Shaping of Intestinal Microbiota in Nlrp6- and Rag2-Deficient Mice Depends on Community Structure

Abstract

Contradicting observations have been made regarding the relative contributions of immune sensors to shaping the microbiome, yet the reasons for these discrepancies are not fully understood. Here, we investigated the contribution of environmental factors in shaping the microbiome in mice deficient in adaptive immunity (Rag2) and Nlrp6, an immune sensor proposed to be involved in regulation of microbiota composition. In conventionally housed Nlrp6 mice, familial transmission has a significant effect on microbiota composition, complicating the analysis of genotype-dependent effects. Notably, after rederivation into standardized specific pathogen-free (SPF) conditions devoid of pathobionts, microbiota composition was indistinguishable between WT, Rag2, and Nlrp6 mice. However, upon reintroduction of a pathobiont-containing community host, genotype-dependent differences reappear, specifically affecting the relative abundance of pathobionts such as Helicobacter spp. Our results show that the impact of Nlrp6 and also of adaptive immunity on microbiota composition depends on community structure and primarily influences pathobionts but not commensals.

The inflammasomes, immune guardians at defence barriers

“…However, it has been proposed that NLRP6 does contribute to microbiota balance, but this contribution is dependent on microbiota community structure (and especially in the presence of pathobionts such as Helicobacter spp.). Both of these studies point to familial transmission of microbiota rather than NLRP6 impairment for the observed changes in previous studies . How the cells activate NLRP6 and whether NLRP6 forms an active inflammasome are still not fully answered questions.…”

“…Both of these studies point to familial transmission of microbiota rather than NLRP6 impairment for the observed changes in previous studies. 59,60 How the cells activate NLRP6 and whether NLRP6 forms an active inflammasome are still not fully answered questions. No direct evidence shows NLRP6 forming an inflammasome but Nlrp6 À/À studies mimic the results of Caspase-1 À/À and Asc À/À , suggesting that this might be the case.…”

The NLRP6 inflammasome in health and disease

“…Therefore, it is difficult to explain these contradictory results as both studies used littermate control mice and 16s RNA sequencing to analyze microbiota composition. One interesting study by Galvez et al 52 reported that microbiota composition varies greatly within the segregated The NLRP6 inflammasome in health and disease L Ghimire et al…”

When Cultures Meet: The Landscape of “Social” Interactions between the Host and Its Indigenous Microbes

“…These mice have been shown to harbor a dysbiotic microbiome [82] at some vivaria, which contributes to modelsof autoinflammation [82] and cardiometabolic disease. [72,[84][85][86][87][88] Moreover, the dysbiotic microbiome in NLRP6deficient mice features an inherent dominance over the indigenous wild-type (WT) gut microbiome as, upon transfer, it takes over the niche and transmits disease susceptibility into recipient WT mice. [72,[84][85][86][87][88] Moreover, the dysbiotic microbiome in NLRP6deficient mice features an inherent dominance over the indigenous wild-type (WT) gut microbiome as, upon transfer, it takes over the niche and transmits disease susceptibility into recipient WT mice.…”

“…[83] Microbiome transfer experiments suggest that dysbiosis in these mice is host genotype-and surrounding microbiome-dependent rather than driven by husbandry effects. [72,[84][85][86][87][88] Moreover, the dysbiotic microbiome in NLRP6deficient mice features an inherent dominance over the indigenous wild-type (WT) gut microbiome as, upon transfer, it takes over the niche and transmits disease susceptibility into recipient WT mice. [82,83] Importantly, similar dominance of disease-associated microbiome configurations has been reported in other dysbiotic animal models, [4,89] suggesting that this "hostile dominance" may be a common feature of some disease-transmitting microbiomes.…”