A groundbreaking study published in Genes & Diseases has revealed that exogenous pyruvate significantly alleviates the symptoms of ulcerative colitis (UC) by targeting cytosolic phospholipase A2 (cPLA2). This discovery opens new avenues for the treatment of UC, which remains a chronic inflammatory bowel disease with limited therapeutic options. The study shows that pyruvate can suppress the TNFα/NFκB signaling pathway, which is pivotal in driving inflammation, thereby offering a novel approach to mitigating UC symptoms.
Ulcerative colitis is characterized by chronic intestinal inflammation, leading to symptoms such as abdominal pain, diarrhea, rectal bleeding, and weight loss. Current treatments, including aminosalicylic acids, glucocorticoids, and immunosuppressants, often present significant side effects and limited efficacy. Moreover, biological therapies targeting TNFα, though effective, lack oral formulations, making them less convenient for patients. The discovery of pyruvate as an orally administered therapeutic alternative holds promise for improving patient outcomes.
The research team conducted extensive in vitro and in vivo experiments to investigate the anti-inflammatory potential of pyruvate. Initial screening of various cellular metabolites identified pyruvate as the most potent inhibitor of TNFα/NFκB signaling. In mouse models of dextran sodium sulfate (DSS)-induced colitis, pyruvate administration significantly reduced colonic inflammation, maintained tight junction integrity, and improved overall clinical disease activity indices. Histopathological analysis revealed that pyruvate preserved colonic structure and reduced immune cell infiltration, suggesting its ability to stabilize the intestinal mucosal barrier.
Further molecular investigations identified cPLA2 as a previously unrecognized target of pyruvate. Through drug affinity responsive target stability (DARTS) assays and cellular thermal shift assays (CETSA), the researchers demonstrated that pyruvate binds directly to cPLA2, stabilizing it and preventing its degradation. This interaction is crucial as cPLA2 mediates the production of pro-inflammatory lipid mediators, including arachidonic acid, which activate the NFκB pathway and exacerbate colitis. In cPLA2-deficient mice, pyruvate lost its therapeutic efficacy, confirming that its anti-inflammatory effects are mediated through this enzyme.
Importantly, the study showed that pyruvate effectively reduced the levels of key pro-inflammatory cytokines such as IL-1β and IL-6 in both the serum and colonic tissues of treated mice. Additionally, pyruvate administration was shown to normalize the expression of tight junction proteins such as claudin-2, ZO-1, and occludin, which are critical in maintaining intestinal barrier function. The therapeutic effects of pyruvate were comparable to those of 5-aminosalicylic acid (5-ASA), a standard UC treatment, but with the added benefit of being an oral small molecule.
These findings not only position pyruvate as a potential novel oral therapy for ulcerative colitis but also highlight the therapeutic relevance of targeting cPLA2 in inflammatory bowel diseases. By inhibiting the TNFα/NFκB pathway, pyruvate may also prove beneficial in other TNFα-associated inflammatory conditions. Future clinical trials are warranted to validate these promising preclinical results and establish pyruvate's role in human UC management.
