Abstract
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.
Data availability
The 16S rRNA amplicon sequencing data and raw bulk RNA sequencing data generated in this study have been deposited in the Genome Sequence Archive (GSA) in National Genomics Data Center (NGDC) under accession codes CRA018493 and CRA018487, respectively. The fecal metabolomic profiles and tryptophan-related metabolite profiles generated in this study are provided in the Supplementary Data 3 and 4. The feature table of the amplicon-based metagenomic dataset from the study by Lloyd-Price et al. was obtained from the Inflammatory Bowel Disease Multi-omics Database (IBDMDB, https://ibdmdb.org/). The raw metagenomic datasets analyzed in this study were obtained from the previously published studies and are publicly available at European Nucleotide Archive under the following project accessions: PRJEB15371 (HeQ_2017), PRJNA385949 (HallAB_2017), PRJNA398089 (LloydPriceJ_2019), PRJNA389280 (SchirmerM_2018), PRJNA429990 (WengY_2019), PRJEB67456 (YanQ_2023c). The genome sequence and annotation files for Mus musculus (GRCm39, release 110) were downloaded from the Ensembl database. The genome sequences of Homo sapiens were download from NCBI database with accession code GCF_000001405.40. The genome, coding, and protein sequences of Clostridium sporogenes strain ATCC 15579, Peptostreptococcus russellii strain RT-10B and Blautia coccoides strain DSM 935 were downloaded from the NCBI database under accession numbers GCF_000155085.1, GCF_003012055.1 and GCF_034355335.1, respectively. Source data are provided with this paper.
Code availability
The intermediate results, analysis and visualization codes used in this study have been uploaded into the GitHub repository, accessible at https://github.com/mengjx855/25-BC-IPA-ISC.
References
Miyoshi, H., Ajima, R., Luo, C. T., Yamaguchi, T. P. & Stappenbeck, T. S. Wnt5a potentiates TGF-beta signaling to promote colonic crypt regeneration after tissue injury. Science 338, 108–113 (2012).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Wu, N. et al. MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche. Nature 592, 606–610 (2021).
Wang, R. et al. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature 580, 386–390 (2020).
Villablanca, E. J., Selin, K. & Hedin, C. R. H. Mechanisms of mucosal healing: treating inflammatory bowel disease without immunosuppression? Nat. Rev. Gastroenterol. Hepatol. 19, 493–507 (2022).
Montgomery, R. K. et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc. Natl. Acad. Sci. USA 108, 179–184 (2011).
Powell, A. E. et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149, 146–158 (2012).
Yan, K. S. et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl. Acad. Sci. USA 109, 466–471 (2012).
Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011).
Tao, S. et al. Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage. EMBO J. 36, 2920–2921 (2017).
Metcalfe, C., Kljavin, N. M., Ybarra, R. & de Sauvage, F. J. Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159 (2014).
Wang, Y. et al. Long-term culture captures injury-repair cycles of colonic stem cells. Cell 179, 1144–1159 e1115 (2019).
Stewart, A. S. et al. HOPX(+) injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia. Am. J. Physiol. Gastrointest. Liver Physiol. 321, G588–G602 (2021).
Ayyaz, A. et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature 569, 121–125 (2019).
Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. USA 102, 99–104 (2005).
Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 167, 1137 (2016).
Peck, B. C. E., Shanahan, M. T., Singh, A. P. & Sethupathy, P. Gut microbial influences on the mammalian intestinal stem cell niche. Stem Cells Int. 2017, 5604727 (2017).
Manichanh, C., Borruel, N., Casellas, F. & Guarner, F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599–608 (2012).
Shan, Y., Lee, M. & Chang, E. B. The gut microbiome and inflammatory bowel diseases. Annu. Rev. Med. 73, 455–468 (2022).
Abdulla, A., Awla, D., Thorlacius, H. & Regner, S. Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis. J. Leukoc. Biol. 90, 975–982 (2011).
Wang, G. et al. Ginsenoside Rg3 enriches SCFA-producing commensal bacteria to confer protection against enteric viral infection via the cGAS-STING-type I IFN axis. ISME J. 17, 2426–2440 (2023).
Zhang, Y. et al. Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway. Nat. Commun. 15, 1333 (2024).
Subramanian, B. C. Inflammatory bowel disease: DCs sense LTB(4) to drive T(H)1 and T(H)17 differentiation. Cell Mol. Immunol. 17, 307–309 (2020).
Gregorieff, A., Liu, Y., Inanlou, M. R., Khomchuk, Y. & Wrana, J. L. Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 526, 715–718 (2015).
Richmond, C. A. et al. JAK/STAT-1 signaling is required for reserve intestinal stem cell activation during intestinal regeneration following acute inflammation. Stem Cell Rep. 10, 17–26 (2018).
Zhang, Y. et al. Microbiota-derived IPA protects against colitis by regulating intestinal HMGCS2-mediated ketogenesis to facilitate mucosal healing. Nat Commun. https://doi.org/10.1038/s41467-026-69341-z (2026).
Agus, A., Planchais, J. & Sokol, H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23, 716–724 (2018).
Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).
Holmberg, S. M. et al. The gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids. Nat. Commun. 15, 3502 (2024).
Cheng, C. W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115–1131 e1115 (2019).
Terranova, C. J. et al. Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine. Cell Rep. 37, 110044 (2021).
Roda, G., Jharap, B., Neeraj, N. & Colombel, J. F. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin. Transl. Gastroenterol. 7, e135 (2016).
Dahmus, J., Rosario, M. & Clarke, K. Risk of lymphoma associated with anti-TNF therapy in patients with inflammatory bowel disease: implications for therapy. Clin. Exp. Gastroenterol. 13, 339–350 (2020).
Singh, S., Facciorusso, A., Dulai, P. S., Jairath, V. & Sandborn, W. J. Comparative risk of serious infections with biologic and/or immunosuppressive therapy in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 18, 69–81 e63 (2020).
Sinha, A. K. et al. Dietary fibre directs microbial tryptophan metabolism via metabolic interactions in the gut microbiota. Nat. Microbiol. 9, 1964–1978 (2024).
Kitada, Y. et al. Bioactive polyamine production by a novel hybrid system comprising multiple indigenous gut bacterial strategies. Sci. Adv. 4, eaat0062 (2018).
Jia, D. et al. Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer. Cell 187, 1651–1665 e1621 (2024).
Babickova, J. et al. Sex differences in experimentally induced colitis in mice: a role for estrogens. Inflammation 38, 1996–2006 (2015).
Tshikudi, D. M., Bernstein, C. N., Mishra, S., Ghia, J. E. & Armstrong, H. K. Influence of biological sex in inflammatory bowel diseases. Nat. Rev. Gastroenterol. Hepatol. 22, 415–437 (2025).
Weigmann, B. et al. Isolation and subsequent analysis of murine lamina propria mononuclear cells from colonic tissue. Nat. Protoc. 2, 2307–2311 (2007).
Xu, S. et al. Using clusterProfiler to characterize multiomics data. Nat. Protoc. 19, 3292–3320 (2024).
Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
Kim, D., Paggi, J. M., Park, C., Bennett, C. & Salzberg, S. L. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37, 907–915 (2019).
Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290–295 (2015).
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
Acknowledgements
We thank Dr. Daqian Xu, Dr. Dingjiacheng Jia and Dr. Yuhao Wang for their valuable comments for the manuscript. We appreciate Dr. Bin Zhou from Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences for providing Hopx-CreERT2 mice. The professional editing service NB Revisions was used for technical preparation of the text prior to submission. This work is supported by grants from the National Natural Science Foundation of China (No. 323B2007, No. 82174467, No. 82572567, No. 82574811 and No. 32471329) to Y.Z., S.J.Z., L.Z., and H. C.
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S.J.Z., H.C., and Y.Z. designed the experiments. Y.Z., S.T., L.M., X.Z., J.G., J.W., and W. X. performed the experiments. J.M. conducted bioinformatics analysis. L.Z. collected samples and data. S.C coordinated the project. L.Z. and H.C. commented on and revised drafts of the manuscript. S.J.Z., Y.Z., S.T., J.M., and H.C. wrote the paper. S.J.Z. supervised research, coordination, and strategy.
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Zhang, Y., Meng, J., Tu, S. et al. A microbiota-IPA axis facilitates intestinal stem cell-mediated regeneration in colitis through a Hopx-associated program. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70062-6
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DOI: https://doi.org/10.1038/s41467-026-70062-6
