnitine levels, and promote infiltration of immune cells and proinflammatory cytokines.

FIGURE 6

Metabolites affect chronic systemic inflammation. First, the beneficial metabolites in the intestinal tract decrease intestinal pH value and increase the expression of tight junction proteins (ZO‐1, Occludin, and Claudin), improve intestinal barrier and permeability, and reduce lipopolysaccharide (LPS) entry into the body. Metabolites then enter the body, preventing LPS‐stimulated neutrophil production of proinflammatory factors, reducing the maturation of macrophages and dendritic cells (DCs), or promoting the differentiation of M2 anti‐inflammatory cells. In addition, they are able to balance Treg/TH17 cells to regulate immunity while enhancing the ability of DCs to promote regulatory T (Treg) cell differentiation. Negative metabolites increase intestinal permeability and damage the intestinal barrier, and LPS easily enters the body, leading to systemic inflammation.