Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota

Hsu, C.-Y.; Tsai, Y.-W.; Fu, S.-H.; Liu, Y.-W.; Dong, J.-L.; Yang, Y.-J.; Mai, Y.-W.; Tsai, L.-C.; Wu, C.-E.; Liang, H.-I.; Sun, C.-C.; Chen, C.-T.; Wang, S.-P.; Miaw, S.-C.; Sytwu, H.-K.

doi:10.64898/2026.06.15.732285

bioRxiv · 10.64898/2026.06.15.732285

Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota

Hsu, C.-Y.·Tsai, Y.-W.·Fu, S.-H.·Liu, Y.-W.·Dong, J.-L.·Yang, Y.-J.·Mai, Y.-W.·Tsai, L.-C.·Wu, C.-E.·Liang, H.-I.·Sun, C.-C.·Chen, C.-T.·Wang, S.-P.·Miaw, S.-C.·Sytwu, H.-K.

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Abstract

We have previously demonstrated a critical role of c-Maf SUMOylation in the regulation of autoimmune diabetogenesis, but its physiological relevance to and potential clinical impact on gut inflammation need further elucidation. Here, integrating a 14-year population-based time-trend cohort study of 139,204 type 1 diabetes patients with experiments in non-obese diabetic mice, we illustrated that autoimmune diabetes confers resistance to colitis mediated by an impaired c-Maf SUMOylation-driven IL-21-IgA axis. Utilizing T cell-specific c-Maf SUMOylation site-mutated mice, we further demonstrated that SUMOylation-defective c-Maf enhances IL-21 expression in CD4+ T cells to promote fecal IgA production and colitis resistance via microbiota remodeling, specifically through Lactobacillus johnsonii enrichment and activating lithocholic acid (LCA)-mediated AMPK anti-inflammatory pathway. Pharmacological HDAC2 inhibition by BRD6688 promotes c-Maf-mediated IL-21 and suppresses colitis in PBMC-humanized mice. Altogether, we revealed how SUMOylation reciprocally modulates the inflammatory process between autoimmune diabetes and colitis in a T cell-restricted and single transcription factor-based manner.

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Hsu, C.-Y., Tsai, Y.-W., Fu, S.-H., Liu, Y.-W., Dong, J.-L., Yang, Y.-J., Mai, Y.-W., Tsai, L.-C., Wu, C.-E., Liang, H.-I., Sun, C.-C., Chen, C.-T., Wang, S.-P., Miaw, S.-C., Sytwu, H.-K.. 2026-06-19. Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota. https://doi.org/10.64898/2026.06.15.732285

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