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A microbiota-IPA axis facilitates intestinal stem cell-mediated regeneration in colitis through a Hopx-associated program
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A microbiota-IPA axis facilitates intestinal stem cell-mediated regeneration in colitis through a Hopx-associated program
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Journal Article
A microbiota-IPA axis facilitates intestinal stem cell-mediated regeneration in colitis through a Hopx-associated program
2026
Overview
The gut microbiota plays a crucial role in maintaining intestinal stem cell (ISC) homeostasis and epithelial barrier integrity. Here, we report that
Blautia coccoides
(
B. coccoides
) is significantly reduced in inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. Through an integrated approach combining RNA sequencing, metabolomic profiling, and ISC lineage tracing across multiple mucosal injury models, we demonstrate that
B. coccoides
colonization enhances β-hydroxybutyrate (BHB) production in intestinal epithelial cells (IECs), which activates HOPX⁺ reserve ISCs and promotes regeneration of the LGR5⁺ ISC pool, thereby accelerating epithelial repair. We further show that
B. coccoides
-derived indole-3-lactic acid (ILA), a tryptophan (Trp) metabolite, is converted into indole-3-propionic acid (IPA) by commensal bacteria such as
P. russellii
or
C. sporogenes
, stimulating IEC BHB synthesis. Using an engineered
Escherichia coli
strain expressing BC-derived phenyllactate dehydrogenase (
fldH
), we establish that both dietary Trp and bacterial fldH activity are essential for ILA/IPA generation and subsequent mucosal healing. Our findings reveal a microbiota-metabolite-ISC regulatory axis critical for epithelial regeneration and propose novel metabolite-based therapeutic strategies for IBD and other intestinal disorders associated with barrier dysfunction.
Here, Zhang
et al
. show that the gut bacterium
Blautia coccoides
promotes intestinal repair by activating regenerative stem cells through indole lactic acid, providing a potential therapeutic avenue for inflammatory bowel disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/100
/ 13/31
/ 14/19
/ 3-Hydroxybutyric Acid - metabolism
/ 49/91
/ Animals
/ Bacteria
/ Blautia
/ Colitis
/ Colitis - chemically induced
/ Colon
/ Dextran
/ Dextrans
/ E coli
/ Epithelial Cells - metabolism
/ Female
/ Gastrointestinal Microbiome - physiology
/ Humanities and Social Sciences
/ Humans
/ Indoles
/ Inflammatory Bowel Diseases - metabolism
/ Inflammatory Bowel Diseases - microbiology
/ Intestinal Mucosa - metabolism
/ Intestinal Mucosa - microbiology
/ Intestinal Mucosa - pathology
/ Male
/ Mice
/ Mucosa
/ Receptors, G-Protein-Coupled - metabolism
/ Science
