Cellular and molecular gastroenterology and hepatology · 2026
Dysbiosis-Associated Lysophosphatidic Acid Primes Immune Checkpoint Inhibitor-Induced Intestinal Barrier Dysfunction via the Lysophosphatidic Acid Receptor 2-Myosin Light Chain Kinase Axis.
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Xiong Lei, Huang Jianshang, Liu Qiuyuan, Xia Hanqi, Zhu Nina, Xiang Weizhen, Xu Wentao, Dong Yunsheng, Zhu Rumeng, Han Yiran, Rahman Abduxukur, Xu Huiqing, Xie Weiwei, Luo Zehua, He Wei, Turner Jerrold R, Zhou Yubao, Hu Ruolei, Wang Hua, Zuo Li
Аннотация
BACKGROUND & AIMS: Immune checkpoint inhibitor therapy is frequently limited by severe gastrointestinal toxicity. Although the immune mechanisms driving late-stage, overt mucosal inflammation are increasingly recognized, the early microbiota-metabolic events that prime epithelial barrier dysfunction remain poorly defined.
METHODS: We employed an integrated multiomics approach in a murine model of early immune checkpoint inhibitor-induced injury, with validation in a clinical cohort of patients with immune checkpoint inhibitor colitis. Mechanisms were investigated using in vitro receptor screening, genetically engineered mice with altered myosin light chain kinase 1 activity, and pharmacologic intervention with repurposed low-dose tacrolimus. Subcutaneous melanoma models were utilized to evaluate the relationship between barrier modulation and antitumor outcomes.
RESULTS: Early immune checkpoint inhibitor treatment induced a distinct dysbiotic state characterized by Pseudomonadota expansion, which was associated with the accumulation of bioactive lysophosphatidic acid-a metabolic signature also observed in human patients. Mechanistically, we identified lysophosphatidic acid receptor 2 as the key epithelial sensor that transduces this metabolic signal into pathological myosin light chain kinase 1 activation, driving the priming phase of barrier dysfunction. Genetic ablation of myosin light chain kinase 1 prevented this early barrier loss and was associated with improved tumor control and favorable regional immune alterations. Conversely, constitutive activation of myosin light chain kinase 1 exacerbated barrier disruption, which correlated with accelerated tumor progression and a systemic immunosuppressive shift. Furthermore, repurposing low-dose tacrolimus as a selective modulator to disrupt FKBP8-dependent myosin light chain kinase 1 recruitment effectively mitigated barrier injury without dampening antitumor responses.
CONCLUSIONS: The dysbiosis-associated lysophosphatidic acid-lysophosphatidic acid receptor 2-myosin light chain kinase axis acts as an early metabolic trigger for the priming phase of immune checkpoint inhibitor-induced barrier dysfunction. Modulating this upstream initiation step provides a temporal and mechanism-based strategy to uncouple intestinal toxicity from anti-tumor efficacy.
METHODS: We employed an integrated multiomics approach in a murine model of early immune checkpoint inhibitor-induced injury, with validation in a clinical cohort of patients with immune checkpoint inhibitor colitis. Mechanisms were investigated using in vitro receptor screening, genetically engineered mice with altered myosin light chain kinase 1 activity, and pharmacologic intervention with repurposed low-dose tacrolimus. Subcutaneous melanoma models were utilized to evaluate the relationship between barrier modulation and antitumor outcomes.
RESULTS: Early immune checkpoint inhibitor treatment induced a distinct dysbiotic state characterized by Pseudomonadota expansion, which was associated with the accumulation of bioactive lysophosphatidic acid-a metabolic signature also observed in human patients. Mechanistically, we identified lysophosphatidic acid receptor 2 as the key epithelial sensor that transduces this metabolic signal into pathological myosin light chain kinase 1 activation, driving the priming phase of barrier dysfunction. Genetic ablation of myosin light chain kinase 1 prevented this early barrier loss and was associated with improved tumor control and favorable regional immune alterations. Conversely, constitutive activation of myosin light chain kinase 1 exacerbated barrier disruption, which correlated with accelerated tumor progression and a systemic immunosuppressive shift. Furthermore, repurposing low-dose tacrolimus as a selective modulator to disrupt FKBP8-dependent myosin light chain kinase 1 recruitment effectively mitigated barrier injury without dampening antitumor responses.
CONCLUSIONS: The dysbiosis-associated lysophosphatidic acid-lysophosphatidic acid receptor 2-myosin light chain kinase axis acts as an early metabolic trigger for the priming phase of immune checkpoint inhibitor-induced barrier dysfunction. Modulating this upstream initiation step provides a temporal and mechanism-based strategy to uncouple intestinal toxicity from anti-tumor efficacy.