Influenza Virus Affects Intestinal Microbiota and Secondary Salmonella Infection in the Gut through Type I Interferons

Abstract

Human influenza viruses replicate almost exclusively in the respiratory tract, yet infected individuals may also develop gastrointestinal symptoms, such as vomiting and diarrhea. However, the molecular mechanisms remain incompletely defined. Using an influenza mouse model, we found that influenza pulmonary infection can significantly alter the intestinal microbiota profile through a mechanism dependent on type I interferons (IFN-Is). Notably, influenza-induced IFN-Is produced in the lungs promote the depletion of obligate anaerobic bacteria and the enrichment of Proteobacteria in the gut, leading to a “dysbiotic” microenvironment. Additionally, we provide evidence that IFN-Is induced in the lungs during influenza pulmonary infection inhibit the antimicrobial and inflammatory responses in the gut during Salmonella-induced colitis, further enhancing Salmonella intestinal colonization and systemic dissemination. Thus, our studies demonstrate a systemic role for IFN-Is in regulating the host immune response in the gut during Salmonella-induced colitis and in altering the intestinal microbial balance after influenza infection.

Author Summary

Influenza is a respiratory illness. Symptoms of flu include fever, headache, extreme tiredness, dry cough, sore throat, runny or stuffy nose, and muscle aches. Some people, especially children, can have additional gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. In humans, there is no evidence that the influenza virus replicates in the intestine. Using an influenza mouse model, we found that influenza infection alters the intestinal microbial community through a mechanism dependent on type I interferons induced in the pulmonary tract. Futhermore, we demonstrate that influenza-induced type I interferons increase the host susceptibility to Salmonella intestinal colonization and dissemination during secondary Salmonella-induced colitis through suppression of host intestinal immunity.