Hosea, C. | Search bioRxiv

bioRxiv2026

Neuroendocrine arylhydrocarbon receptor regulates gut microbiome of C. elegans via redox tone

The gut microbiome profoundly influences host health, with disrupted microbial communities implicated in inflammatory, metabolic, and neurological diseases. The aryl hydrocarbon receptor (AHR) shapes intestinal immunity and microbial composition, yet the mechanisms by which AHR mediates selective microbiome assembly remain poorly understood. Whether distant organ systems such as the nervous system actively participate in microbial community regulation is unexplored. Here we show that Caenorhabditis elegans neuronal AHR-1 orchestrates selective gut microbiome assembly through a neuroendocrine cascade that calibrates intestinal redox tone. Using a defined natural microbiome community, we demonstrate that ahr-1 loss triggers specific microbiome changes, as Enterobacterales and Pseudomonadales bloom up to 24-fold while Sphingobacteriales decline. Adult-specific AHR-1 depletion recapitulates this dysbiosis, separating the role of AHR-1 in neurodevelopment from its regulation of the microbiome. Neuronal AHR-1 regulates expression of the neuropeptide FLP-8 in oxygen-sensing URX neurons, which in turn signals to the intestine to modulate intestinal redox tone. Elevated intestinal redox tone in ahr-1 mutants favors growth of oxidative stress-tolerant Enterobacterales and Pseudomonadales, which also exhibit functional and genomic enrichment for stress resistance and AHR ligand biosynthesis pathways. This establishes a precise feedback circuit whereby AHR-1 senses bacterial metabolic output to regulate colonization by ligand-producing taxa. AHR-1 signaling regulates redox tone through downstream regulation of glutathione S-transferase GST-4 and alpha-arrestin ARRD-11. Intestinal gst-4 knockdowns had the greatest impact on restoring redox tone and microbiome compositional control in the gut. These findings reveal an evolutionarily ancient molecular circuit where AHR serves as a precision metabolic sensor that coordinates whole organismal physiology to maintain host-microbiome homeostasis.

genetics↗

bioRxiv2021

Natural genetic variation drives microbiome selection in the Caenorhabditis elegans gut

Host genetic landscapes can shape microbiome assembly in the animal gut by contributing to the establishment of distinct physiological environments. However, the genetic determinants contributing to the stability and variation of these microbiome types remain largely undefined. Here, we use the free-living nematode Caenorhabditis elegans to identify natural genetic variation among wild strains of C. elegans strains that drives assembly of distinct microbiomes. To achieve this, we first established a diverse model microbiome that represents the phylogenetic and functional diversity naturally found in the C. elegans microbiome. Using this community, we show that C. elegans utilizes immune, xenobiotic and metabolic signaling pathways to favor the assembly of different microbiome types. Variations in these pathways were associated with the enrichment for specific commensals, including the Alphaproteobacteria Ochrobactrum. Using RNAi and mutant strains, we showed that host selection for Ochrobactrum is mediated specifically by host insulin signaling pathways. Ochrobactrum recruitment is blunted in the absence of daf-2/IGFR and requires the insulin signaling transcription factors daf-16/FOXO and pqm-1/SALL2. Further, the ability of C. elegans to enrich for Ochrobactrum is correlated positively with host outcomes, as animals that develop faster are larger and have higher gut Ochrobactrum colonization as adults. These results highlight a new role for the highly conserved insulin signaling pathways in the regulation of microbiome composition in C. elegans.

microbiology↗