Respiratory Viral Infection Alters the Gut Microbiota by Inducing Inappetence

Abstract

Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined. IMPORTANCE The gut microbiota has an important role in health and disease: gut bacteria can generate metabolites that alter the function of immune cells systemically. Understanding the factors that can lead to changes in the gut microbiome may help to inform therapeutic interventions. This is the first study to systematically dissect the pathway of events from viral lung infection to changes in gut microbiota. We show that the cellular immune response to viral lung infection induces inappetence, which in turn alters the gut microbiome and metabolome. Strikingly, there was an increase in lipids that have been associated with the resolution of disease. This opens up new paths of investigation: first, what is the (presumably secreted) factor made by the T cells that can induce inappetence? Second, is inappetence an adaptation that accelerates recovery from infection, and if so, does the microbiome play a role in this?

Interferon-Induced Protein 44 and Interferon-Induced Protein 44-Like Restrict Replication of Respiratory Syncytial Virus

“…Decreased production of this key cytokine along with increased viral replication, due to changes in cellular proliferation and metabolism driven by the loss of IFI44, may go some way to explaining these observations. We saw no change in tumor necrosis factor (TNF) but an increase in CD8 cells; this reflects our recent findings that TNF is associated with early weight loss after RSV infection but not later time points, whereas CD8 cells are associated with reduced food intake leading to weight loss (27).…”

The wastewater microbiome: A novel insight for COVID-19 surveillance

“…Notably, opportunistic pathogens from the Bacteroides genera showed high modulation during the study, and some species positively correlated with the SARS-CoV-2 levels. This evidence can be connected with a recent study where the sphingosine gene expression was signi cantly correlated with increased Bacteroides in patients with acute respiratory viral infections 28 and gastrointestinal in ammation disorders 30 .…”

“…Studies connecting the microbiota with distal organs in regulatory functions such as gut-lung axis have revealed a key role in the respiratory system 27 . It has been reported that respiratory viral infections alter the gut microbiota, modulating the antiviral immune response through TNF-and CD8 + cells 28 . For example, gastric disorders during respiratory syncytial virus (RSV) or in uenza virus infection in mice resulted in signi cantly altered gut microbiota diversity, increased Bacteroidetes, and a concomitant decrease in Firmicutes phyla abundance.…”

Probiotics in Treatment of Viral Respiratory Infections and Neuroinflammatory Disorders

“…It has been suggested that novel coronavirus infects intestinal epithelial cells via ACE2 receptors and transmembrane protease serine and induces proinflammatory chemokines and cytokines production, which leads to acute intestinal inflammation [52,53]. Furthermore, some reports indicate gastrointestinal symptoms such as diarrhea, as well as detection of SARS-Cov2 RNA in fecal samples of some patients affected by COVID-19 [50,54]. On the other hand, the gut microbial imbalance is associated with acute respiratory distress syndrome (ARDS) [50,55], and COVID-19 may progress to the acute ARDS [56].…”