Gut metabolite TCDCA attenuates sepsis-induced intestinal injury via TGR5-dependent mitochondrial protection and anti-inflammatory effect

Intestinal injury due to sepsis is a key mediator of systemic inflammatory response. The circulating levels of the gut microbial metabolite, taurochenodeoxycholic acid (TCDCA), are strongly decreased in septic patients and in mouse models, and correlates with disease severity. TCDCA significantly enhances survival, maintains tight junction integrity, and inhibits intestinal inflammation in septic mice. TCDCA acts through TGR5 to maintain mitochondrial homeostasis. This prevents activation of the cGAS-STING and NF-κB inflammatory signaling cascades. To address the solubility and limited targeting capability of TCDCA, a biomimetic nanoparticle system (AmEVs@Ru-PIC/TCDCA) was developed and incorporated into dissolvable abdominal microneedle patches to enable localized and sustained drug delivery. This nanoplatform demonstrates excellent biocompatibility, pH-responsive release, and efficient intestinal targeting, improving the pharmacokinetic profiles of TCDCA, with prolonged circulation, increased systemic drug exposure and evident small-intestinal accumulation, which contributes to alleviating sepsis-related intestinal damage. In summary, the results show that the TCDCA-TGR5 axis maintains intestinal barrier function depending on mitochondria and offers a new treatment therapy for the sepsis. Proposed mechanism by which gut microbiota-derived TCDCA alleviates septic intestinal injury via the TGR5–mitochondria–mtDNA–cGAS/STING axis and targeted delivery using a biomimetic microneedle system. Sepsis (CLP) induces gut microbiota dysbiosis and bile acid metabolic remodeling, reducing microbial-derived TCDCA. This leads to downregulation of the TGR5 axis in intestinal epithelial cells (IECs), resulting in mitochondrial damage, including elevated mtROS, Ca²⁺ overload, mPTP opening, Δψm collapse, impaired ATP production, and mtDNA leakage. The leaked mtDNA activates the cGAS-STING pathway, which triggers NF-κB/IRF3-mediated inflammatory responses and systemic inflammation, disrupting tight junctions and leading to loss of intestinal barrier function. TCDCA administration activates TGR5, restoring mitochondrial homeostasis (reducing mtROS, Ca²⁺ overload, and mPTP opening; maintaining Δψm; improving OXPHOS; inhibiting Drp1-mediated fission) and suppressing mtDNA-cGAS-STING/NF-κB signaling, preserving barrier integrity and reducing inflammation. An abdominally dissolvable microneedle patch delivering biomimetic Akkermansia muciniphila extracellular vesicle (AmEV)-coated Ru-PIC/TCDCA nanoplatform shows obvious intestinal accumulation and enables sustained local release of TCDCA, improving uptake in IECs, alleviating mitochondrial injury, and restoring barrier function in septic mice