High-fat diet induces intestinal mucosal barrier dysfunction in ulcerative colitis: emerging mechanisms and dietary intervention perspective

Abstract

The incidence of ulcerative colitis (UC) is increasing worldwide, but its pathogenesis remains largely unclear. The intestinal mucosa is a barrier that maintains the stability of the body's internal environment, and dysfunction of this barrier leads to the occurrence and aggravation of UC. A high-fat diet (HFD) contains more animal fat and low fiber, and accumulating evidence has shown that long-term intake of an HFD is associated with UC. The mechanism linking an HFD with intestinal mucosal barrier disruption is multifactorial, and it typically involves microbiota dysbiosis and altered metabolism of fatty acids, bile acids, and tryptophan. Dysbiosis-induced metabolic changes can enhance intestinal permeability through multiple pathways. These changes modulate the programmed death of intestinal epithelial cells, inhibit the secretion of goblet cells and Paneth cells, and impair intercellular interactions. Gut metabolites can also induce intestinal immune imbalance by stimulating multiple proinflammatory signaling pathways and decreasing the effect of anti-inflammatory immune cells. In this review, we critically analyze the molecular mechanisms by which an HFD disrupts the intestinal mucosal barrier (IMB) and contributes to the development of UC. We also discuss the application and future direction of dietary intervention in the treatment of the IMB and prevention of UC.

Keywords: High-fat diet; dietary intervention; gut metabolites; intestinal mucosal barrier; microbiota dysbiosis; ulcerative colitis.

Figure 1

Physiologic structure of the colonic mucosal barrier. The intestinal mucosal barrier is mainly composed of the mucus layer and epithelial layer, and it is affected by intestinal microbiota, its metabolites, and the immune system of lamina propria. The epithelial layer is mainly composed of intestinal epithelial cells (IECs) and intercellular junctions such as tight junctions (TJ), adhesive junctions (AJ), and desmosomes. TJs are the apical intercellular junctions composed of the transmembrane proteins occludin and claudin and cytoplasmic scaffold proteins Zonula occludens-1 (ZO-1), Zonula occludens-2 (ZO-2), Zonula occludens-3 (ZO-3). AJs consist of the transmembrane protein E-cadherin and intracellular components α-catenin and β-catenin. The mucus layer is divided into the outer layer and the inner layer; the outer layer is the habitat of intestinal microbiota, while the inner layer is mainly composed of mucin 2 (MUC2) secreted by goblet cells and antimicrobial peptides (AMPs) secreted by Paneth cells. The IMB forms a physical and chemical barrier between the intestinal lumen and lamina propria, which can “separate” and “regulate” intestinal microbiota and immune cells to maintain intestinal health. MLCK, Myosin Light Chain Kinase.

Figure 2

A high-fat diet impairs the metabolic homeostasis of intestinal microbiota, fatty acids, bile acids, and tryptophan in the intestinal lumen. High-fat diet (HFD) contains more animal fat and less fiber, which can disrupt intestinal microbiota and its metabolism. The specific manifestations are as follows: (1) Metabolic disorder of bile acids (BAs), that is, increased production and inhibition of reabsorption of BAs. Abnormal levels of BAs can promote the differentiation of T cells into T helper cells 17 (Th17), resulting in increased interleukin-17 (IL-17) production. (2) The production of short-chain fatty acids (SCFAs) is decreased. SCFAs can bind to G protein-coupled receptors 41 (GPR41), G protein-coupled receptors 43 (GPR43), and G protein-coupled receptors 109A (GPR109A) of intestinal epithelial cells (IECs) and then activate the NLRP3 inflammasome to release interleukin-18 (IL-18). SCFAs also induce T cells to differentiate into regulatory T cells (Treg) and release interleukin-10 (IL-10). Low levels of SCFAs in the colon weaken these pathways. (3) Tryptophan (TRP) metabolism disorder, that is, inhibition of the indole pathway and enhancement of the kynurenine and serotonin pathways, leading to the decrease in interleukin-22 (IL-22) production and the increase in kynurenine and serotonin production. Dysregulated intestinal substances can further disrupt the lamina propria immune system and impair Th17/Treg balance, leading to an increase in proinflammatory cytokines and the decrease in anti-inflammatory cytokines and promoting the occurrence of intestinal inflammation. TGF-β, Transforming Growth Factor-β; DC, Dendritic Cell; Th0, T Helper cell 0; Mφ, Macrophages; 5-HT, serotonin; IDO, Indoleamine 2,3-Dioxygenase.

Figure 3

A high-fat diet affects programmed death of intestinal epithelial cells. A high-fat diet (HFD) can change the content of normal intestinal microbiota, fatty acids, and bile acids in the intestine, thus affecting the apoptosis, autophagy, pyroptosis, and ferroptosis of intestinal epithelial cells (IECs). (1) Apoptosis: High levels of deoxycholic acid (DCA), long-chain fatty acids (LCFAs), and lipopolysaccharide (LPS) in the colon can activate the caspase cascade through the mitochondrial pathway, endoplasmic reticulum pathway, and death receptor pathway and then induce apoptosis of IECs. (2) Autophagy: Following mitochondrial autophagy dysfunction and the increase in intracellular lipid autophagy, mitochondria with autophagy disorder can produce more reactive oxygen species (ROS), which will further promote the apoptosis of IECs. (3) Ferroptosis: Fatty acids (FAs) contained in an HFD can inhibit the expression of glutathione peroxidase 4 (GPX4) and increase the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) in the mitochondrial plasma membrane, resulting in lipid peroxidation (LPO) and ferroptosis. (4) Pyroptosis: An HFD can activate the caspase-1-dependent classical pathway and the caspase-4/5/11-dependent nonclassical pathway. TNF, Tumor Necrosis Factor; TNFR, Tumor Necrosis Factor Receptor; Cyt C, Cytochrome c; Apaf-1, apoptotic protease activating factor-1; NLPR3, NLR family pyrin domain containing 3; ACS, apoptosis-associated speck-like protein containing a CARD; IRE1α, inositol-requiring transmembrane kinase endoribonuclease-1α; ASK1, apoptosis signal-regulating kinase 1; TRAF2, TNF receptor-associated factor 2; JNK, c-Jun N-terminal kinase; CHOP, C/EBP homologous protein.

Figure 4

A high-fat diet (HFD) can impair intercellular connections through intestinal microbiota and its metabolites. (1) Intestinal bacterial lipopolysaccharide (LPS) can activate the Toll-like receptor 4 (TLR4) signal transduction pathway, and the nuclear factor kappa B (NF-κB) pathway promotes myosin light chain kinase (MLCK) expression. (2) Deoxycholic acid (DCA) promotes MLCK expression by activating the epidermal growth factor receptor (EGFR) pathway. MLCK can promote the opening of tight junction (TJ) barrier through the phosphorylation of myosin II regulatory light chain (MLC). (3) Fatty acids such as medium-chain fatty acids (MCFAs) and polyunsaturated fatty acids (PUFAs) can disrupt the TJ barrier by altering the distribution and expression of TJs. Finally, this leads to the increase in intestinal permeability, and the pathogenic antigens in the intestinal lumen enter the lamina propria through paracellular permeation, which leads to the occurrence of intestinal inflammation. LBP, lipopolysaccharide binding protein; MD-2, myeloid differentiation 2; FAK, focal adhesion kinase; MyD88, myeloid differentiation primary response 88; TIRAP, Toll/interleukin-1 receptor domain-containing adapter protein; TRIF, TIR-domain-containing adapter-inducing interferon-β; TRAM, translocating chain-associating membrane protein; IRAK4, interleukin-1 receptor-associated kinase; TAK-1, transforming growth factor-β-activated kinase 1; NEMO, nuclear factor-κB essential modulator; IKKα, inhibitor of nuclear factor kappa-B kinase subunit alpha; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; ERK1/2, extracellular signal-regulated protein kinase; Elk-1, ETS like-1 protein; ROS, reactive oxygen species; AJ, adhesion junction; PKC, protein kinase C; MMP-2, matrix metallopeptidase 2.