Department of Chemical and Bioprocess Engineering, School of Engineering, Pontificia Universidad Católica de Chile, Santiago, Chile.
Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
mSystems. 2022 Oct 26;7(5):e0064622. doi: 10.1128/msystems.00646-22. Epub 2022 Aug 25.
The gut microbiota is constituted by thousands of microbial interactions, some of which correspond to the exchange of metabolic by-products or cross-feeding. Inulin and xylan are two major dietary polysaccharides that are fermented by members of the human gut microbiota, resulting in different metabolic profiles. Here, we integrated community modeling and bidirectional culturing assays to study the metabolic interactions between two gut microbes, and Lachnoclostridium symbiosum, growing in inulin or xylan, and how they provide a protective effect in cultured cells. (previously belonging to the genus) was able to consume inulin and xylan, while only used certain inulin fractions to produce butyrate as a major end product. Constrained-based flux simulations of refined genome-scale metabolic models of both microbes predicted high lactate and succinate cross-feeding fluxes between and when growing in each fiber. Bidirectional culture assays in both substrates revealed that growth increased in the presence of . Carbohydrate consumption analyses showed a faster carbohydrate consumption in cocultures compared to monocultures. Lactate and succinate concentrations in bidirectional cocultures were lower than in monocultures, pointing to cross-feeding as initially suggested by the model. Butyrate concentrations were similar across all conditions. Finally, supernatants from both bacteria cultured in xylan in bioreactors significantly reduced tumor necrosis factor-α-induced inflammation in HT-29 cells and exerted a protective effect against the TcdB toxin in Caco-2 epithelial cells. Surprisingly, this effect was not observed in inulin cocultures. Overall, these results highlight the predictive value of metabolic models integrated with microbial culture assays for probing microbial interactions in the gut microbiota. They also provide an example of how metabolic exchange could lead to potential beneficial effects in the host. Microbial interactions represent the inner connections in the gut microbiome. By integrating mathematical modeling tools and microbial bidirectional culturing, we determined how two gut commensals engage in the exchange of cross-feeding metabolites, lactate and succinate, for increased growth in two fibers. These interactions underpinned butyrate production in cocultures, resulting in a significant reduction in cellular inflammation and protection against microbial toxins when applied to cellular models.
肠道微生物群由数千种微生物相互作用构成，其中一些对应于代谢产物的交换或交叉喂养。菊糖和木聚糖是两种主要的膳食纤维多糖，它们被人类肠道微生物群的成员发酵，产生不同的代谢谱。在这里，我们整合了群落建模和双向培养实验，研究了在菊糖或木聚糖中生长的两种肠道微生物 和 Lachnoclostridium symbiosum 之间的代谢相互作用，以及它们如何在培养细胞中提供保护作用。（以前属于 属）能够消耗菊糖和木聚糖，而 仅使用某些菊糖分数产生丁酸作为主要终产物。对两种微生物的精细化基因组规模代谢模型进行基于约束的通量模拟预测，当在每种纤维中生长时， 和 之间存在高乳酸和琥珀酸交叉喂养通量。在两种基质中的双向培养实验表明， 在 的存在下生长增加。碳水化合物消耗分析表明，共培养物中的碳水化合物消耗比单培养物更快。双向共培养物中的乳酸和琥珀酸浓度低于单培养物，这表明最初由模型提示的交叉喂养。所有条件下的丁酸盐浓度相似。最后，在生物反应器中从木聚糖中培养的两种细菌的上清液显著降低了 HT-29 细胞中肿瘤坏死因子-α诱导的炎症，并对 Caco-2 上皮细胞中的 TcdB 毒素发挥了保护作用。令人惊讶的是，在菊糖共培养物中没有观察到这种效果。总体而言，这些结果突出了代谢模型与微生物培养实验相结合，用于探测肠道微生物群中微生物相互作用的预测价值。它们还提供了一个例子，说明代谢交换如何导致宿主中的潜在有益效果。微生物相互作用代表了肠道微生物组的内部联系。通过整合数学建模工具和微生物双向培养，我们确定了两种肠道共生菌如何通过交换交叉喂养代谢物（乳酸和琥珀酸）来增加在两种纤维中的生长。这些相互作用支撑了共培养物中的丁酸盐产生，导致细胞炎症显著减少，并对细胞模型中的微生物毒素具有保护作用。
