ABSTRACT

Ruminococcus gnavus is a prevalent member of the human gut microbiota, which is over-represented in inflammatory bowel disease and neurological disorders. We previously showed that the ability of R. gnavus to forage on mucins is strain-dependent and associated with sialic acid metabolism. Here, we showed that mice monocolonized with R. gnavus ATCC 29149 (Rg-mice) display changes in major sialic acid derivatives in their cecum content, blood, and brain, which is accompanied by a significant decrease in the percentage of sialylated residues in intestinal mucins relative to germ-free (GF) mice. Changes in metabolites associated with brain function such as tryptamine, indolacetate, and trimethylamine N-oxide were also detected in the cecal content of Rg-mice when compared to GF mice. Next, we investigated the effect of R. gnavus monocolonization on hippocampus cell proliferation and behavior. We observed a significant decrease of PSA-NCAM immunoreactive granule cells in the dentate gyrus (DG) of Rg-mice as compared to GF mice and recruitment of phagocytic microglia in the vicinity. Behavioral assessments suggested an improvement of the spatial working memory in Rg-mice but no change in other cognitive functions. These results were also supported by a significant upregulation of genes involved in proliferation and neuroplasticity. Collectively, these data provide first insights into how R. gnavus metabolites may influence brain regulation and function through modulation of granule cell development and synaptic plasticity in the adult hippocampus. This work has implications for further understanding the mechanisms underpinning the role of R. gnavus in neurological disorders.

摘要

Ruminococcus gnavus是人类肠道微生物群的普遍成员，在炎症性肠病和神经系统疾病中数量过多。我们之前表明R. gnavus在粘蛋白上觅食的能力是菌株依赖性的并且与唾液酸代谢有关。在这里，我们发现用R. gnavus ATCC 29149 单克隆化的小鼠（Rg-小鼠）在盲肠含量、血液和大脑中显示出主要唾液酸衍生物的变化，伴随着肠道中唾液酸化残留物百分比的显着降低相对于无菌 (GF) 小鼠的粘蛋白。与脑功能相关的代谢物的变化，例如色胺、吲哚乙酸和三甲胺N与 GF 小鼠相比，在Rg小鼠的盲肠内容物中也检测到 - 氧化物。接下来，我们研究了R. gnavus单克隆化对海马细胞增殖和行为的影响。我们观察到，与 GF 小鼠相比， Rg小鼠齿状回 (DG) 中 PSA-NCAM 免疫反应性颗粒细胞显着减少，并且附近有吞噬性小胶质细胞募集。行为评估表明Rg小鼠的空间工作记忆有所改善，但其他认知功能没有变化。这些结果也得到了参与增殖和神经可塑性的基因显着上调的支持。总的来说，这些数据提供了关于R. gnavus如何运作的初步见解代谢物可能通过调节成年海马体中的颗粒细胞发育和突触可塑性来影响大脑调节和功能。这项工作对进一步了解R. gnavus在神经系统疾病中的作用机制具有重要意义。