Akkermansia muciniphila primes lung-resident antiviral immunity via the gut–lung axis during SARS-CoV-2 infection

Introduction The gut microbiota plays a central role in shaping systemic immunity and modulating the gut–lung axis, which is crucial during respiratory infections such as COVID-19. SARS-CoV-2 infection is known to disrupt the gut microbiome, but the downstream functional impacts on microbial metabolism and host immune responses remain insufficiently understood. Methods Using K18-hACE2 transgenic mice, researchers investigated the effects of SARS-CoV-2 variants (WA and Omicron) on the gut microbiome and host immunity. Microbial composition and functional profiles were assessed post-infection. To test the therapeutic potential of Akkermansia muciniphila ( A. muciniphila ), live bacteria were administered prophylactically, and various outcomes were evaluated, including weight loss, lung pathology, immune cell phenotypes, and cytokine production. Results In K18-hACE2 transgenic mice infected with SARS-CoV-2, there was a marked reduction in gut microbial diversity, accompanied by a consistent enrichment of A. muciniphila . This microbial shift was associated with functional disruptions in key metabolic pathways, particularly those involved in glycosaminoglycan degradation and lipid metabolism, suggesting a broader impact of infection on microbial functionality. Remarkably, prophylactic administration of live A. muciniphila prior to infection led to significant protective effects. Treated mice exhibited reduced weight loss and improved lung histopathology compared to untreated controls. Local antiviral immune responses in the lung were notably enhanced without triggering excessive systemic inflammation. Mice receiving A. muciniphila also demonstrated elevated production of Th2 and Th17 cytokines, robust expansion of tissue-resident memory T cells, and the formation of inducible bronchus-associated lymphoid tissue (iBALT)—all indicative of potentiated mucosal immunity. These findings highlight a functional role for A. muciniphila not only as a microbial signature of COVID-19-associated dysbiosis but also as an active modulator of host immune responses during respiratory viral infections. Discussion These findings position A. muciniphila as both a biomarker of COVID-19-related gut dysbiosis and a potent live biotherapeutic candidate for respiratory infections. Its ability to enhance mucosal immune responses through gut–lung axis modulation highlights its promise in prophylactic strategies against viral respiratory diseases, including SARS-CoV-2.