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Fisetin modulates the gut microbiota alongside biomarkers of senescence and inflammation in a DSS-induced murine model of colitis

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Abstract

Colitis, a subtype of inflammatory bowel disease (IBD), is a multifactorial disorder characterized by chronic inflammation of the colon. Among various experimental models used in the study of IBD, the chemical colitogenic dextran sulfate sodium (DSS) is most commonly employed to induce colitis in vivo. In the search for new therapeutic strategies, Fisetin, a flavonoid found in many fruits and vegetables, has recently garnered attention for its senolytic properties. Female mice were administered 2.5% DSS in sterile drinking water and were subsequently treated with Fisetin or vehicle by oral gavage. DSS significantly upregulated beta-galactosidase activity in colonic proteins, while Fisetin remarkably inhibited its activity to baseline levels. Particularly, qPCR revealed that the senescence and inflammation markers Vimentin and Ptgs2 were elevated by DSS exposure with Fisetin treatment inhibiting the expression of p53, Bcl2, Cxcl1, and Mcp1, indicating that the treatment reduced senescent cell burden in the DSS targeted intestine. Alongside, senescence and inflammation associated miRNAs miR-149-5p, miR-96-5p, miR-34a-5p, and miR-30e-5p were significantly inhibited by DSS exposure and restored by Fisetin treatment, revealing novel targets for the treatment of IBDs. Metagenomics was implemented to assess impacts on the microbiota, with DSS increasing the prevalence of bacteria in the phyla Bacteroidetes. Meanwhile, Fisetin restored gut health through increased abundance of Akkermansia muciniphila, which is negatively correlated with senescence and inflammation. Our study suggests that Fisetin mitigates DSS-induced colitis by targeting senescence and inflammation and restoring beneficial bacteria in the gut indicating its potential as a therapeutic intervention for IBDs.

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Acknowledgements

The authors acknowledge the support from the USF Center for Microbiome Research and its core facilities for performing microbiome sequencing and bioinformatics support.

Funding

We would like to thank the National Institutes of Health (R56 AG074499, R56AG069676, R56AG064075, RF1AG071762, R21AG072379, U01AG076928, R21DE032197), the Department of Defense (W81XWH-18-PRARP AZ180098), the Ed and Ethel Moore Alzheimer’s Disease Research Program of the Florida Department of Health (22A17) for Drs. Masternak and Yadav groups, the Florida Legislative Grant 2014–2022 for Drs. Masternak and Naser groups, the European Commission program HORIZON 2020-MSCA-RISE, Marie Sklodowska-Curie Staff Actions for MMM, BR, AG, MS, and the Richard Tucker Gerontology Applied Research Grant sponsored by the Learning Institute for Elders at the University of Central Florida for the support for Sarah Ashiqueali.

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Authors and Affiliations

  1. University of Central Florida College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA

    Sarah A. Ashiqueali, Xiang Zhu, Sarah Noureddine, Sarah Siddiqi, Mishfak A. M. Mansoor, Saleh A. Naser & Michal M. Masternak

  2. University of South Florida Morsani College of Medicine, Neurosurgery & Brain Repair, Tampa, FL, USA

    Diptaraj Chaudhari & Hariom Yadav

  3. Faculdade de Nutricao, Universidade Federal de Pelotas, Pelotas, Rio Grande Do Sul, Brazil

    Driele N. Garcia, Bianka M. Zanini & Augusto Schneider

  4. Poznan University of Medical Sciences, Department of Pharmaceutical Chemistry, Poznan, Poland

    Aleksandra Gostynska, Maciej Stawny & Blazej Rubis

  5. Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland

    Michal M. Masternak

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  1. Sarah A. Ashiqueali
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  2. Diptaraj Chaudhari
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Contributions

SAA, DC, AS, SAN, HY, and MMM conceptualized the project. SAA, DC, XS, AS, SAN, HY, and MMM developed the methodology. SAA, DC, SN, SS, DNG, AG, MS, BR, BMZ, and MAAM performed the experiments. MMM, HY, SN, BR, AG, MS, SAA acquired funding. HY, SAN, and MMM supervised the project. SAA wrote the original draft of the manuscript. All authors were responsible for editing and review of the manuscript.

Corresponding author

Correspondence to Michal M. Masternak.

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Conflict of interest

Dr. Yadav is co-founder and chief scientific officer of the Postbiotics Inc, but has no conflict in the work presented in this manuscript. Other authors declare that no competing interests exist related to this study.

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Ashiqueali, S.A., Chaudhari, D., Zhu, X. et al. Fisetin modulates the gut microbiota alongside biomarkers of senescence and inflammation in a DSS-induced murine model of colitis. GeroScience 46, 3085–3103 (2024). https://doi.org/10.1007/s11357-024-01060-z

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