Sunday, May 18, 2025
5/18/2025
Microbiota and Inflammation in Adiposity: The Ground Squirrel Model - During development of obesity, an altered diet leads to changes in the gut microbiota, including decreased diversity and shifts in relative abundance of certain phyla. This leads to a pro-inflammatory gut environment, inflammation in distant tissues (i.e., adipose), accumulation of fat and eventually insulin resistance (IR). Current rodent models of fat accumulation focus on one etiological cause and use in-bred laboratory strains; however, translation of these studies to human medicine has been limited, presumably because a) humans are a heterogeneous outbred population with a more variable microbiota than laboratory rodents, and b) the development of obesity and IR results from a combination of dietary, metabolic and genetic factors. Hibernating mammals like 13-lined ground squirrels (Ictidomys tridecemlineatus) naturally increase adiposity each year during a “pre-hibernation fattening phase”. We have previously shown that this increased adiposity is accompanied by inflammation of metabolic tissues. Results of our current award show that cecal microbiota transfer from lean squirrels or supplementation with Akkermansia muciniphila ameliorated some inflammation in fattening ground squirrels. Treatment with the gut-specific anti-inflammatory drug mesalazine significantly suppressed inflammation in gut and adipose tissues and increased caloric intake without affecting body mass. The experiments outlined in this proposal take the next step by using gut microbiota transfer (GMT) to reaffirm the obesogenic role of the microbiota in ground squirrels by using GMT to transfer the phenotype to mice. We will then test prebiotic (to increase microbiota diversity) and mesalazine treatments in mice and ground squirrels to assess whether manipulating the microbiota and immune system together can curb adiposity and the development of IR. The hypotheses for this investigation are that 1) changes in the gut microbiome and immune system of squirrels soon after emergence from hibernation encourage adiposity in non- hibernators and 2) boosting gut microbial diversity with a diet containing prebiotics in conjunction with mesalazine treatment will ameliorate fat accumulation, metabolic inflammation and IR more effectively than either treatment alone. The proposed experimental approach uses GMT from fattening ground squirrels into outbred mouse strains to elucidate the obesogenic properties of the squirrel microbiota. By using GMT of samples collected at different points post-hibernation, Specific Aim 1 will identify the point at which the ground squirrel’s microbiota harvest the most energy from the diet. In Specific Aim 2 we will treat fattening ground squirrels and outbred mice after GMT with prebiotics, mesalazine or both together to evaluate the cumulative effect of promoting microbiota diversity and curbing inflammation on adiposity. Our experiments promise to further clarify the role of the gut microbiota and immune system in the accumulation of fat and development of IR in hibernating and non-hibernating species, ultimately contributing to our overall knowledge of how fat accumulation and IR are induced.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).