Disturbances of the Gut Microbiota and Microbiota-Derived Metabolites in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is characterized as a chronic and recurrent inflammatory disease whose pathogenesis is still elusive. The gut microbiota exerts important and diverse effects on host physiology through maintaining immune balance and generating health-benefiting metabolites. Many studies have demonstrated that IBD is associated with disturbances in the composition and function of the gut microbiota. Both the abundance and diversity of gut microbiota are dramatically decreased in IBD patients. Furthermore, some particular classes of microbiota-derived metabolites, principally short-chain fatty acids, tryptophan, and its metabolites, and bile acids have also been implicated in the pathogenesis of IBD. In this review, we aim to define the disturbance of gut microbiota and the key classes of microbiota-derived metabolites in IBD pathogenesis. In addition, we also focus on scientific evidence on probiotics, not only on the molecular mechanisms underlying the beneficial effects of probiotics on IBD but also the challenges it faces in safe and appropriate application.

Keywords: dysbiosis; gut microbiota; inflammatory bowel disease; microbiota-derived metabolites; probiotic.

Figure 1

The disturbance of gut microbiota and microbiome metabolites in the pathogenesis of IBD. CA: cholic acid; CDCA: chenodeoxycholic acid; LCA: lithocholic acid; DCA: deoxycholic acid; TGR5: G-protein-coupled bile acid receptor 1; FXR: farnesoid X receptor; FGF19: fibroblast growth factor 19; IAA: indole-3-acetic acid; IAld: indole-3-aldehyde; IPA: indole-3-propionic acid; AhR: aryl hydrocarbon receptor; SCFAs: short-chain fatty acids. The decrease in the abundance and diversity of gut microbiota weakens the intestinal microbial barrier in IBD, which provides opportunistic pathogens an opportunity to invade gut mucosa and induce imbalance between Th17 and Treg cells, thus aggravating intestinal inflammation. The contents of metabolites, such as SCFAs, indole derivatives, and secondary BAs, derived from carbohydrates, tryptophan, and primary BAs under the action of the gut microbiota are significantly decreased due to gut microbiota dysbiosis. SCFAs mediate diverse effects on mucosal immunity, such as the maintenance of mucosal integrity, by supplying an energy source to colonocytes and expending Treg cell proportions. Therefore, SCFA reduction can aggravate intestinal injury in IBD patients. In addition, dysbiosis leads to loss of the microbial activation of tryptophan, which makes the endogenous ligands AhR, IAA, IPA, and IAld decreased. Gut microbiota disturbance in IBD can also decrease the contents of secondary BAs in the colon, such as LCA and DCA, which downregulates the activation of TGR5 and FXR and enhances NF-κB transcription, respectively.

Figure 2

Tryptophan metabolism disturbance in IBD. There are three main metabolic pathways of tryptophan. The major pathway is the Kyn pathway, with tryptophan also being metabolized into indole derivatives. In healthy individuals, the gut microbiota metabolize tryptophan into IAA, IPA, and IAld, which can activate AhR to exert a protective effect in the colon via inhibiting NF-κB and increasing TJPs expressions. In IBD, gut microbiota dysbiosis leads to the microbial activation of tryptophan, aggravating intestinal inflammation. TPH1: tryptophan hydroxylase 1; 5-HTtp: 5-hydroxytryptophan.

Figure 3

Bile acid metabolism disturbance in IBD. BA metabolism is altered in IBD patients. Dietary cholesterol is digested and absorbed in the gastrointestinal tract. Cholesterol is biotransformed to conjugated primary BAs in the liver and then secreted in the gut. Gut microbiota dysbiosis in IBD impairs BSH activity and 7α-dehydroxylation, leading to decreased secondary BAs. This induces decreases in the expressions of FXR and TGR5, which makes the transcription of NF-κB relevantly enhanced, thus aggravating IBD severity. In addition, decreased secondary BAs caused by dysbiosis reduce the production of FGF19, leading to primary BA accumulation in the liver.