The enteric nervous system promotes intestinal health by constraining microbiota composition

Abstract

Sustaining a balanced intestinal microbial community is critical for maintaining intestinal health and preventing chronic inflammation. The gut is a highly dynamic environment, subject to periodic waves of peristaltic activity. We hypothesized that this dynamic environment is a prerequisite for a balanced microbial community and that the enteric nervous system (ENS), a chief regulator of physiological processes within the gut, profoundly influences gut microbiota composition. We found that zebrafish lacking an ENS due to a mutation in the Hirschsprung disease gene, sox10, develop microbiota-dependent inflammation that is transmissible between hosts. Profiling microbial communities across a spectrum of inflammatory phenotypes revealed that increased levels of inflammation were linked to an overabundance of pro-inflammatory bacterial lineages and a lack of anti-inflammatory bacterial lineages. Moreover, either administering a representative anti-inflammatory strain or restoring ENS function corrected the pathology. Thus, we demonstrate that the ENS modulates gut microbiota community membership to maintain intestinal health.

The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system

“…Because the ENS is important for the propulsive movements of the intestine, patients with Hirschsprung disease exhibit intestinal obstruction leading to an accumulation of gut content on the proximal side . Animal models have shown that loss of the ENS results in defective intestinal motility leading to intestinal bacterial overgrowth and increased abundance of pro‐inflammatory bacterial lineages . Furthermore, patients with Hirschsprung‐associated enterocolitis have an altered gut microbial composition compared to patients with Hirschsprung disease who had never had enterocolitis, suggesting that a microbial dysbiosis could contribute to the enterocolitis …”

The scales of the zebrafish: host–microbiota interactions from proteins to populations

“…However, beyond these relatively reductionist experimental approaches, we have seen an increased role of stochastic effects, from the potentially random influence of population bottlenecks during the initial colonization of the intestine [12], to the importance of passive bacterial transmission in determining the overall composition of intestinal microbiota [32,34]. Furthermore, where fine scale gnotobiotic studies have identified specific bacterial factors inducing changes in zebrafish hosts [5,7–9,11], broader scale studies can inform the circumstances under which those interactions even have the potential to occur (for example, by determining whether or not the bacterium is even able to colonize a zebrafish [17]), and to what degree the overall effect on the host can be predicted by the population size of individual bacterial species [18,19]. …”

“…Interestingly, each species had disproportional effects on neutrophil response, such that predicting the host response to a complex microbiota requires knowing both the abundance and per capita effect of each species. To a first approximation, these same rules were found to apply to much more complex microbiota that assembled in a mutant zebrafish line, sox10 , that has defective peristalsis and develops spontaneous intestinal inflammation [19]. The extent of inflammation varied across mutant siblings reared in a shared aquatic environment and could be explained by the relative abundances of pro-inflammatory Vibrio sp.…”

Evolutionary “Experiments” in Symbiosis: The Study of Model Animals Provides Insights into the Mechanisms Underlying the Diversity of Host–Microbe Interactions

“…The zebrafish research community has invested heavily in developing valuable genetic tools such as transgenic lines that highlight myriads of different cell types during their developmental dynamics and a growing collection of mutants, originally from forward genetic screens and more recently from genome engineering. [59][60][61] Large numbers of germ-free animals can also be used in bioassays for the discovery of novel bacterial effector proteins, such as BefA, which promotes pancreatic βcell proliferation and AimA, [62] which reduces intestinal inflammation. The ex utero embryonic development allows for surface sterilization of the chorion and easy derivation of hundreds of axenic or "germ-free" larval animals at a time, [58] enabling gnotobiotic experiments on a scale that would be impossible to achieve with mammalian systems.…”