Identification of distinct stool metabolites in women with endometriosis for non-invasive diagnosis and potential for microbiota-based therapies

Chandni Talwar; Goutham Venkata Naga Davuluri; Abu Hena Mostafa Kamal; Cristian Coarfa; Sang Jun Han; Surabi Veeraragavan; Krishna Parsawar; Nagireddy Putluri; Kristi Hoffman; Patricia Jimenez; Scott Biest; Ramakrishna Kommagani

doi:10.1016/j.medj.2024.09.006

Identification of distinct stool metabolites in women with endometriosis for non-invasive diagnosis and potential for microbiota-based therapies

Med. 2024 Oct 3:S2666-6340(24)00373-8. doi: 10.1016/j.medj.2024.09.006. Online ahead of print.

Affiliations

¹ Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
² Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA.
³ Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA; Center for Precision and Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Molecular Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Analytical and Biological Mass Spectrometry Core Facility, University of Arizona, Tucson, AZ 85721, USA.
⁷ Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA.
⁹ Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 63110, USA.
¹⁰ Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 63110, USA; Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 63110, USA.
¹¹ Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].

PMID: 39395412
DOI: 10.1016/j.medj.2024.09.006

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Conclusions: 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.

Funding: This work was funded by the NIH/NICHD grants (R01HD102680, R01HD104813) and a Research Scholar Grant from the American Cancer Society to R.K.

Keywords: Pre-clinical research; endometriosis; gut; inflammation; microbiome; microbiome therapeutics; non-invasive diagnosis; pelvic pain; stool metabolites.