Anti-inflammatory drug and prebiotics alter metabolic inflammation in fattening ground squirrels and outbred mice.

Metabolic inflammation is an inflammation event that occurs during fattening driven by diet-induced changes to the microbiota leading to increased permeability of the gut barrier and infiltration of bacterial products. This triggers inflammation in the gut and distant tissues (i.e., white adipose [WAT]). We have previously shown that 13-lined ground squirrels (Ictidomys tridecemlineatus), obligate hibernators, develop metabolic inflammation during their fattening season and that this inflammation can be attenuated by the gut-specific anti-inflammatory drug mesalazine. Here, we manipulated the gut immune system of ground squirrels and diversity outbred (DO) mice with mesalazine, affected the microbiota with prebiotics, or combined both together. Mesalazine, prebiotics or both were provided through the diet to squirrels starting 48 hr after emergence from hibernation, and to DO mice after receipt of a gut microbiota transplant from ground squirrels at the same timepoint. Squirrels and mice stayed on their assigned treatment for up to 8 weeks, with tissues collected from a subset of animals after 4 and 8 weeks of treatment. We examined body mass, adiposity, glucose tolerance, and cytokines as markers of metabolic inflammation, hypothesizing that the combination of mesalazine and prebiotics would have the greatest effect. Body weight increased over time in all groups, whereas energy intake remained steady for mice and increased for squirrels. Adipocyte diameter increased in mesalazine/prebiotic treated squirrels over time. Glucose tolerance fluctuated over time and treatment in ground squirrels and mice, but prebiotic-treated animals tended to remain steady. In ground squirrel ileum, anti-inflammatory interleukin (IL)-10 increased over time and proinflammatory tumor necrosis factor (TNF)-α decreased in mesalazine-treated animals. Proinflammatory IL-6 increased over time in the prebiotic treatment ground squirrels. In DO mice, IL-10 was highest in animals receiving prebiotics, with or without mesalazine. In the colon of squirrels, prebiotics decreased TNF-α and increased IL-10 levels. A similar decrease in TNF-α was seen in prebiotic-treated mice. Omental WAT cytokines did not change in any of the animals or treatments. Together, our results indicate that prebiotics and mesalazine have separate effects on metabolic inflammation, and that their additive effect is not as strong as expected.