The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.

尽管微生物组成波动的下游机制仍然是推测性的，但微生物组对 HIV 疾病的影响已得到广泛认可。我们在 cART 启动后的两年内检测到易位微生物成分的快速动态变化。一种公正的系统生物学方法揭示了由沙雷氏菌与其他细菌属的丰度比变化驱动的两条不同的途径。第一年增加的 CD4 T 细胞数量与高沙雷氏菌丰度、促炎先天细胞因子和驱动 Th17 基因表达特征和恢复粘膜完整性的代谢物有关。随后，沙雷氏菌减少先天细胞因子的丰度和下调允许重建全身 T 细胞稳态，促进 Th1 和 Th2 基因表达特征的恢复。对其他三个地理上不同的治疗 HIV 感染队列的分析建立了一个更普遍的原则，即易位微生物物种的多样性和组成的变化会影响全身炎症，从而影响 CD4 T 细胞的恢复。