HIF-1 attenuates high-fiber diet-mediated proliferation and stemness of colonic epithelium
The complex interplay between diet, microbiota, and host is exemplified by the effects of dietary fiber on the intestine. Inulin ingestion triggers epithelial changes in the colon that depend on microbiota-derived molecules, including enhanced proliferation, increased mucus production, and elevated antimicrobial peptide secretion. Here we employed a multilayered and multi-omics approach, including dietary interventions, intestinal organoids, and both genetic and pharmacological interventions to investigate the impact of inulin on two aspects of diet-microbiota-host interactions: intestinal hypoxia and hypoxia-inducible factor (HIF)-1 signaling in intestinal epithelial cells (IECs). We found that inulin, a soluble fiber, promotes intestinal hypoxia, stabilizing HIF-1 in IECs in a microbiota- and host-dependent manner. Furthermore, we show that HIF-1 stabilization modulates intestinal stem cell (ISC) function through metabolic reprogramming in a microbiota-dependent manner. Our findings reveal an unrecognized role for HIF-1 in orchestrating microbiota-dependent epithelial metabolism and proliferation in the colon, underscoring the complexity of diet-microbiota-host interactions.
Authors
- Patrícia Brito Rodrigues (ORCID: https://orcid.org/0000-0002-1687-7742)
- Arilson Bernardo dos Santos Pereira Gomes
- Victor Corasolla Carregari (ORCID: https://orcid.org/0000-0001-6863-1333)
- Mariane Font Fernandes (ORCID: https://orcid.org/0000-0002-0262-4509)
- Mariana X. Byndloss (ORCID: https://orcid.org/0000-0002-2122-4156)
- Vinícius de Rezende Rodovalho (ORCID: https://orcid.org/0000-0003-4216-7143)
- José Luís Fachi (ORCID: https://orcid.org/0000-0002-1035-5193)
- Marco Aurélio Ramirez Vinolo (ORCID: https://orcid.org/0000-0003-1335-760X)
- Nicolas G. Shealy (ORCID: https://orcid.org/0000-0002-1700-7570)
- Daniel Martins‐de‐Souza (ORCID: https://orcid.org/0000-0003-3595-5846)
- Patrick Varga‐Weisz
- Jaqueline de Souza Felipe
- Vinícius Dias Nirello (ORCID: https://orcid.org/0000-0001-7358-042X)
- Catherine Shelton
- Guilherme Reis‐de‐Oliveira (ORCID: https://orcid.org/0000-0002-7696-0716)
- Bradley J. Smith (ORCID: https://orcid.org/0000-0003-1383-5851)
- Pedro M. Moraes‐Vieira (ORCID: https://orcid.org/0000-0002-8263-786X)
- Laís Passariello Pral (ORCID: https://orcid.org/0000-0002-3008-0465)
- Renan Oliveira Corrêa (ORCID: https://orcid.org/0000-0002-3333-0482)
- Pollyana Ribeiro Castro (ORCID: https://orcid.org/0000-0002-1404-6873)
- Monara Kaélle Sérvulo Cruz Angelim (ORCID: https://orcid.org/0000-0001-6235-956X)
- Sarah de Oliveira (ORCID: https://orcid.org/0000-0002-9449-9740)
Institutions
- University of Essex (GB)
- Howard Hughes Medical Institute (US)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Washington University in St. Louis (US)
- Centro Infantil Boldrini (BR)
- Immunité et Cancer (FR)
- Innovation Cluster (Canada) (CA)
- Institute for Disease Modeling (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Gut Microbes
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1080/19490976.2025.2543123
- Citations
- 3
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 3.49
Funders
- Pew Charitable Trusts
- University of Essex
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institutes of Health