Diet leaves a genetic signature in a keystone member of the gut microbiota. Dapa et al.

Dietary switch from a low-fat and high-fiber diet to a Western-style high-fat and high-sugar diet is a common cause of microbiota imbalances underlying a variety of pathological conditions (i.e. dysbiosis). Although the effects of such dietary changes on microbiota composition and functions are well documented, their putative impact in gut bacterial evolution remains unexplored. We reasoned that the microbiota-dependent functional consequences observed in diet-induced dysbiosis could be caused not only by changes in microbiota composition and in gene/metabolic regulation, but also by evolutionary changes, via the emergence of de novo mutations, which can lead to intra-species changes. To address this hypothesis, we determined the effects of diet on mutational changes in genes at the single species level by monitoring evolutionary adaptation to the gut of mice undergoing different dietary regimens. We focused on Bacteroides thetaiotaomicron (hereafter referred as B. theta) due to its predominance in the mammalian gut. B. theta is a strict anaerobe, and is among the fiber degrading Bacteroides that in the absence of dietary plant polysaccharides can consume host glycans. This bacterium shows phenotypic plasticity by gene and metabolic regulatory mechanisms, which enable it to prioritize usage of carbon sources, and to consume host glycans only in the absence of dietary complex polysaccharides. By following the evolutionary dynamics of B. theta over a 3-month timescale, we observe genetic signatures resulting from diet-specific evolution, fluctuating rapidly as the diet consumed by the mice alternates from high in fat and sugar and low in fiber (Western-style Diet (WD)) to standard high-fiber chow diet (Standard Diet (SD)). Periodic changes in diet led to fluctuations in the frequency of such mutations and were associated with metabolic shifts, resulting in the maintenance of higher intra-species genetic diversity compared to constant dietary regimens. We show that adaptation under WD specifically favors the emergence of mutations advantageous in consumption of mucin O-glycans. This supports the hypothesis that intra-species evolution can influence the microbiota-dependent phenotypes observed upon dietary changes. Finally, through an integrative multi-omic analysis, combining metabolomic and microbiota profiling with the B. theta mutational profile, we show that intra-species mutational diversity is a powerful biomarker of dietary differences between individuals.

从低脂高纤维饮食转变为西式高脂高糖饮食，是引发微生物群失衡的常见诱因，而这类失衡正是多种病理状态的核心基础（即菌群失调（dysbiosis））。尽管这类饮食改变对微生物群组成与功能的影响已有大量研究记载，但其对肠道细菌演化的潜在影响仍未得到探索。我们推测，饮食诱导菌群失调过程中所观察到的微生物群依赖性功能改变，其成因不仅包括微生物群组成及基因/代谢调控的变化，还可能涉及通过新发突变（de novo mutations）产生的演化改变——这类突变可引发种内变异。为验证这一假说，我们通过监测不同饮食方案下小鼠肠道内的演化适应过程，在单物种层面解析了饮食对基因突变的调控效应。我们选取多形拟杆菌（Bacteroides thetaiotaomicron，后文简称B. theta）作为研究对象，因其在哺乳动物肠道中占据优势地位。B. theta为专性厌氧菌，属于可降解膳食纤维的拟杆菌属成员，在膳食植物多糖缺乏时可利用宿主糖蛋白聚糖（host glycans）。该细菌通过基因与代谢调控机制展现出表型可塑性，可优先利用碳源，且仅在膳食复合多糖缺乏时才会消耗宿主糖蛋白聚糖。通过追踪3个月周期内B. theta的演化动态，我们观察到饮食特异性演化所产生的遗传特征——当小鼠饮食从高脂高糖低纤维的西式饮食（Western-style Diet, WD）切换为标准高纤维饲料饮食（Standard Diet, SD）时，这类遗传特征会快速波动。周期性饮食改变会导致这类突变的频率发生波动，并伴随代谢组的改变，相较于固定饮食方案，该过程可维持更高水平的种内遗传多样性。我们发现，西式饮食环境下的适应过程会特异性地促进利于黏蛋白O-聚糖（mucin O-glycans）利用的突变产生。这一结果验证了我们的假说：种内演化可影响饮食改变后所观察到的微生物群依赖性功能表型。最后，我们通过整合多组学（multi-omic）分析——将代谢组学（metabolomic）谱分析、微生物群谱分析与B. theta突变谱相结合——证实种内突变多样性可作为个体间饮食差异的高效生物标志物（biomarker）。