Title : From gut dysbiosis to lung vulnerability: Influenza risk in diabetes
Abstract:
Respiratory viral infections, including influenza, remain a major global health concern and disproportionately affect individuals with diabetes, who are at increased risk of severe disease and complications. This heightened susceptibility has traditionally been attributed to the direct effects of hyperglycemia on lung epithelial integrity and immune cell function. Here, we identify a previously underappreciated gut-lung axis through which diabetes- associated gut microbiota alterations impair pulmonary innate immunity and antiviral defense. Using a streptozotocin-induced diabetic mouse model, we demonstrate that diabetes-driven changes in gut microbiota composition lead to increased systemic dissemination of lipopolysaccharide (LPS), a key microbial-derived inflammatory mediator. Elevated circulating LPS reprograms mitochondrial metabolism in alveolar macrophages (AMs), resulting in excessive mitochondrial reactive oxygen species (mitoROS) production and enhanced pro-inflammatory signaling. This metabolic reprogramming compromises AM phagocytic capacity and increases their susceptibility to infection-induced cell death, thereby weakening early antiviral responses to influenza A virus (IAV). Importantly, pharmacological inhibition of mitoROS restores AM function and improves host resistance to IAV infection in diabetic mice, highlighting a potential therapeutic target. Consistent with these experimental findings, analysis of colonic biopsies from diabetic patients revealed positive correlations between HbA1c levels, the abundance of mucosa-associated Gram-negative bacteria, and LPS concentrations, supporting the clinical relevance of this pathway. Furthermore, transfer of mucosal microbiota from diabetic patients into germ-free mice recapitulated AM dysfunction and increased susceptibility to IAV infection in a Toll-like receptor 4 (TLR4)-dependent manner. Collectively, these findings establish a mechanistic link between diabetes- associated gut dysbiosis, mitochondrial dysfunction in AMs, and impaired antiviral immunity. Targeting microbiota-derived signals or mitochondrial stress pathways may represent promising strategies to reduce the burden of respiratory viral infections in individuals with diabetes.
