Seasonal influenza represents a contagious family of respiratory viruses that infect 5–30% of the global population yearly and account for as many as 500,000 deaths annually. Flu infection is characterized by symptoms such as fever, cough, sore throat, runny nose, body aches, and fatigue. Interestingly, some people also develop diarrhea, even though the virus tropism is for respiratory tissue. Despite being a well-studied viral infection, the underlying mechanisms involved in the development of gastroenteritis-like syndrome with flu infection are poorly understood.
Now, Wang et al. have used a mouse model to show that influenza infection not only causes lung inflammation but also causes intestinal inflammation, even though influenza virus was not detectable in the gastrointestinal tract. They showed that during intranasal flu infection, CCR9+CD4+ T cells migrate from the lung into the intestinal mucosa in a CCL25/CCR9-dependent manner and alter the composition of the gut microbiota by secreting IFN-γ. Homeostasis of the intestinal microbiota was altered, and increased numbers of Escherichia coli were detected after flu infection. Antibiotic treatment of intranasal flu-infected mice protected them against infection-induced diarrhea. These data suggest that the dysbiosis generated after flu infection leads to intestinal injury. The changes generated in the gut microbiota induced the production of IL-15 by intestinal epithelial cells. IL-15 induced the expansion of Th17 cells in the small intestine, which then mediated intestinal immune injury.
It is noteworthy that not all flu-infected patients develop gastroenteritis-like symptoms. Why is this? One possibility could be that the migration of pathogenic cells into the intestine depends on the severity of the infection. Consequently only highly infected patients may get diarrhea. Alternatively, the specific microbial landscape in some individuals and the existence of regulatory bacteria, could obstruct the growth of E. coli or promote regulatory T cells which in turn can control intestinal inflammation.
The data presented in this paper corroborate the hypothesis that the intestine is a suitable place to defuse an immune response. The abundance of antiinflammatory cytokines, such as IL-10 and TGF-β, regulatory cells and continuous regeneration of the tissue predispose the intestine with an ability to control effector cells. Moreover, if effector T cells escape all possible regulatory mechanisms, diverting them to the lumen—in essence flushing them away—could still be less dangerous than allowing them to remain in situ and risking lung tissue damage.