Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine.

Autor:	Kellogg TD; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA.; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA., Ceglia S; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA.; Department of Pathology, UMass Chan Medical School, Worcester, MA, USA., Mortzfeld BM; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA.; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA., Zeamer AL; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA., Foley SE; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Current address: Transformational and Translational Immunology Discovery Department, AbbVie, Cambridge, MA, USA., Ward DV; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA., Bhattarai SK; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA.; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA., McCormick BA; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA.; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA., Reboldi A; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA.; Department of Pathology, UMass Chan Medical School, Worcester, MA, USA., Bucci V; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA.; Program in Microbiome Dynamics, UMass Chan Medical School, Worcester, MA, USA.; Immunology and Microbial Pathogenesis Program, UMass Chan Medical School, Worcester, MA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 31. Date of Electronic Publication: 2024 Jan 31.
DOI:	10.1101/2024.01.29.574039
Abstrakt:	Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout (Δfrd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile -induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3 +/- , and nullified in the tuft cell knockout mouse, Pou2f3 -/- , confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens. Competing Interests: Competing interests: VB reports consulting fees Vedanta Biosciences, Inc. BAM is a scientific co-founder and adviser of Adiso Therapeutics. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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