Interleukin‐6 promotes skeletal muscle catabolism by activating tryptophan–indoleamine 2,3‐dioxygenase 1–kynurenine pathway during intra‐abdominal sepsis

**Background:** Intra-abdominal sepsis (IAS) is a common complication after abdominal trauma or surgery, with 70–100% of patients developing metabolic disorders including skeletal muscle wasting and sarcopenia. The inflammatory cytokine interleukin-6 (IL-6) is known to play a pivotal role in muscle degradation during sepsis, but the underlying mechanisms remain incompletely understood. Indoleamine 2,3-dioxygenase 1 (IDO-1) is a key enzyme that converts tryptophan into kynurenine, and kynurenine has been implicated in muscle catabolism. This study hypothesized that IL-6 promotes muscle wasting via the tryptophan–IDO-1–kynurenine pathway in IAS patients.

**Methods:** The study enrolled 12 IAS patients and 27 non-IAS controls undergoing laparotomy. Serum and rectus abdominis (RA) muscle samples were collected. In parallel, a mouse model of IAS was generated using cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) injection in C57BL/6J male mice. IL-6 signaling was blocked using anti-mouse IL-6 antibody (IL-6-AB), and the IDO-1 pathway was inhibited using navoximod (NLG-919). Kynurenine was administered to septic mice treated with IL-6-AB to assess its role in muscle wasting. Muscle cross-sectional area (MCSA) was measured by laminin staining, and protein expression was analyzed by western blot. Tryptophan and kynurenine concentrations were quantified by ultra-high-performance liquid chromatography (UHPLC).

**Key Results:** In IAS patients, serum kynurenine levels were elevated 2.30-fold vs. non-IAS (P < 0.001), and muscle kynurenine levels increased 3.11-fold (P < 0.001). Tryptophan levels decreased by 53.65% in serum (P < 0.01) and 61.39% in muscle (P < 0.01). Serum IL-6 was 5.82-fold higher in IAS patients (P = 0.01), and MCSA was reduced by 27.73% (P < 0.01). In animal models, IDO-1 expression was upregulated in the small intestine, colon, and blood of CLP- or LPS-treated mice, but not in skeletal muscle. A significant correlation was found between serum and muscle kynurenine concentrations (R² = 0.66, P < 0.01). Navoximod treatment mitigated IAS-induced muscle loss, increasing MCSA by 22.94% vs. CLP (P < 0.05) and 23.71% vs. LPS (P < 0.01), and increased p-AKT (2.15-fold vs. CLP, P < 0.01; 3.44-fold vs. LPS, P < 0.01) and myosin heavy chain (MyHC) expression (3.64-fold vs. CLP, P < 0.01; 2.13-fold vs. LPS, P < 0.01). Anti-IL-6 antibody significantly decreased IDO-1 expression in the small intestine, colon, and blood (all P < 0.01) and increased MCSA by 37.43% vs. CLP + IgG (P < 0.001) and 30.72% vs. LPS + IgG (P < 0.001). Kynurenine supplementation reversed these protective effects, decreasing MCSA in septic mice treated with IL-6-AB (both P < 0.01).

**Clinical Implications:** This study provides novel evidence that the IL-6–IDO-1–kynurenine axis is a key mechanism driving skeletal muscle catabolism during intra-abdominal sepsis. The findings suggest that targeting IDO-1 or blocking IL-6 signaling could represent therapeutic strategies for preventing or treating sepsis-induced muscle wasting and critical illness myopathy. The study also highlights the potential role of the gut–muscle axis, as IDO-1 upregulation occurred primarily in intestinal tissues rather than in muscle itself. Limitations include the small clinical sample size (n=12 IAS patients), lack of dynamic kynurenine monitoring, and use of pharmacological inhibition rather than genetic knockout models.