NLRP6 Protects Il10 Mice from Colitis by Limiting Colonization of Akkermansia muciniphila

Abstract

Summary Dysfunction in host immune responses and pathologic alterations in the gut microbiota, referred to as dysbiosis, can both contribute to the development of inflammatory bowel disease (IBD). However, it remains unclear how specific changes in host immunity or the microbiota cause disease. We previously demonstrated that the loss of the innate immune receptor NLRP6 in mice resulted in impaired production of IL18 and increased susceptibility to epithelial-induced injury. Here, we show that NLRP6 is important for suppressing the development of spontaneous colitis in the IL10−/− mice model of IBD and that NLRP6-deficiency results in the enrichment of Akkermansia muciniphila. A. muciniphila was sufficient for promoting intestinal inflammation in both specific-pathogen free and germfree IL10−/− mice. Our results demonstrate that A. muciniphila can act as a pathobiont to promote colitis in a genetically-susceptible host and that NLRP6 is a key regulator of its abundance.

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

“…Strikingly, fecal microbiota analyses of these ex-GF mice showed an impact of Nlrp6 on intestinal ecology within two weeks. 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. 23 These discordant observations in ex-GF mice illustrate that the nature of the donor SPF microbiota could determine potential host genetic effects on the gut microbiota in these experiments. Likewise, factors such as diet and the nature of the resident SPF microbiota composition may influence the impact of a host gene on the gut microbiota when investigated in different animal facilities.…”

“…23 This study investigated the effect of Nlrp6 deficiency on a colitogenic IL-10-deficient background and observed altered gut microbiota composition in Il10 −/− / Nlrp6 −/− versus Il10 −/− / Nlrp6 +/+ littermates. 23 However, the authors also detected differential intestinal inflammation between these Il10 −/− / Nlrp6 −/− and Il10 −/− / Nlrp6 +/+ littermates that could underlie the observed effects on intestinal ecology, as intestinal inflammation is known to influence the composition of the gut microbiota. 24 Therefore, Seregin et al.…”

“…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.…”