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Syringaresinol delays immunosenescence in aged mice: rejuvenating the immune system and reconstituting the gut microbiota

ABSTRACT: Improving immune function during aging contributes to the extension of healthspan. However, little is known about interventions for overcoming immunosenescence. Here, we investigated whether syringaresinol (SYR), an activator of FOXO3, overcomes immunosenescence and the factors associated with this effect. To address this, we administered SYR to 42-week-old mice for 10 weeks and analyzed immunological parameters and the gut microbiota. Compared to control mice, SYR-treated mice exhibited reversal of the age-related changes in lymphocyte subsets—such as CD3+ T, CD19+ B and Foxp3+ regulatory T (Treg) cells—and T-cell function in vitro. SYR induced the expression of Bim as well as the activation of FOXO3 in Tregs, which probably regulated Treg homeostasis. Furthermore, SYR reduced the serum level of lipopolysaccharide-binding protein, an inflammatory marker, and enriched the gut microbiota with beneficial bacteria, Lactobacillus and Bifidobacterium, effects that were closely associated with the changes in lymphocyte subsets. Finally, SYR enhanced humoral immunity against influenza vaccination to the level of young control mice. Collectively, these findings indicate that SYR may rejuvenate immunosenescence by enhancing the immune response and modulating the gut microbiota, possibly affecting systemic inflammation, although the precise mechanism awaits further study, and suggest SYR to be a potent candidate for anti-immunosenescence intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE75825 | GEO | 2017/02/08

SECONDARY ACCESSION(S): PRJNA305478

REPOSITORIES: GEO

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Project description:Chronic diseases arise when pathophysiological processes achieve a steady state by self-reinforcing. Here, we explored the possibility of a self-reinforcement state in a common condition, chronic constipation, where alterations of the gut microbiota have been reported. The functional impact of the microbiota shifts on host physiology remains unclear, however we hypothesized that microbial communities adapted to slow gastrointestinal transit affect host functions in a way that reinforces altered transit, thereby maintaining the advantage for microbial self-selection. To test this, we examined the impact of pharmacologically (loperamide)-induced constipation (PIC) on the structural and functional profile of altered gut microbiota. PIC promoted changes in the gut microbiome, characterized by decreased representation of butyrate-producing Clostridiales, decreased cecal butyrate concentration and altered metabolic profiles of gut microbiota. PIC-associated gut microbiota also impacted colonic gene expression, suggesting this might be a basis for decreased gastrointestinal (GI) motor function. Introduction of PIC-associated cecal microbiota into germ-free (GF) mice significantly decreased GI transit time. Our findings therefore support the concept that chronic diseases like constipation are caused by disease-associated steady states, in this case, caused by reciprocating reinforcement of pathophysiological factors in host-microbe interactions. We used microarrays to detail the global gene expression profile in the proximal colon smooth muscle tissues of germ-free, conventionalized, or specific pathogen free mouse C57Bl/6 female and male specific pathogen free (SPF) mice were bred and housed in the animal care facility at the University of Chicago. Mice of 8–10 weeks of age were treated with 0.1% loperamide in the drinking water for 7 days. Age matched, germ-free (GF) C57Bl/6 mice were gavaged orally with cecal luminal contents harvested from control or loperamide-treated C57Bl/6 donor mice. Recipient mice were sacrificed 4 weeks post-colonization.

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Syringaresinol delays immunosenescence in aged mice: rejuvenating the immune system and reconstituting the gut microbiota

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