Talwar Chandni, Davuluri Goutham Venkata Naga, Kamal Abu Hena Mostafa, Coarfa Cristian, Han Sang Jun, Veeraragavan Surabi, Parsawar Krishna, Putluri Nagireddy, Hoffman Kristi, Jimenez Patricia, Biest Scott, Kommagani Ramakrishna
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA.
Med. 2025 Feb 14;6(2):100517. doi: 10.1016/j.medj.2024.09.006. Epub 2024 Oct 11.
Endometriosis, a poorly studied gynecological condition, is characterized by the presence of ectopic endometrial lesions resulting in pelvic pain, inflammation, and infertility. These associated symptoms contribute to a significant burden, often exacerbated by delayed diagnosis. Current diagnostic methods involve invasive procedures, and existing treatments provide no cure.
Microbiome-metabolome signatures in stool samples from individuals with and without endometriosis were determined using unbiased metabolomics and 16S bacteria sequencing. Functional studies for selected microbiota-derived metabolites were conducted in vitro using patient-derived cells and in vivo by employing murine and human xenograft pre-clinical disease models.
We discovered a unique bacteria-derived metabolite signature intricately linked to endometriosis. The altered fecal metabolite profile exhibits a strong correlation with that observed in inflammatory bowel disease (IBD), revealing intriguing connections between these two conditions. Notably, we validated 4-hydroxyindole, a gut-bacteria-derived metabolite that is lower in stool samples of endometriosis. Extensive in vivo studies found that 4-hydroxyindole suppressed the initiation and progression of endometriosis-associated inflammation and hyperalgesia in heterologous mouse and in pre-clinical models of the disease.
Our findings are the first to provide a distinct stool metabolite signature in women with endometriosis, which could serve as stool-based non-invasive diagnostics. Further, the gut-microbiota-derived 4-hydroxyindole poses as a therapeutic candidate for ameliorating endometriosis.
This work was funded by the NIH/NICHD grants (R01HD102680, R01HD104813) and a Research Scholar Grant from the American Cancer Society to R.K.
子宫内膜异位症是一种研究较少的妇科疾病，其特征是存在异位子宫内膜病变，导致盆腔疼痛、炎症和不孕。这些相关症状造成了巨大负担，而诊断延迟往往会加重这种负担。目前的诊断方法涉及侵入性操作，且现有治疗方法无法治愈该病。
使用无偏向代谢组学和16S细菌测序法，确定患有和未患有子宫内膜异位症个体粪便样本中的微生物组-代谢组特征。对选定的微生物群衍生代谢物进行功能研究，体外使用患者来源的细胞，体内采用小鼠和人类异种移植临床前疾病模型。
我们发现了一种与子宫内膜异位症复杂相关的独特细菌衍生代谢物特征。粪便代谢物谱的改变与炎症性肠病（IBD）中观察到的情况密切相关，揭示了这两种疾病之间的有趣联系。值得注意的是，我们验证了4-羟基吲哚，一种肠道细菌衍生的代谢物，在子宫内膜异位症患者的粪便样本中含量较低。广泛的体内研究发现，4-羟基吲哚可抑制异源小鼠和该疾病临床前模型中与子宫内膜异位症相关的炎症和痛觉过敏的发生和进展。
我们的研究结果首次为患有子宫内膜异位症的女性提供了独特的粪便代谢物特征，这可作为基于粪便的非侵入性诊断方法。此外，肠道微生物群衍生的4-羟基吲哚有望成为改善子宫内膜异位症的治疗候选物。
这项工作由美国国立卫生研究院/儿童健康与人类发展研究所的资助（R01HD102680、R01HD104813）以及美国癌症协会授予R.K.的研究学者奖资助。
