Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor

Abstract

Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown. Here, we describe roles for three metabolites—indole-3-ethanol, indole-3-pyruvate, and indole-3-aldehyde—which are derived from gut bacterial metabolism of the essential amino acid tryptophan, in regulating intestinal barrier function. We determined that these metabolites protect against increased gut permeability associated with a mouse model of colitis by maintaining the integrity of the apical junctional complex and its associated actin regulatory proteins, including myosin IIA and ezrin, and that these effects are dependent on the aryl hydrocarbon receptor. Our studies provide a deeper understanding of how gut microbial metabolites affect host defense mechanisms and identify candidate pathways for prophylactic and therapeutic treatments for IBDs.

Tryptophan Metabolites and Aryl Hydrocarbon Receptor in Severe Acute Respiratory Syndrome, Coronavirus-2 (SARS-CoV-2) Pathophysiology

“…As such, the tryptophan metabolite pathway may be a rich source for AhR ligands that will be variably induced under different cellular conditions. It is also of note that the gut microbiome is an important source of I3P and I3A, with AhR activation in the gut being important to the maintenance of the gut barrier [ 23 ]. Future research will have to clarify as to whether I3P and/or its metabolites are AhR agonists.…”

The aryl hydrocarbon receptor as a mediator of host-microbiota interplay

“…A recent study determined that IEt, IPyA and IAld derived from tryptophan by gut microbiota could regulate gut barrier function via AHR activation. 68 IPyA, a transamination product of dietary tryptophan by microbiota, such as Clostridium sporogenes, 69 is a precursor of several microbiota-derived AHR agonists, such as I3A, IAld, and IAAld, and can form various AHR agonists in the reaction of aqueous solution. 70 Several intestinal bacteria, including Bacteroides fragilis, Bacteroides thetaiotaomicron and Citrobacter sp.…”

The Microbiota/Host Immune System Interaction in the Nose to Protect from COVID-19

“…However, AhR is a promiscuous receptor that can bind multiple ligands with both positive and negative effects on inflammation, immunity, and infections [ 66 ]. In particular, microbial ligands working as AhR agonists may play a beneficial activity in the regulation of mucosal homeostasis, for instance by promoting epithelial barrier integrity [ 70 , 71 , 72 ], thus increasing the resistance to infection, and, in turn, AhR may regulate the composition of the microbiome [ 73 ]. Therefore, it remains to be seen whether AhR antagonism or agonism would be the most promising therapeutic strategy in COVID-19.…”