Show simple item record

dc.contributor.authorKellogg, Tasia D
dc.contributor.authorCeglia, Simona
dc.contributor.authorMortzfeld, Benedikt M
dc.contributor.authorZeamer, Abigail L
dc.contributor.authorFoley, Sage E
dc.contributor.authorWard, Doyle V
dc.contributor.authorBhattarai, Shakti K
dc.contributor.authorMcCormick, Beth A
dc.contributor.authorReboldi, Andrea
dc.contributor.authorBucci, Vanni
dc.date.accessioned2024-03-11T18:06:49Z
dc.date.available2024-03-11T18:06:49Z
dc.date.issued2024-01-31
dc.identifier.citationKellogg TD, Ceglia S, Mortzfeld BM, Zeamer AL, Foley SE, Ward DV, Bhattarai SK, McCormick BA, Reboldi A, Bucci V. Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine. bioRxiv [Preprint]. 2024 Jan 31:2024.01.29.574039. doi: 10.1101/2024.01.29.574039. PMID: 38352546; PMCID: PMC10862725.en_US
dc.identifier.doi10.1101/2024.01.29.574039en_US
dc.identifier.pmid38352546
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53171
dc.descriptionThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.en_US
dc.description.abstractMetabolic 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.en_US
dc.language.isoenen_US
dc.relation.ispartofbioRxiven_US
dc.relation.urlhttps://doi.org/10.1101/2024.01.29.574039en_US
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.en_US
dc.rightsAttribution-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nd/4.0/*
dc.subjectClostridioides difficileen_US
dc.subjectDLCK1en_US
dc.subjectIL-25en_US
dc.subjectMicrobiomeen_US
dc.subjectSuccinateen_US
dc.subjectTuft Cellsen_US
dc.subjectType 2 Immunityen_US
dc.titleMicrobiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during infection in the large intestine [preprint]en_US
dc.typePreprinten_US
dc.source.journaltitlebioRxiv : the preprint server for biology
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalbioRxiv : the preprint server for biology
refterms.dateFOA2024-03-11T18:06:51Z
dc.contributor.departmentMicrobiology and Physiological Systemsen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentPathologyen_US
dc.contributor.studentTasia D Kellogg
dc.contributor.studentAbigail L Zeamer


Files in this item

Thumbnail
Name:
2024.01.29.574039v1.full.pdf
Size:
1.342Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.