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<p>Loss of host–microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (T<sub>reg</sub>) cells to preserve gut–immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired T<sub>reg</sub> cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs T<sub>reg</sub> cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut–immune homeostasis and dictates outcome in pathobiont infections.</p>

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Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Annamaria Regina,
  • Francesca Solagna,
  • Malkon Sanchez Estrada,
  • Maaike M. E. Jacobs,
  • Daniel Martinez-Martinez,
  • Theodoros Georgomanolis,
  • Irma Alibashikj,
  • Sara Gjurgji,
  • Claire Pearson,
  • Dehui Chang,
  • Chrysanthi Moschandrea,
  • Ana Sagrera Aparisi,
  • Elena Crespo,
  • Jessica Buechel,
  • Farina Schneider,
  • Lea Trojahn,
  • Paulina Pfelzer,
  • Milica Popovic,
  • Elena Potenza,
  • Agnieszka M. Kabat,
  • Carien Niessen,
  • Borko Amulic,
  • Niloufar Safinia,
  • Sara Cogliati,
  • David E. Sanin,
  • Matteo Villa,
  • Edward J. Pearce,
  • Christian Frezza,
  • Erika L. Pearce,
  • Filipe Cabreiro,
  • Fiona Powrie,
  • Mauro Corrado

摘要

Loss of host–microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (Treg) cells to preserve gut–immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired Treg cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs Treg cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut–immune homeostasis and dictates outcome in pathobiont infections.