Microbial phosphoketolase promotes histone lactylation to improve anti-TNF therapy efficacy in inflammatory bowel disease.

Anti-tumor necrosis factor (TNF) therapy is widely used for inflammatory bowel disease, yet primary non-response and secondary loss of response remain challenges in clinical practice. In this study, we demonstrate that bacterial phosphoketolase improves the primary response to anti-TNF antibodies during induction therapy by enhancing Treg-mediated immunosuppression and maintaining higher serum drug concentrations. Mechanistically, phosphoketolase acts as a microbial host enzyme in macrophages, increasing phosphoketolase pathway flux and lactate production. Elevated lactate induces histone H4K12 lactylation, leading to the upregulation of the serotonin transporter, which mediates serotonin uptake for subsequent conversion to 5-hydroxyindoleacetic acid, a potential inhibitor of TNF-α-converting enzyme. This increases surface transmembrane TNF levels, thereby enhancing TNFR2 signaling in Tregs and promoting their proliferation and differentiation. In a prospective clinical trial, phosphoketolase-producing Bifidobacterium enhanced anti-TNF antibody efficacy during induction therapy. These findings support phosphoketolase-producing probiotics as an effective adjunct to anti-TNF therapy in inflammatory bowel disease.