2. Academic Validation
  3. A 4-guanidinobutanoic acid-SLC36A1 axis drives a microbiota‒host feedback loop to regulate intestinal homeostasis

A 4-guanidinobutanoic acid-SLC36A1 axis drives a microbiota‒host feedback loop to regulate intestinal homeostasis

  • Gut Microbes. 2026 Dec 31;18(1):2639216. doi: 10.1080/19490976.2026.2639216.
Jianming Yang 1,  Yawen Xiao 1 2 3 4 5,  Jifang Cui 4,  Ruofan Song 1 3,  Wanxia Ma 1 3,  Jiangpeng Liu 1 3,  Chunhui Miao 1,  Xinyu Sun 1 3,  Xueting Kong 1 3,  Zhi-Song Zhang 2,  Lu Zhou 6,  Zhi Yao 1,  Quan Wang 3
Affiliations

Affiliations

  • 1 Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
  • 2 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Experimental Hematology, Beijing, China.
  • 4 Department of Gastroenterology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, China.
  • 5 Department of Basic Medical Sciences, Tianjin Medical College, Tianjin, China.
  • 6 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.
PMID: 41782409 DOI: 10.1080/19490976.2026.2639216
Abstract

The role of gut microbiota‒derived metabolites in regulating the intestinal mucosal barrier remains poorly defined. Here, we identified 4-guanidinobutanoic acid (4-GBA), produced by Bacteroides stercorirosoris, as a critical regulator of intestinal homeostasis. Using untargeted metabolomics, Organoid co-cultures, mouse models, and single-cell RNA Sequencing, we demonstrated that 4-GBA enhances intestinal stem cells (ISCs) function and goblet cell differentiation. This promotes Akkermansia muciniphila enrichment through mucus-dependent niche expansion, establishing a microbiota‒host feedback loop. Mechanistically, 4-GBA upregulates the proton-coupled Amino acid Transporter SLC36A1 and activates the Hedgehog signaling pathway to drive epithelial reprogramming. Clinically, SLC36A1 expression inversely correlates with ulcerative colitis (UC) severity in human samples. Furthermore, the SLC36A1 agonist sarcosine enhances barrier homeostasis and attenuates colitis in mice, highlighting the diagnostic and therapeutic potential of this axis in UC. Our findings reveal a novel microbiome-host axis through which a microbial metabolite modulates epithelial function and microbial ecology, offering a potential therapeutic strategy targeting microbiota-epithelial crosstalk for UC management.

Keywords

4-Guanidinobutanoic acid; Akkermansia muciniphila; SLC36A1; intestinal mucosal barrier; ulcerative colitis.

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