A holistic study of the effect of the murine microbiome on metabolism and systemic inflammation using integrated molecular imaging technologies

关键词：分子成像微生物组炎症摘要：肠道微生物组对宿主健康、营养和药物代谢和吸收至关重要。许多研究都强调了微生物组的积极作用，但很明显，肠道微生物和免疫系统之间的相互作用可以调节代谢，诱导和加剧炎症病理。肠胃炎或抗生素治疗等损伤引发肠道微生物组组成紊乱，可导致针对特定微生物抗原的免疫反应，但也会攻击宿主肠道组织。许多疾病中全身性炎症背后的机制仍有待发现，但肠道的核心作用和肠道菌群控制后症状的显著缓解表明，肠道菌群在疾病中发挥了重要作用。了解这种关系可能有助于对一系列动物疾病进行干预，这些疾病与人类疾病相似，肠道微生物组的作用远远超出了肠道。我们最近应用质谱成像（MSI）方法来研究肠道微生物组与宿主生理之间的联系，确定肠道中产生的微生物产物并与宿主组织系统相互作用。这些方法有可能揭示肠道微生物群和宿主免疫系统之间通讯的分子基础。事实上，我们最近采用这种方法的工作是第一次描述原核生物和哺乳动物大脑之间直接的分子间通讯，导致脑细胞功能的抑制。这种方法使我们能够做一些其他人无法做到的事情，将一种机制功能归因于新发现的肠道微生物组产品。在平行合作中，再次使用MSI，我们也证明了我们可以同时检测一系列治疗药物在绒毛轴上的吸收谱。我们的成像细胞计数（IMC）能力（小鼠特异性面板，允许>40-plex免疫组织化学），我们可以首次将代谢与细胞表型，途径分析和功能联系起来。这将使我们能够研究微生物组与炎症之间的相互作用以及对健康代谢生理的影响。结合起来，这三个研究流现在使我们处于一个独特的位置，以无与伦比的分辨率研究微生物组对代谢和全身炎症的影响。

Studentship strategic priority area: Basic Bioscience Underpinning HeathKeywords: Molecular Imaging Microbiome Inflammation Abstract: The gut microbiome is essential to host health, nutritional and pharmaceutical metabolism and absorption. Numerous studies have highlighted the positive role of the microbiome but it is clear that the interaction between gut microbes and the immune system can contribute to modulation of metabolism and induction and exacerbation of inflammatory pathologies. Perturbation in gut microbiome composition, triggered by insults such as gastroenteritis or antibiotic treatment, can result in an immune response that may be targeted at specific microbial antigens but which also attacks host gut tissues. The mechanisms behind systemic inflammation in many diseases remain to be discovered but the central role of the intestine and the significant remission in symptoms post-manipulation of the intestinal microbiota point towards a significant gut microbiota input into disease. Understanding this relationship may allow intervention across a range of animal diseases, where similar to human disease, the gut microbiome exerts effects far beyond the intestine. We have recently applied mass spectrometry imaging (MSI) approaches to investigate links between the gut microbiome and host physiology, identifying microbial products that are produced in the gut and that interact with host tissues systemically. These approaches have the potential to reveal the molecular basis of the communication between the gut microbiota and the host immune system. Indeed our recent work employing this approach is the first to describe direct molecular inter-kingdom communication between prokaryotes and the mammalian brain leading to inhibition of brain cell function. This approach has enabled us to do something others cannot, ascribe a mechanistic function to newly identified products from the gut microbiome. In a parallel collaboration, again using MSI, we have also demonstrated that we can detect the absorption profile of a range of therapeutics, simultaneously, across the villi axis. With our imaging mass cytometry (IMC) capability, (murine specific panel allowing >40-plex immunohistochemistry) we can for the first-time link metabolism with cell phenotyping, pathway analysis & function. This will allow us to study the interplay between microbiome and inflammation and the effect on healthy metabolism physiology. Combined, these three research streams have now put us in a unique position to study, in unparalleled resolution, the effect of the microbiome on metabolism and systemic inflammation.