Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway

Abstract

The commensal bacteria that make up the gut microbiota impact the health of their host on multiple levels. In particular, the interactions taking place between the microbe-associated molecule patterns (MAMPs) and pattern recognition receptors (PRRs), expressed by intestinal epithelial cells (IECs), are crucial for maintaining intestinal homeostasis. While numerous studies showed that TLRs and NLRs are involved in the control of gut homeostasis by commensal bacteria, the role of additional innate immune receptors remains unclear. Here, we seek for novel MAMP-PRR interactions involved in the beneficial effect of the commensal bacterium Akkermansia muciniphila on intestinal homeostasis. We show that A. muciniphila strongly activates NF-κB in IECs by releasing one or more potent activating metabolites into the microenvironment. By using drugs, chemical and gene-editing tools, we found that the released metabolite(s) enter(s) epithelial cells and activate(s) NF-κB via an ALPK1, TIFA and TRAF6-dependent pathway. Furthermore, we show that the released molecule has the biological characteristics of the ALPK1 ligand ADP-heptose. Finally, we show that A. muciniphila induces the expression of the MUC2, BIRC3 and TNFAIP3 genes involved in the maintenance of the intestinal barrier function and that this process is dependent on TIFA. Altogether, our data strongly suggest that the commensal A. muciniphila promotes intestinal homeostasis by activating the ALPK1/TIFA/TRAF6 axis, an innate immune pathway exclusively described so far in the context of Gram-negative bacterial infections.

Akkermansia muciniphilacounteracts the deleterious effects of dietary emulsifiers on microbiota and host metabolism

“… 17 37 The mechanism by which A. muciniphila protects the intestine from emulsifiers remains to be defined but might involve membrane-associated Amuc_100, 17 38 secreted P9, 19 membrane-associated phospholipid diacyl phosphatidylethanolamine, 39 and/or the ADP-heptose-like molecule, recently identified as being released by A. muciniphila with the ability to modulate the NF-kB signalling pathway. 40 Moreover, accumulating evidence suggest that A. muciniphila interaction with the host involves TLR2-signalling pathways 17 39 as well as modulation of IL10 and IL22 cytokines. 41 42 Thus, future studies to identify the mechanism at play during protection against emulsifier-induced metabolic deregulations are warranted.…”

Akkermansia muciniphila: a potential candidate for ameliorating metabolic diseases

“…The degree of tight junctions between intestinal epithelial cells is determined by the proliferation capacity of intestinal epithelial cells and the expression level of tight junction proteins. It has been reported that A. muciniphila upregulates MUC2, BIRC3 and TNFAIP3 (BIRC3 and TNFAIP3 are anti-apoptotic genes of intestinal epithelial cells involved in their proliferation process) via ADP-heptose-dependent activation of the ALPK1/TIFA pathway, which maintains intestinal barrier function and reduce its permeability ( 93 ). This subsequently inhibits chronic low-grade inflammation induced by LPS and insulin resistance.…”

Akkermansia muciniphila as a Next-Generation Probiotic in Modulating Human Metabolic Homeostasis and Disease Progression: A Role Mediated by Gut–Liver–Brain Axes?

“…For example, Akk colonization alleviates high-fructose- and restraint-stress-induced jejunal mucosal barrier disruption by enhancing the function of NLRP6, promoting autophagy, maintaining the normal secretion of antimicrobial peptides in Paneth cells, promoting the expression of tight junction proteins, negatively regulating the NF-kB signaling pathway, and inhibiting the expression of inflammatory cytokines [ 166 ]. A recent report suggests that Akk upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway, which indicates that Akk promotes intestinal barrier homeostasis by activating an innate immune response [ 167 ]. Amuc-1100 promotes IL-10 production by activating TLR2 and TLR4 and eventually activates the NF-kB pathway to promote the production of cytokines [ 168 ].…”