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The gut microbiome is essential for maintaining organismal health. Gut microbiota may be disrupted through external factors like dietary change, which can lead to gut inflammation, resulting in obesity. Hibernating mammals develop low-grade gut inflammation when they accumulate fat deposits in preparation for hibernation, making them useful models for studying the relationship between the microbiome, inflammation, and weight gain. Nonsteroidal anti-inflammatory drugs and steroids are commonly used in humans to target gut inflammation, but how these drugs affect the gut microbiome and its stability is unclear. We investigated the effect of the glucocorticoid drug budesonide on the gut microbiome and cytokine levels of an obligate hibernator, the 13-lined ground squirrel, during the fattening season. We used 16S rRNA gene sequencing to characterize bacterial communities in the lumen and mucosa of the cecum and colon and measured proinflammatory [tumor necrosis factor-α (TNF-α)/interleukin 6 (IL-6)] and anti-inflammatory (IL-10) cytokine levels. Budesonide affected the microbiome only in the cecum lumen, where bacterial diversity was higher in the control group, and communities significantly differed between treatments. Across gut sections, Marvinbryantia and Enterococcus were significantly higher in the budesonide group, whereas Sarcina was higher in the control group. TNF-α and IL-6 levels were higher in control squirrels compared with the budesonide group, but there was no difference in IL-10 levels. Overall, budesonide treatment affected the microbial community and diversity of 13-lined ground squirrels in the cecum lumen. Our study presents another step toward developing ground squirrels as a model for studying the interaction between the microbiota and host inflammation. NEW & NOTEWORTHY Disruptions of gut microbiota can lead to inflammation, resulting in weight gain. Inflammation can be treated with budesonide, but how budesonide affects gut microbiota is unclear. Thirteen-lined ground squirrels experience low-grade gut inflammation during prehibernation fattening, which compares with human inflammation-weight gain mechanisms. We showed that budesonide treatment decreased microbiome diversity and lead to a shift in community in the cecum lumen. Our study supports developing ground squirrels as a model for studying microbiome-inflammation interactions.

The active season of hibernators corresponds to rapid adiposity in preparation for the next hibernation season. We have previously shown that this dramatic increase in adipose mass is associated with metabolic inflammation similar to what is seen in obesity and metabolic disease. We next sought to determine whether curbing this inflammation at its source (i.e., the gut) would attenuate weight gain in fattening 13-lined ground squirrels ( Ictidomys tridecemlineatus ). We fed active yearling ground squirrels a diet containing the gut-specific nonsteroidal anti-inflammatory drug mesalazine (5-aminosalicylic acid) for 10 wk. Mesalazine treatment had slight effects on microbial community diversity in the cecum and colon. Not surprisingly, mesalazine treatment decreased inflammatory cytokine levels in the ileum and colon. Mesalazine also decreased proinflammatory and increased anti-inflammatory cytokines in omental white adipose tissue (oWAT). Despite this, body mass was unaffected, and caloric intake increased in mesalazine-treated squirrels, mainly in males. Mass of the primary WAT depot, intra-abdominal WAT (iaWAT), or the highly metabolic oWAT were unaltered by treatment, as was adiposity index. Together, these results suggest that mesalazine treatment has some effects on adiposity in fattening ground squirrels, but this treatment needs to be modified to overcome the strong drive to fatten in this species. NEW & NOTEWORTHY Adiposity and obesity are caused, at least in part, by inflammation of metabolic tissues. Hibernators, like ground squirrels, undergo this same metabolic inflammation during their summer fattening period. We attempted to curb this inflammation, and thus fattening, using mesalazine. We found that mesalazine did curb the inflammation but did not affect fattening, likely due to the strong drive to fatten in hibernators.