Microbial phosphoketolase promotes histone lactylation to improve anti-TNF therapy efficacy in inflammatory bowel disease PMID: 42134325

ADC Targets in Oncology

2026-04-10

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

Cell Metab. 2026 Jul 7;38(7):1443-1459.e6. doi: 10.1016/j.cmet.2026.04.012.

Yi Jiang ¹ , Yanru Ma ¹ , Lijun Ning ¹ , Hao Wu ² , Hongli Huang ³ , Nan Shen ⁴ , Xia Xie ⁵ , Xiaoqiang Zhu ¹ , Jinmei Ding ¹ , Zhenyu Wang ¹ , Ying Sun ¹ , Ying Zhao ¹ , Yilu Zhou ¹ , Yue Zhang ¹ , Yuqi Shao ¹ , Xi Xu ¹ , Muni Hu ¹ , Lingxi Li ¹ , Jing-Yuan Fang ¹ , Haoyan Chen ¹ , Zhijun Cao ⁶ , Baoqin Xuan ⁷ , Xitao Xu ⁸ , Jie Hong ⁹

Affiliations

1. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
2. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200001, China.
3. Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou 510180, China.
4. Department of Infectious Diseases, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
5. Department of Gastroenterology, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing 400037, China.
6. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: [email protected].
7. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: [email protected].
8. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: [email protected].
9. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: [email protected].

Abstract

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.

Keywords

5-hydroxyindoleacetic acid; Bifidobacterium; anti-TNF biologics; inflammatory bowel disease; lactylation; macrophage; microbial-host isozyme; phosphoketolase; regulatory T cells.