Valdés-Mas Rafael, Leshem Avner, Zheng Danping, Cohen Yotam, Kern Lara, Zmora Niv, He Yiming, Katina Corine, Eliyahu-Miller Shimrit, Yosef-Hevroni Tal, Richman Liron, Raykhel Barbara, Allswang Shira, Better Reut, Shmueli Merav, Saftien Aurelia, Cullin Nyssa, Slamovitz Fernando, Ciocan Dragos, Ouyang Kyanna S, Mor Uria, Dori-Bachash Mally, Molina Shahar, Levin Yishai, Atarashi Koji, Jona Ghil, Puschhof Jens, Harmelin Alon, Stettner Noa, Chen Minhu, Suez Jotham, Honda Kenya, Lieb Wolfgang, Bang Corinna, Kori Michal, Maharshak Nitsan, Merbl Yifat, Shibolet Oren, Halpern Zamir, Shouval Dror S, Shamir Raanan, Franke Andre, Abdeen Suhaib K, Shapiro Hagit, Savidor Alon, Elinav Eran
Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Cell. 2025 Feb 20;188(4):1062-1083.e36. doi: 10.1016/j.cell.2024.12.016. Epub 2025 Jan 20.
Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a "compositional dysbiosis" and a concomitant species-specific "functional dysbiosis" driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.
宿主-微生物组-饮食相互作用在调节人类健康方面发挥着关键作用，但其直接功能评估仍具有挑战性。我们在小鼠和人类中采用了宏基因组学指导的宏蛋白质组学（MIM），以在共生菌和病原体定植、营养改变以及抗生素诱导的扰动过程中，非侵入性地探索物种水平的微生物组-宿主相互作用。同时，粪便MIM准确地描绘了多种临床和饮食背景下的营养暴露情况。在小鼠自身炎症和人类炎症性肠病（IBD）中实施MIM，发现了一种“组成性失调”以及由共生菌对炎症宿主信号的反应受抑制所驱动的伴随物种特异性“功能失调”。微生物组转移揭示了这些宿主-共生菌交叉反应模式的早期动力学，而预测分析确定了优于S100A8/S100A9（钙卫蛋白）的候选粪便宿主-微生物组IBD生物标志物蛋白对。重要的是，同时进行的粪便营养MIM评估能够确定IBD相关的消费模式、饮食治疗依从性以及小肠消化异常。总体而言，并行的饮食-细菌-宿主MIM评估从功能上揭示了塑造胃肠道生态的跨王国相互作用组，同时为微生物组相关疾病提供个性化的诊断和治疗见解。
