New insights into the mechanisms of high-fat diet mediated gut microbiota in chronic diseases

Abstract

High-fat diet (HFD) has been recognized as a primary factor in the risk of chronic disease. Obesity, diabetes, gastrointestinal diseases, neurodegenerative diseases, and cardiovascular diseases have long been known as chronic diseases with high worldwide incidence. In this review, the influences of gut microbiota and their corresponding bacterial metabolites on the mechanisms of HFD-induced chronic diseases are systematically summarized. Gut microbiota imbalance is also known to increase susceptibility to diseases. Several studies have proven that HFD has a negative impact on gut microbiota, also exacerbating the course of many chronic diseases through increased populations of Erysipelotrichaceae, facultative anaerobic bacteria, and opportunistic pathogens. Since bile acids, lipopolysaccharide, short-chain fatty acids, and trimethylamine N-oxide have long been known as common features of bacterial metabolites, we will explore the possibility of synergistic mechanisms among those metabolites and gut microbiota in the context of HFD-induced chronic diseases. Recent literature concerning the mechanistic actions of HFD-mediated gut microbiota have been collected from PubMed, Google Scholar, and Scopus. The aim of this review is to provide new insights into those mechanisms and to point out the potential biomarkers of HFD-mediated gut microbiota.

Keywords: characteristic metabolites; chronic diseases; gut microbiota dysbiosis; high‐fat diet; targeted biomarkers.

Figure 1

Roles of gut microbiota in chronic diseases induced by HFD. BDNF, brain‐derived neurotrophic factor; F/B ratio, ratio of Firmicutes to Bacteroidetes; HFD, high‐fat diet; LPS, lipopolysaccharide; SCFAs, Short‐chain fatty acids; TMAO, trimethylamine N‐oxide.

Figure 2

Influence of intestinal microbiota in chronic diseases under HFD model. HFD, high‐fat diet.

Figure 3

Potential mechanisms of interaction between HFD and chronic diseases via bile acid. Cholesterol can stimulate the secretion of bile acids, which forms a secondary bile acid with the help of intestinal bacteria through a 7α‐dehydroxylation reaction. Secondary bile acids like DCA with high hydrophobicity disrupt the plasma membrane structure and destroy the intestinal barrier, while opportunistic pathogens resistant to bile rapidly multiply. As a signal molecule, bile acids bind FXR and TGR5 to further promote immune‐cell infiltration, regulate insulin resistance and regulate lipid metabolism. DCA, deoxycholic acid; FXR, farnesoid X receptor; TGR5, Takeda G protein‐coupled receptor 5; UDCA, ursodeoxycholic acid.

Figure 4

Potential mechanisms of interaction between HFD and chronic diseases via LPS. LPS, a structural component of the outer membrane of gram‐negative bacteria, penetrate the intestinal wall and reaches the corresponding tissues such as the blood systemic circulation and brain. TLR4 is expressed in immune cells, adipocytes, glial cells, and other cells. Hence, LPS causes inflammation via NF‐κB, thus promoting obesity and brain degeneration. Furthermore, LPS inhibits the expression of BDNF and CREB phosphorylation, and inhibits the expression level of synapsin‐1 in the brain. BDNF, brain derived neurotrophic factor; CD14, cluster of differentiation 14; CREB, cAMP response element‐binding protein; IL‐6, interleukin 6; IL‐1β, interleukin 1β; LPS, lipopolysaccharide; NF‐κB, nuclear factor κB; TLR4, Toll‐like receptor 4; TNF‐α, tumor necrosis factor α.

Figure 5

Potential mechanisms of interaction between HFD and chronic diseases through SCFAs. HFD reduces the synthesis of SCFAs in the host. SCFAs can inhibit an inflammatory reaction, maintain the anaerobic environment of the intestinal cavity, and regulate appetite, energy metabolism, glucose and lipid metabolism. GPL1, glucagon‐like peptide‐1; GPR, G protein‐coupled receptor; NF‐κB, nuclear factor κB; PPAR‐γ, peroxisome proliferator‐activated receptor γ; PPY, peptide YY; SCFAs, short‐chain fatty acids.

Figure 6

Potential mechanisms of interaction between HFD and chronic diseases through TMAO. Choline can be metabolized into TMA by intestinal bacteria, which is further processed into TMAO by FMO in the liver. In addition, the expression of FMO is also affected by bile. TMAO entering the blood vessels is related to vascular inflammation, endothelial dysfunction, foam cell formation, atherogenic plaques as well as insulin resistance. TMAO in the brain can affect synaptic plasticity and cause neurodegeneration, and the atherosclerosis of brain blood vessels is also an important factor of dementia. CREB, cAMP response element‐binding protein; FMO, flavin‐containing monooxygenase; HFD, high‐fat diet; NF‐κB, nuclear factor κB; NO, nitric oxide; PERK, protein kinase RNA‐like ER kinase; TMA, trimethylamine; TMAO, trimethylamine N‐oxide.