Department of Bioengineering, Northeastern University, Boston, Massachusetts, USA.
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts, USA.
Gut Microbes. 2022 Jan-Dec;14(1):2039002. doi: 10.1080/19490976.2022.2039002.
Considerable effort has been put forth to understand mechanisms by which the microbiota modulates and responds to inflammation. Here, we explored whether oxidation metabolites produced by the host during inflammation, sodium nitrate and trimethylamine oxide, impact the composition of a human stool bacterial population in a gut simulator. We then assessed whether an immune-competent intestinal model responded differently to spent medium from bacteria exposed to these cues compared to spent medium from a control bacterial population. The host-derived oxidation products were found to decrease levels of and overall microbiota metabolic potential, while increasing levels of proinflammatory and lipopolysaccharide in bacterial cultures, reflecting shifts that occur in inflammation. Spent microbiota media induced elevated intracellular mucin levels and reduced intestinal monolayer integrity as reflected in transepithelial electrical resistance relative to fresh medium controls. However, multiplexed cytokine analysis revealed markedly different cytokine signatures from intestinal cultures exposed to spent medium with added oxidation products relative to spent control medium, while cytokine signatures of cultures exposed to fresh media were similar regardless of addition of host-derived cues. Further, the presence of immune cells in the intestinal model was required for this differentiation of cytokine signatures. This study indicates that simple immune-competent intestinal models can capture bacterial-mammalian cross-talk in response to host-derived oxidation products and supports utility of these systems for mechanistic studies of interactions between the gut microbiome and host in inflammation.
人们已经付出了相当大的努力来了解微生物群通过何种机制来调节和响应炎症。在这里，我们探讨了宿主在炎症期间产生的氧化代谢物，即硝酸钠和氧化三甲胺，是否会影响肠道模拟器中人类粪便细菌群的组成。然后，我们评估了免疫功能健全的肠道模型是否会对暴露于这些信号的细菌的用过培养基与对照细菌种群的用过培养基产生不同的反应。结果发现，宿主来源的氧化产物降低了 和总体微生物代谢潜能的水平，同时增加了细菌培养物中促炎 和脂多糖的水平，反映了炎症中发生的变化。与新鲜培养基对照相比，用过的微生物群培养基诱导了细胞内粘蛋白水平的升高和肠道单层完整性的降低，这反映在跨上皮电阻相对于新鲜培养基对照的降低。然而，多重细胞因子分析显示，与添加氧化产物的对照用过培养基相比，暴露于添加氧化产物的用过培养基中的肠道培养物的细胞因子特征明显不同，而暴露于新鲜培养基的培养物的细胞因子特征无论是否添加宿主来源的信号都相似。此外，免疫细胞在肠道模型中的存在是区分细胞因子特征所必需的。这项研究表明，简单的免疫功能健全的肠道模型可以捕捉到宿主来源的氧化产物对细菌-哺乳动物相互作用的影响，并支持这些系统用于研究炎症中肠道微生物组与宿主之间相互作用的机制。
