Information regarding the possible or actual role of the gastrointestinal microbiome in the etiology and sequelae of a variety of diseases and syndromes in both human and nonhuman animals is now appearing almost daily in the scientific and popular media. Type 2 (“adult onset”) diabetes mellitus (T2DM) in humans is one such disease; there is mounting evidence that gastrointestinal dysbiosis is present in these individuals. Specifically, there are decreased numbers of bacteria producing butyrate, a short-chain fatty acid (SCFA), in T2DM patients compared to controls. The SCFAs: acetate, butyrate, and propionate, are produced through fermentation of complex polysaccharides by microbes in the large intestine; these substances help facilitate glucose and energy metabolism and support local immune function. Butyrate in particular supplies energy for the cells in the colonic mucosa, and may increase insulin sensitivity and energy expenditure. Decreased butyrate levels may be significantly associated with the development of insulin resistance.
Feline diabetes mellitus (FDM) is considered to be an animal model of human T2DM. As in their human counterparts, cats with FDM are middle-aged to elderly, frequently overweight to obese, and have impaired insulin secretion, peripheral insulin resistance, loss of beta islet cells, and development of amyloid deposits in the insulin-producing pancreatic islets. The current study involved genetic sequencing of 121 microbial DNA samples from feces of 82 privately owned cats from Denmark and Switzerland and consisted of two parts: (1) a cross-sectional study aimed at identifying differences between the gastrointestinal microbiomes of diabetic (group DM), healthy lean (LN; BCS 4-5/9), and healthy overweight/obese cats (OB; BCS 7-9/9), and (2) an interventional study to determine if changes could be made to the gastrointestinal microbiome of a subset of these cats by feeding a high-protein/low-carbohydrate commercial diet specifically formulated for feline diabetics.
After extraction from the fecal samples, the microbial DNA concentrations were estimated, then amplified multiple times by PCR. The fecal bacterial microbiota composition was determined by next-generation sequencing of 16S ribosomal RNA.
Of the 121 fecal samples, those from 62 of the cats (23 DM, 15 OB, and 24 LN) had sufficient nucleic acid reads to be included in a statistical analysis. Most of the cats were indoor only, although 4 DM, 2 LN, and 2 OB had limited outdoor access. All cats in the study were over 6 years of age, had not received any antibiotics within the four months previous to recruitment, and also had not received any probiotics or prebiotics within two weeks of inclusion.
All but one (newly diagnosed) of the DM cats were receiving insulin of some kind. In the genetic sequencing portion of the study, the DM cats were found to have a less diverse gastrointestinal microbiome than the LN or OB groups. Moreover, hemoglobin and packed cell volume correlated positively with the richness of the gastrointestinal microbiome, while serum bile acid levels, serum fructosamine, and serum glucose levels correlated negatively with gastrointestinal microbiome richness. Compared to the LN and OB cats, the DM cats had decreased proportions of Bacteroidetes, Bacteroida, Bacteroidales, Prevotellaceae, and Prevotella. Breed, sex, and age of the subjects were not found to influence the composition of the microbial communities.
Butyrate-producing bacterial genera were decreased in the DM group compared to the LN group. Numbers of Enterobacteriaceae family bacteria, which are associated with systemic low-grade inflammation, correlated positively with serum fructosamine levels, while Prevotellaceae family numbers correlated negatively with serum fructosamine levels. Some members of the Prevotellaceae are known to be associated with improved glucose tolerance in mice.
The reduced diversity of the gastrointestinal microbiome and a tendency to harbor more pro-inflammatory microbiota as well as substantial decreases in butyrate-producing bacteria observed in diabetic cats parallel findings in humans with T2DM. These changes were not found in the healthy OB group, so it is likely that body composition alone does not predispose to the development of FDM.
In the second, interventional portion of the study, a subset of the cats from Denmark only (10 DM, 11 LN, and 13 OB) were fed a commercial high-protein, low-carbohydrate dry diet (Royal Canin Diabetic Feline) for four weeks, and fecal samples were again collected for analysis of microbial genetic material. The dietary intervention did not improve the diversity or composition of the gastrointestinal microbiome in the DM cats compared to that in the LN or OB cats. Although the small sample size and relatively short length of treatment involved in this portion of the study could have contributed to the lack of significant change observed, it is possible that probiotic supplementation, including butyrate-producing bacteria, or fecal transplantation, could be important in the future treatment of diabetic cats. Another potential avenue of future research could be to evaluate the influence of a canned high-protein diet designed for diabetic cats on the gastrointestinal microbiome of these patients and healthy controls. [PJS]
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