Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape

Succinate produced by the commensal protist ( ) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-deriv...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-06, Vol.120 (23), p.e2216908120
Main Authors: Fung, Connie, Fraser, Lisa M, Barrón, Gabriel M, Gologorsky, Matthew B, Atkinson, Samantha N, Gerrick, Elias R, Hayward, Michael, Ziegelbauer, Jennifer, Li, Jessica A, Nico, Katherine F, Tyner, Miles D W, DeSchepper, Leila B, Pan, Amy, Salzman, Nita H, Howitt, Michael R
Format: Article
Language:English
Subjects:
Animals
Anti-Infective Agents - metabolism
Antiinfectives and antibacterials
Antimicrobial peptides
Bacteria
Biological Sciences
Chemoreception
Colonization
Commensals
Dysbacteriosis
Homeostasis
Immunity
Interleukin 13
Intestinal microflora
Intestinal Mucosa - metabolism
Intestine
Intestine, Small - metabolism
Intestines
Metabolites
Mice
Microbiota
Microorganisms
Receptors
Small intestine
Succinic Acid - metabolism
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Summary:Succinate produced by the commensal protist ( ) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2216908120