Karandikar Kalyani, Bhonde Gauri, Palav Harsha, Padwal Varsha, Velhal Shilpa, Pereira Jacintha, Meshram Himali, Goel Akshat, Shah Ira, Patel Vainav, Bhor Vikrant M
Department of Molecular Immunology and Microbiology, ICMR- National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), J. M. Street, Parel, Mumbai, India.
Department of Viral Immunopathogenesis, ICMR- National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), J. M. Street, Parel, Mumbai, India.
Gut Pathog. 2024 Nov 14;16(1):67. doi: 10.1186/s13099-024-00663-3.
Gut microbiome dysbiosis and related immune dysfunction have been associated with the pathogenesis of Human Cytomegalovirus (HCMV) infection in infants with neonatal cholestasis (NC) as previously reported by us. However, the interaction of a perturbed microbiome, HCMV infection, and dysregulated immunity leading to exacerbation of disease severity has not been investigated so far. In this study, we examined the association of gut microbiome, host inflammatory and homeostatic markers that are likely to govern increased pathogenesis of NC in HCMV infected IgM positive infants (N = 15) compared to IgM negative (N = 15) individuals. Stool samples of HCMV infected infants and age-matched healthy controls (N = 10) were assessed for gut bacteria-derived metabolites like short-chain fatty acids (SCFAs), Lipopolysaccharide (LPS), cytokines and markers of gut barrier integrity. Data were correlated with previously determined gut microbiome composition and frequency of immune cell subsets. Finally, validation of clinical potential was undertaken by principal component analysis (PCA) of integrated data to delineate the spectrum of clinical pathology.
Significantly lower levels of SCFAs and elevated fecal levels of soluble inflammatory mediators were observed in IgM positive HCMV infected infants. Further, increased plasma LPS levels and markers of gut permeability, suggestive of microbial translocation due to a 'leaky gut' were observed in HCMV infected IgM positive group. PCA of integrated data revealed clearly disparate profiles representative of IgM positive, IgM negative, and uninfected healthy states.
Our results suggest the utility of an integrated approach involving dysregulated microbiome-immune axis for gaining a better understanding of pathogenesis associated with HCMV infection in NC.
如我们之前所报道，肠道微生物群失调及相关免疫功能障碍与新生儿胆汁淤积（NC）婴儿的人巨细胞病毒（HCMV）感染发病机制有关。然而，迄今为止，尚未研究微生物群紊乱、HCMV感染和免疫失调之间的相互作用如何导致疾病严重程度加剧。在本研究中，我们检测了肠道微生物群、宿主炎症和稳态标志物之间的关联，这些因素可能在HCMV感染的IgM阳性婴儿（N = 15）与IgM阴性（N = 15）个体中导致NC发病机制增加。对HCMV感染婴儿和年龄匹配的健康对照（N = 10）的粪便样本进行评估，检测肠道细菌衍生的代谢产物，如短链脂肪酸（SCFAs）、脂多糖（LPS）、细胞因子和肠道屏障完整性标志物。数据与先前确定的肠道微生物群组成和免疫细胞亚群频率相关。最后，通过对综合数据进行主成分分析（PCA）来验证临床潜力，以描绘临床病理学范围。
在IgM阳性的HCMV感染婴儿中，观察到SCFAs水平显著降低，粪便中可溶性炎症介质水平升高。此外，在HCMV感染的IgM阳性组中，观察到血浆LPS水平升高和肠道通透性标志物增加，提示由于“肠道渗漏”导致微生物易位。综合数据的PCA显示，代表IgM阳性、IgM阴性和未感染健康状态的图谱明显不同。
我们的结果表明，采用涉及微生物群 - 免疫轴失调的综合方法有助于更好地理解与NC中HCMV感染相关的发病机制。
