Abstract
We recently hypothesized that the intestinal microbiota and the innate immune system play key roles in the mechanism of Kilham Rat Virus-induced type 1 diabetes in the LEW1.WR1 rat. We used this animal model to test the hypothesis that maternal therapy with short-chain fatty acids can modulate the intestinal microbiota and reverse virus-induced proinflammatory responses and type 1 diabetes in rat offspring. We observed that administration of short-chain fatty acids to rat breeders via drinking water prior to pregnancy and further treatment of the offspring with short-chain fatty acids after weaning led to disease amelioration. In contrast, rats that were administered short-chain fatty acids beginning at weaning were not protected from type 1 diabetes. Short-chain fatty acid therapy exerted a profound effect on the intestinal microbiome in the offspring reflected by a reduction and an increase in the abundances of Firmicutes and Bacteroidetes taxa, respectively, on day 5 post-infection, and reversed virus-induced alterations in certain bacterial taxa. Principal component analysis and permutation multivariate analysis of variance tests further revealed that short-chain fatty acids induce a distinct intestinal microbiota compared with uninfected animals or rats that receive the virus only. Short-chain fatty acids downregulated Kilham Rat Virus-induced proinflammatory responses in the intestine. Finally, short-chain fatty acids altered the B and T cell compartments in Peyer’s patches. These data demonstrate that short-chain fatty acids can reshape the intestinal microbiota and prevent virus-induced islet autoimmunity and may therefore represent a useful therapeutic strategy for disease prevention.
Highlights
The intestinal microbiota is critical for gut development, metabolism, and normal immune function
We found that Short-chain fatty acids (SCFAs) therapy that commences prenatally but not after weaning can alter the intestinal microbiota and virus-induced intestinal immunity and ameliorate diabetes in LEW1.WR1 offspring
We tested the hypothesis that SCFA therapy that commences prenatally can ameliorate type 1 diabetes (T1D)
Summary
The intestinal microbiota is critical for gut development, metabolism, and normal immune function (reviewed in refs. [1, 2]). It is hypothesized that the dietary intake in developed nations has shifted to a high-fat, high carbohydrate, low-fiber diet that may have resulted in functional changes in the intestinal microbiota [12,13,14,15]. Such dietinduced alterations to gut bacterial communities are postulated to play a key role in the rising incidence of proinflammatory disorders in the developed world, including obesity, inflammatory bowel disease, and T1D [16]. Short-chain fatty acids (SCFAs) produced by the fermentation of indigestible dietary plant fiber by the intestinal microbiota (reviewed in refs. [17, 18]) can enter the circulation and regulate innate and adaptive immunity [19]
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