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Identification of environmental factors that promote intestinal inflammation.

ABSTRACT: Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)¹-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity². However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.

SUBMITTER: Sanmarco LM

PROVIDER: S-EPMC9898826 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Identification of environmental factors that promote intestinal inflammation.

Sanmarco Liliana M LM Chao Chun-Cheih CC Wang Yu-Chao YC Kenison Jessica E JE Li Zhaorong Z Rone Joseph M JM Rejano-Gordillo Claudia M CM Polonio Carolina M CM Gutierrez-Vazquez Cristina C Piester Gavin G Plasencia Agustin A Li Lucinda L Giovannoni Federico F Lee Hong-Gyun HG Faust Akl Camilo C Wheeler Michael A MA Mascanfroni Ivan I Jaronen Merja M Alsuwailm Moneera M Hewson Patrick P Yeste Ada A Andersen Brian M BM Franks Diana G DG Huang Chien-Jung CJ Ekwudo Millicent M Tjon Emily C EC Rothhammer Veit V Takenaka Maisa M de Lima Kalil Alves KA Linnerbauer Mathias M Guo Lydia L Covacu Ruxandra R Queva Hugo H Fonseca-Castro Pedro Henrique PH Bladi Maha Al MA Cox Laura M LM Hodgetts Kevin J KJ Hahn Mark E ME Mildner Alexander A Korzenik Joshua J Hauser Russ R Snapper Scott B SB Quintana Francisco J FJ

Nature 20221020 7937

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)<sup>1</sup>-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity<sup>2</sup>. However, the identification of environm ...[more]

PMID: 36266581

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Project description:Crohn's disease (CD) represents a chronic inflammatory disorder of the intestinal tract. Several susceptibility genes have been linked to CD, though their precise role in the pathogenesis of this disorder remains unclear. Immunity-related GTPase M (IRGM) is an established risk allele in CD. We have shown previously that conventionally raised (CV) mice lacking the IRGM ortholog, Irgm1 exhibit abnormal Paneth cells (PCs) and increased susceptibility to intestinal injury. In the present study, we sought to utilize this model system to determine if environmental conditions impact these phenotypes, as is thought to be the case in human CD. To accomplish this, wild-type and Irgm1-/- mice were rederived into specific pathogen-free (SPF) and germ-free (GF) conditions. We next assessed how these differential housing environments influenced intestinal injury patterns, and epithelial cell morphology and function in wild-type and Irgm1-/- mice. Remarkably, in contrast to CV mice, SPF Irgm1-/- mice showed only a slight increase in susceptibility to dextran sodium sulfate-induced inflammation. SPF Irgm1-/- mice also displayed minimal abnormalities in PC number and morphology, and in antimicrobial peptide expression. Goblet cell numbers and epithelial proliferation were also unaffected by Irgm1 in SPF conditions. No microbial differences were observed between wild-type and Irgm1-/- mice, but gut bacterial communities differed profoundly between CV and SPF mice. Specifically, Helicobacter sequences were significantly increased in CV mice; however, inoculating SPF Irgm1-/- mice with Helicobacter hepaticus was not sufficient to transmit a pro-inflammatory phenotype. In summary, our findings suggest the impact of Irgm1-deficiency on susceptibility to intestinal inflammation and epithelial function is critically dependent on environmental influences. This work establishes the importance of Irgm1-/- mice as a model to elucidate host-environment interactions that regulate mucosal homeostasis and intestinal inflammatory responses. Defining such interactions will be essential for developing novel preventative and therapeutic strategies for human CD.

Project description:BackgroundExploiting soil microorganisms in the rhizosphere of plants can significantly improve agricultural productivity; however, the mechanism by which microorganisms specifically affect agricultural productivity is poorly understood. To clarify this uncertainly, the rhizospheric microbial communities of super rice plants at various growth stages were analysed using 16S rRNA high-throughput gene sequencing; microbial communities were then related to soil properties and rice productivity.ResultsThe rhizospheric bacterial communities were characterized by the phyla Proteobacteria, Acidobacteria, Chloroflexi, and Verrucomicrobia during all stages of rice growth. Rice production differed by approximately 30% between high- and low-yield sites that had uniform fertilization regimes and climatic conditions, suggesting the key role of microbial communities. Mantel tests showed a strong correlation between soil conditions and rhizospheric bacterial communities, and microorganisms had different effects on crop yield. Among the four growing periods, the rhizospheric bacterial communities present during the heading stage showed a more significant correlation (p < 0.05) with crop yield, suggesting their potential in regulating crop production. The biological properties (i.e., microbes) reflected the situation of agricultural land better than the physicochemical characterics (i.e., nutrient elements), which provides theoretical support for agronomic production. Molecular ecological network (MEN) analysis suggested that differences in productivity were caused by the interaction between the soil characteristics and the bacterial communities.ConclusionsDuring the heading stage of rice cropping, the rhizospheric microbial community is vital for the resulting rice yield. According to network analysis, the cooperative relationship (i.e., positive interaction) between between microbes may contribute significantly to yield, and the biological properties (i.e., microbes) better reflected the real conditions of agricultural land than did the physicochemical characteristics (i.e., nutrient elements).

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Identification of environmental factors that promote intestinal inflammation.

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Identification of environmental factors that promote intestinal inflammation.

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