Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation.
Animals
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Chemoreceptor Cells
/ immunology
Crohn Disease
/ immunology
DNA, Bacterial
/ genetics
Disease Models, Animal
Feces
/ microbiology
Female
Gastrointestinal Microbiome
/ immunology
Humans
Ileitis
/ immunology
Ileum
/ cytology
Intestinal Mucosa
/ cytology
Male
Mice
Mice, Knockout
Protective Factors
RNA, Ribosomal, 16S
/ genetics
RNA-Seq
Single-Cell Analysis
Succinic Acid
/ immunology
IBD
epithelium
heterogeneity
metabolism
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
04
06
2020
revised:
12
08
2020
accepted:
15
08
2020
pubmed:
24
8
2020
medline:
16
4
2021
entrez:
24
8
2020
Statut:
ppublish
Résumé
Countries endemic for parasitic infestations have a lower incidence of Crohn's disease (CD) than nonendemic countries, and there have been anecdotal reports of the beneficial effects of helminths in CD patients. Tuft cells in the small intestine sense and direct the immune response against eukaryotic parasites. We investigated the activities of tuft cells in patients with CD and mouse models of intestinal inflammation. We used microscopy to quantify tuft cells in intestinal specimens from patients with ileal CD (n = 19), healthy individuals (n = 14), and TNF Inflamed ileal tissues from patients and mice had reduced numbers of tuft cells, compared with healthy individuals or wild-type mice. Expansion of tuft cells was associated with increased expression of genes that regulate the tricarboxylic acid cycle, which resulted from microbe production of the metabolite succinate. Experiments in which we manipulated the intestinal microbiota of mice revealed the existence of an ATOH1-independent population of tuft cells that was sensitive to metabolites produced by microbes. Administration of succinate to mice expanded tuft cells and reduced intestinal inflammation in TNF We found that tuft cell expansion reduced chronic intestinal inflammation in mice. Strategies to expand tuft cells might be developed for treatment of CD.
Sections du résumé
BACKGROUND & AIMS
Countries endemic for parasitic infestations have a lower incidence of Crohn's disease (CD) than nonendemic countries, and there have been anecdotal reports of the beneficial effects of helminths in CD patients. Tuft cells in the small intestine sense and direct the immune response against eukaryotic parasites. We investigated the activities of tuft cells in patients with CD and mouse models of intestinal inflammation.
METHODS
We used microscopy to quantify tuft cells in intestinal specimens from patients with ileal CD (n = 19), healthy individuals (n = 14), and TNF
RESULTS
Inflamed ileal tissues from patients and mice had reduced numbers of tuft cells, compared with healthy individuals or wild-type mice. Expansion of tuft cells was associated with increased expression of genes that regulate the tricarboxylic acid cycle, which resulted from microbe production of the metabolite succinate. Experiments in which we manipulated the intestinal microbiota of mice revealed the existence of an ATOH1-independent population of tuft cells that was sensitive to metabolites produced by microbes. Administration of succinate to mice expanded tuft cells and reduced intestinal inflammation in TNF
CONCLUSIONS
We found that tuft cell expansion reduced chronic intestinal inflammation in mice. Strategies to expand tuft cells might be developed for treatment of CD.
Identifiants
pubmed: 32828819
pii: S0016-5085(20)35068-X
doi: 10.1053/j.gastro.2020.08.029
pmc: PMC7725941
mid: NIHMS1623623
pii:
doi:
Substances chimiques
Atoh1 protein, mouse
0
Basic Helix-Loop-Helix Transcription Factors
0
DNA, Bacterial
0
RNA, Ribosomal, 16S
0
Succinic Acid
AB6MNQ6J6L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2101-2115.e5Subventions
Organisme : NLM NIH HHS
ID : T32 LM012412
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA028842
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK106311
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK058404
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA116087
Pays : United States
Organisme : BLRD VA
ID : I01 BX001453
Pays : United States
Organisme : CSRD VA
ID : I01 CX002171
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA236733
Pays : United States
Organisme : NIGMS NIH HHS
ID : F31 GM120940
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103831
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD007502
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR002245
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197570
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI142042
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI138932
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA183727
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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