Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Microbiome. 2021 Nov 3;9(1):215. doi: 10.1186/s40168-021-01161-3.
The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation.
Was mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii's relative abundance was negatively correlated with LCN2 in Was mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Wascompared to WT mice.
These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstract.
肠道微生物组在炎症性肠病患者中发生改变，但这些改变如何导致肠道炎症尚不清楚。 由于在许多遗传易感动物模型中，当重新衍生到无菌环境中时，结肠炎并未发展，因此小鼠模型已经证明了微生物组在结肠炎中的重要性。 我们之前已经表明，Wiskott-Aldrich 综合征蛋白（WASP）缺陷型小鼠（Was）会自发发生结肠炎，类似于人类患者中功能丧失突变的 WAS。 此外，我们发现 Was 小鼠结肠炎的发展依赖于幽门螺旋杆菌。 在这里，我们利用简化模型结合多组学方法来研究宿主-微生物相互作用在肠道炎症中的作用。
同时定植有改变的 Schaedler 菌群（ASF）和幽门螺旋杆菌的 Was 小鼠发生了结肠炎，而单独定植有 ASF 或幽门螺旋杆菌的小鼠则没有。 在 Was 小鼠中，幽门螺旋杆菌的相对丰度与粪便脂钙蛋白-2（LCN2）呈正相关，LCN2 是肠道炎症的标志物。 相比之下，定植有 ASF 和幽门螺旋杆菌的 WT 小鼠没有炎症，并且令人惊讶的是，幽门螺旋杆菌的相对丰度与 LCN2 呈负相关。 在 Was 结肠中，细菌穿透粘液层，ASF457 Mucispirillum schaedleri 的粘膜相对丰度与粪便 LCN2 呈正相关。 元转录组学分析表明，与 WT 小鼠相比，ASF457 在 Was 小鼠中具有更高表达的基因，这些基因预测可增强适应性和免疫原性。 相比之下，ASF519 Parabacteroides goldsteinii 的相对丰度与 Was 小鼠的 LCN2 呈负相关，转录分析表明，ASF519 在 Was 中预测可促进应激适应的基因表达水平低于 WT 小鼠。
这些研究表明，微生物对免疫系统的影响可能取决于具体情况，同一细菌在稳态条件下可引发耐受反应，但在免疫失调宿主中可促进炎症。 此外，在炎症环境中，一些细菌上调增强其适应性和免疫原性的基因，而其他细菌则不太适应并减少丰度。 这些发现强调了在不同背景下研究宿主-微生物相互作用以及考虑细菌的转录谱和适应性如何在不同宿主中发生变化的重要性，因为这是在开发基于微生物组的疗法时需要考虑的因素。 视频摘要。
