Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling

Abstract

Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted ‘postbiotic’ metabolomic intervention may restore a normal microenvironment, as treatment or prevention of dysbiosis-driven diseases.

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

“…23 These observations were similar to a previous study using an adult ex-GF approach, showing that the gut microbiota communities of ex-GF WT and Nlrp6 −/− mice diverged at three weeks after re-colonisation. 15 However, while this latter ex-GF study did not specify whether Prevotellaceae alterations previously observed in non-littermate WT and Nlrp6 −/− mice were reproduced, 15 Seregin et al. did not observe those reported effects on Prevotellaceae and rather found an increase in Akkermansia muciniphila in ex-GF Nlrp6 −/− mice.…”

“…12 , 13 , 15-17 However, each of these earlier reports was based on fecal microbiota comparisons between non-littermate or externally sourced WT and KO mice that were separately housed for multiple generations. Several studies demonstrated animal facility-dependent microbiota differences in otherwise genetically identical mice, 7 , 18-20 indicating that the gut microbiota composition can be influenced by multiple non-genetic factors.…”

“…Nevertheless, the question arises whether re-colonizing non-littermate adult GF mice as in the Nlrp6 studies mentioned above, 15 , 23 is an alternative valid approach for investigating host genetic impacts on the gut microbiota. In our ASC −/− study, we designed an ex-GF approach that resulted in analyzing WT and KO littermates that had all colonized their gastrointestinal tract in a natural manner after birth (Fig 1B).…”

“…14 In contrast, the ex-GF studies showing Nlrp6 effects on the gut microbiota used adult mice that were re-colonized by housing in SPF conditions. 15 , 23 Whereas natural colonization after birth is a gradual process in which niches are occupied by sequential bacterial colonizers, whole microbiota re-colonization in adult mice is likely to be influenced by colonization resistance. In addition, as re-colonizing adult GF mice is accompanied by changes in intestinal physiology and maturation of the host immune system, also these host processes could differentially affect the colonization success of various gut microbes.…”

A wide diversity of bacteria from the human gut produces and degrades biogenic amines

“…In addition, the levels of histamine-secreting bacteria were shown to be increased in the gut of asthma patients compared to healthy volunteers, and the level of one histamine-secreting microbe positively correlated with the severity of disease [21]. In murine models, microbiota-derived taurine, histamine and spermine were shown to influence host–microbiome interactions by co-modulating NLRP6 inflammasome signaling, epithelial interleukin-18 secretion and downstream anti-microbial peptide secretion [22]. …”