Jan Alan, Bayle Perrine, Mohellibi Nacer, Lemoine Clara, Pepke Frédéric, Béguet-Crespel Fabienne, Jouanin Isabelle, Tremblay-Franco Marie, Laroche Béatrice, Serror Pascale, Rigottier-Gois Lionel
Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, F-78350, France.
Toxalim - Research Centre in Food Toxicology, INRAE, ENVT, INP-Purpan, Toulouse University, UT3, Toulouse, F-31300, France.
Microbiome. 2025 May 26;13(1):129. doi: 10.1186/s40168-025-02127-5.
Vancomycin-resistant enterococci (VRE) often originate from the gastrointestinal tract, where their proliferation precedes dissemination into the bloodstream, and can lead to systemic infection. Uncovering the actors and mechanisms reducing the intestinal colonisation by VRE is essential to control infection. We aimed to identify commensal bacteria that interfere with VRE gut colonisation or act as an ecological barrier.
We performed a 3-week longitudinal analysis of the gut microbiota composition and VRE carriage levels during microbiota recovery in mice colonised with VRE after antibiotic-induced dysbiosis. By combining biological data and mathematical modelling, we identified 15 molecular species (OTUs) that negatively correlated with VRE overgrowth. Six strains representative of these OTUs were collected, cultivated and used in mixture with a seventh strain (Mix7) in two different mouse lines challenged with VRE. Of the seven strains, three belonged to Lachnospiraceae, one to Muribaculaceae, one to Ruminococcaceae and two to Lactobacillaceae. We found that Mix7 led to a better recovery of the gut microbiota composition and reduced VRE carriage. Differences in the effect of Mix7 were observed between responder and non-responder mice. These differences were associated with variations in the composition of the initial microbiota and during recovery and represent potential biomarkers for predicting response to Mix7. In a mouse model of alternative stable state of dysbiosis, response to Mix7 was associated with higher concentrations of short-chain fatty acids (acetate, propionate, butyrate) and a range of metabolites including bile acids, reflecting the recovery of the microbiota back to initial state. Furthermore, Muribaculum intestinale strain was required to obtain the Mix7 effect on VRE reduction in vivo, but the presence of at least one of the other six strains was needed. None of the supernatant of the seven strains, alone or in combination, inhibited VRE growth in vitro. Interestingly, five strains belong to species shared among humans and mice, and the other two have human functional equivalents.
An innovative approach based on mathematical modelling of the microbiota composition permitted to identify a mixture of commensal bacterial strains, which improves the ecological barrier effect against VRE. The mechanisms are dependent on the recovery and initial composition of the microbiota. Ultimately, this work will enable a move towards a personalised medicine by targeting predisposed patients presenting a risk of infection, such as neutropenic or bone-marrow transplant patients, and likely to respond to supplementation with commensal strains, providing new live biotherapeutic products and biomarkers to predict response to supplementation. Video Abstract.
耐万古霉素肠球菌（VRE）通常源自胃肠道，在其扩散至血液之前先在胃肠道中增殖，并可导致全身感染。揭示减少VRE肠道定植的因素和机制对于控制感染至关重要。我们旨在鉴定干扰VRE肠道定植或作为生态屏障的共生细菌。
我们对抗生素诱导的生态失调后定植VRE的小鼠在微生物群恢复期间的肠道微生物群组成和VRE携带水平进行了为期3周的纵向分析。通过结合生物学数据和数学模型，我们鉴定出15个与VRE过度生长呈负相关的分子分类单元（OTU）。收集了代表这些OTU的6株菌株，进行培养，并与第7株菌株（Mix7）混合，用于对两种不同的感染VRE的小鼠品系进行实验。这7株菌株中，3株属于毛螺菌科，1株属于肠道杆菌科，1株属于瘤胃球菌科，2株属于乳杆菌科。我们发现Mix7能使肠道微生物群组成更好地恢复，并降低VRE携带量。在反应者和无反应者小鼠之间观察到Mix7效果的差异。这些差异与初始微生物群组成以及恢复过程中的变化有关，并且代表了预测对Mix7反应的潜在生物标志物。在生态失调的替代稳定状态小鼠模型中，对Mix7的反应与较高浓度的短链脂肪酸（乙酸盐、丙酸盐、丁酸盐）以及一系列代谢产物（包括胆汁酸）有关，这反映了微生物群恢复到初始状态。此外，在体内获得Mix7对VRE减少的效果需要肠道杆菌菌株的存在，但也需要其他6株菌株中至少有1株存在。这7株菌株的上清液单独或组合使用时，均未在体外抑制VRE生长。有趣的是，5株菌株属于人和小鼠共有的物种，另外2株在人类中有功能等同物。
基于微生物群组成数学模型的创新方法能够鉴定出一种共生细菌菌株混合物，其可改善针对VRE的生态屏障效应。其机制取决于微生物群的恢复情况和初始组成。最终，这项工作将通过针对有感染风险的易感患者（如中性粒细胞减少或骨髓移植患者），并可能对补充共生菌株有反应，从而迈向个性化医疗，提供新的活生物治疗产品和预测补充反应的生物标志物。视频摘要。
