Maternal treatment with short-chain fatty acids modulates the intestinal microbiota and immunity and ameliorates type 1 diabetes in the offspring

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.

我们此前提出假说：肠道菌群（intestinal microbiota）与固有免疫系统（innate immune system）在LEW1.WR1大鼠感染基尔汉姆大鼠病毒（Kilham Rat Virus）诱发1型糖尿病的机制中发挥关键作用。我们利用该动物模型验证假说：母体接受短链脂肪酸（short-chain fatty acids）治疗可调控子代大鼠的肠道菌群，逆转病毒诱导的促炎反应（proinflammatory responses）与1型糖尿病。我们观察到，若在妊娠前通过饮水给种鼠施加短链脂肪酸，并在子代断奶后继续给予短链脂肪酸治疗，可实现疾病缓解。与之相反，仅从断奶阶段开始给予短链脂肪酸的大鼠并未获得1型糖尿病的保护。短链脂肪酸治疗对子代肠道微生物组（intestinal microbiome）产生了显著影响：感染后第5天时，厚壁菌门（Firmicutes）分类群的丰度降低，而拟杆菌门（Bacteroidetes）分类群的丰度升高，同时逆转了病毒诱导的部分细菌分类群丰度异常。主成分分析（Principal component analysis）与置换多元方差分析（permutation multivariate analysis of variance）进一步显示，与未感染动物或仅感染病毒的大鼠相比，短链脂肪酸处理可塑造独特的肠道菌群结构。短链脂肪酸可下调基尔汉姆大鼠病毒诱导的肠道促炎反应。最后，短链脂肪酸可改变派尔集合淋巴结（Peyer’s patches）内的B细胞与T细胞亚群分布。上述数据表明，短链脂肪酸可重塑肠道菌群，阻止病毒诱导的胰岛自身免疫（islet autoimmunity），因此或可成为预防该疾病的有效治疗手段。