Pyruvate promotes ciliogenesis bypassing IFT88 dependency and attenuates DSS-induced colitis

Primary cilia (PC) are important signaling rheostats, yet their biology in colon remains understudied. We previously reported that the presence of PC on colonic fibroblasts in mice (CF) modulates their susceptibility to colitis. Here, we demonstrate that extracellular pyruvate levels influence both ciliary length and ciliogenesis in CF. Pyruvate supplementation to CF enhanced tubulin and histone acetylation, with the latter promoting MAPK signaling and tubulin detyrosination within PC. MAPK-inhibition reduced tubulin detyrosination and shortened ciliary length, while inhibition of α-tubulin acetylation specifically affected ciliogenesis. Col6a1cre-Ift88flx/flx mice, lacking ciliary Ift88 gene in Col6a1 -expressing CF, displayed reduced ciliogenesis and increased susceptibility to DSS-induced colitis. Surprisingly, in primary CF cultures from these mice, pyruvate supplementation restored PC formation. Moreover, pyruvate administration via drinking water rescued PC formation in Col6a1cre-Ift88flx/flx mice and attenuated DSS-induced colitis. These findings identify pyruvate as a regulator of PC biology in CF and as a therapeutically relevant factor in colitis.