Intestinal dysbiosis exacerbates skin inflammation via microbial metabolite-driven Th2 cell differentiation

  • Immunity. 2026 Jun 9;59(6):1545-1560.e6. doi: 10.1016/j.immuni.2026.03.019.
Lu Yu  1 ,  Shuying Peng  1 ,  Xi Chen  2 ,  Tianxing Wu  1 ,  Lijun Dong  1 ,  Jialiang Luo  3 ,  Shuangbin Xu  4 ,  Jia Zhou  5 ,  Xiaoshan Zhao  6 ,  Lei Zheng  7 ,  Gang Shu  8 ,  Xuemin Wang  9 ,  Liping Huang  10 ,  Qingyun Chen  11 ,  Deke Jiang  12 ,  Liang-Dan Sun  13 ,  Phillip Hylemon  14 ,  Xiang-Yang Wang  15 ,  Ledong Sun  16 ,  Li Ma  17 ,  Daming Zuo  18
Affiliations
  • 1. Institute of Molecular Immunology, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 2. Institute of Molecular Immunology, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 3. Institute of Molecular Immunology, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Medical Products Administration Key Laboratory for research and evaluation of drugs for inflammatory diseases, Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510900, China.
  • 4. Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 5. Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 6. Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 7. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 8. Guangdong Province Key Laboratory of Animal Nutritional Regulation, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.
  • 9. Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 10. Department of Obstetrics and Gynecology, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong 510515, China.
  • 11. Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
  • 12. National Key Laboratory of Prevention and Treatment of Multiple Organ Injuries, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 13. Health Science Center, North China University of Science and Technology, Tangshan, Hebei 063210, China; Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
  • 14. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.
  • 15. Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
  • 16. Guangdong Medical Products Administration Key Laboratory for research and evaluation of drugs for inflammatory diseases, Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510900, China. Electronic address: [email protected].
  • 17. Institute of Molecular Immunology, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 18. Institute of Molecular Immunology, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
PMID: 41997160 DOI: 10.1016/j.immuni.2026.03.019
Abstract

The interplay between gut microbiota and the mucosal immune system critically regulates systemic immunity and disease susceptibility. Here, we demonstrate that intestinal epithelial Toll-like Receptor (TLR)4 deficiency reshaped the gut microbiome and subsequently exacerbated atopic dermatitis (AD) in mice. Mechanistically, TLR4 deficiency reduced Akkermansia muciniphila abundance and enriched choline trimethylamine-lyase (CutC)-expressing bacteria. This enhanced microbial choline-to-trimethylamine conversion and elevated circulating trimethylamine oxide (TMAO) levels. Clinically, AD patients exhibited increased plasma TMAO levels that positively correlated with disease severity and immunoglobulin E (IgE) levels. UK Biobank data also showed that higher dietary choline intake was associated with increased AD risk. TMAO promoted T helper (Th)2 differentiation by directly interacting with protein Phosphatase 5 (PPP5) and enhancing PPP5-mediated dephosphorylation of PPARγ. CD4+ T cell-specific PPARγ deletion abolished TMAO-driven skin pathology in AD mice. Our results reveal intestinal dysbiosis, as a result of innate immune deficiency, as a driver of inflammatory Th2 cells and AD pathology, highlighting a link among the gut immune environment, microbial metabolites, and skin disease.

Keywords
Th2 response; Toll-like receptor 4; atopic dermatitis; choline; gut microbiome; microbial metabolite; peroxisome proliferator-activated receptor γ; trimethylamine oxide.
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