Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses

Abstract

Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10–20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1α, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4 days post flu infection, while increases in Proteobacteria were evident at 7 days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.

Respiratory viral infection alters the gut microbiota by inducing inappetence

“…Other studies in mice have observed that respiratory virus infection is associated with a change in the gut microbiota, but none have proposed that infection-induced inappetence is the driver (Wang et al, 2014;Deriu et al, 2016;Bartley et al, 2017;Yildiz et al, 2018). Bartley et al (2017) observed that influenza infection drives the gut microbiota composition towards a profile similar to that of calorie restricted mice.…”

“…Other studies in mice have observed that respiratory virus infection is associated with a change in the gut microbiota, but none have proposed that infection-induced inappetence is the driver (Wang et al, 2014;Deriu et al, 2016;Bartley et al, 2017;Yildiz et al, 2018). Bartley et al (2017) observed that influenza infection drives the gut microbiota composition towards a profile similar to that of calorie restricted mice. Deriu et al (2016) did not observe any effect on gut microbiota composition when IFNAR -/mice were infected with influenza virus, despite the fact that the mice still lost weight after infection and that IFNAR -/mice are reported to experience more severe weight loss following respiratory viral infection (Goritzka et al, 2014).…”

“…However, several studies have demonstrated that respiratory infections are associated with a change in the composition of the gut microbiota (Wang et al, 2014;Deriu et al, 2016;Bartley et al, 2017;Groves et al, 2018;Hanada et al, 2018;Yildiz et al, 2018). We have previously observed that viral lung infections alter the gut microbiota, leading to an increase in the relative abundance of Bacteroidetes and a decrease in the relative abundance of Firmicutes (Groves et al, 2018).…”

Calorie restriction and its impact on gut microbial composition and global metabolism

“…Several studies found that the composition of the gut microbiota can be greatly changed by restricting dietary intake, without significant alterations in their α-diversity [21,[27][28][29]. CR studies showed that the gut microbiota exerts more prominent effects than some diseases, such as viral infection [30], or physical exercise [3]. However, some reports refute these observations [31][32][33], stating that the effect of CR on the microbiota is minimal.…”

Long-Term Blackcurrant Supplementation Modified Gut Microbiome Profiles in Mice in an Age-Dependent Manner: An Exploratory Study

“…It is now increasingly evident that young and aged hosts have different gut microbiome profiles [12][13][14]. Considering this age-related difference, BC supplementation may affect the gut microbiome of young and aged mice differently.…”