Gut microbiome–derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease
Open accessAbstract
The effect of alterations in intestinal microbiota on microbial metabolites and on disease processes such as graft-versus-host disease (GVHD) is not known. Here we carried out an unbiased analysis to identify previously unidentified alterations in gastrointestinal microbiota-derived short-chain fatty acids (SCFAs) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amount of only one SCFA, butyrate, were observed only in the intestinal tissue. The reduced butyrate in CD326(+) intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored after local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate-producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.
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Butyrate is associated with protection from autoimmune processes and graft-versus-host disease.
“Butyrate is associated with protection from autoimmune processes and graft-versus-host disease16,17.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [17]
Animal models indicate that commensal bacteria affect GVHD pathophysiology.
“Preclinical models have shown that commensal bacteria influence the pathophysiology of GVHD.10,17–20”
From Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation (2020) · cites this paper as [18]
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- Authors
- Mathewson, N. D., Jenq, R., Mathew, A. V., Koenigsknecht, M., Hanash, A., Toubai, T., Oravecz-Wilson, K., Wu, S.-R., Sun, Y., Rossi, C., Fujiwara, H., Byun, J., Shono, Y., Lindemans, C., Calafiore, M., Schmidt, T. M., Honda, K., Young, V. B., Pennathur, S., van den Brink, M., & Reddy, P.
- Affiliations
- University of Michigan (US)
- Memorial Sloan Kettering Cancer Center (US)
- Michigan Medicine (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Corresponding author
- Reddy, Pavan
- ORCID
- Venue
- Nature Immunology
- Published
- 2016-03-21
- Volume
- 17
- Issue
- 5
- Pages
- 505-513
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4836986
- OpenAlex
- W2310441748
- Cited by
- 725
- References
- 47
- Citations by year
- 2026: 61 · 2025: 69 · 2024: 54 · 2023: 77 · 2022: 84 · 2021: 96 · 2020: 77 · 2019: 68 · 2018: 54 · 2017: 61 · 2016: 23
- FWCI
- 35.68
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-09-20)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL128046, R01HL090775, R01HL128046, HL090775, K08HL115355, R01HL125571)
- National Cancer Institute (P01CA023766, R01CA173878, CA-173878, CA46592, P30CA046592)
- National Institute of General Medical Sciences (T32GM007863)
- National Institute of Allergy and Infectious Diseases (R01AI100288)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, DK-097153, U24DK097153, DK089503, DK34933, P30DK089503)
- Michigan Nutrition Obesity Research Center, Medical School, University of Michigan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- gut microbiota, microbial metabolites, short-chain fatty acids, butyrate, graft-versus-host disease, allogeneic bone marrow transplantation, intestinal epithelial cells, histone acetylation, intestinal barrier function, tight junctions, Clostridium, radiation conditioning
- MeSH terms
- Gastrointestinal Microbiome, Acetylation, Animals, Butyrates, Cells, Cultured, Epithelial Cells, Fatty Acids, Volatile, Female, Graft vs Host Disease, Histone Deacetylases, Histones, Intestines, Gas Chromatography-Mass Spectrometry, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Transplantation, Homologous, Immunoblotting, Gene Expression, Bone Marrow Transplantation, Reverse Transcriptase Polymerase Chain Reaction, Histone Acetyltransferases, Metabolome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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