Alterations in the gut microbiome by HIV-1 infection or a high-fat diet associates with systemic immune activation and inflammation in double humanized-BLT mice

Surgery was performed on NSG mice to create humanized bone-marrow, liver, thymus mice (hu-mice). In order to create double hu-mice, the hu-mice were treated with broad spectrum antibiotics to deplete murine gut bacteria and subsequently transplanted with human fecal material from healthy human donors. We characterized 262 fecal samples from hu-mice, double hu-mice, and human fecal donors to determine the impact of HIV-1 infection or high fat diet on the gut microbiome and systemic immune activation and inflammation. We found that HIV-1 infection altered the human-like gut microbiome of double hu-mice, which was associated with decreased human CD4 T cells and increased systemic inflammation and immune activation. Further, using a high fat diet we induced gut microbial dysbiosis in double hu-mice which corresponded with increased systemic immune activation and inflammation.

本研究通过手术操作对NSG小鼠进行改造，构建人源化骨髓-肝脏-胸腺小鼠（hu-mice）。为获得双重人源化小鼠，先对该类人源化小鼠施以广谱抗生素处理以清除其肠道固有菌群，随后移植健康人类供体的粪便菌群。我们共收集并表征了人源化小鼠、双重人源化小鼠及人类粪便供体的262份粪便样本，以探究人类免疫缺陷病毒1型（HIV-1）感染与高脂饮食对肠道微生物组、系统性免疫激活及炎症反应的影响。研究发现，HIV-1感染可改变双重人源化小鼠的类人肠道微生物组结构，该变化与人类CD4 T细胞数量减少、全身炎症及免疫激活水平升高显著相关。此外，通过高脂饮食干预可诱导双重人源化小鼠出现肠道菌群失调，该现象与系统性免疫激活及炎症反应增强相一致。