Antibiotic therapy with metronidazole reduces endometriosis disease progression in mice: a potential role for gut microbiota

Study information

Reviewed Marked as Reviewed by Claregrieve1 on 2022/07/8

study design

laboratory experiment

Citation

PMID PubMed identifier for scientific articles.

31037294

DOI Digital object identifier for electronic documents.

10.1093/humrep/dez041

URI

Authors

Chadchan SB, Cheng M, Parnell LA, Yin Y, Schriefer A, Mysorekar IU, Kommagani R

Journal

Human reproduction (Oxford, England)

Year

2019

Keywords:

endometriosis, gut bacteria, inflammation, metronidazole, microbiome

STUDY QUESTION: Does altering gut microbiota with antibiotic treatment have any impact on endometriosis progression? SUMMARY ANSWER: Antibiotic therapy reduces endometriosis progression in mice, possibly by reducing specific gut bacteria. WHAT IS KNOWN ALREADY: Endometriosis, a chronic condition causing abdominal pain and infertility, afflicts up to 10% of women between the ages of 25 and 40, ~5 million women in the USA. Current treatment strategies, including hormone therapy and surgery, have significant side effects and do not prevent recurrences. We have little understanding of why some women develop endometriosis and others do not. STUDY DESIGN, SIZE, DURATION: Mice were treated with broad-spectrum antibiotics or metronidazole, subjected to surgically-induced endometriosis and assayed after 21 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: The volumes and weights of endometriotic lesions and histological signatures were analysed. Proliferation and inflammation in lesions were assessed by counting cells that were positive for the proliferation marker Ki-67 and the macrophage marker Iba1, respectively. Differences in faecal bacterial composition were assessed in mice with and without endometriosis, and faecal microbiota transfer studies were performed. MAIN RESULTS AND THE ROLE OF CHANCE: In mice treated with broad-spectrum antibiotics (vancomycin, neomycin, metronidazole and ampicillin), endometriotic lesions were significantly smaller (~ 5-fold; P < 0.01) with fewer proliferating cells (P < 0.001) than those in mice treated with vehicle. Additionally, inflammatory responses, as measured by the macrophage marker Iba1 in lesions and IL-1β, TNF-α, IL-6 and TGF-β1 in peritoneal fluid, were significantly reduced in mice treated with broad-spectrum antibiotics (P < 0.05). In mice treated with metronidazole only, but not in those treated with neomycin, ectopic lesions were significantly (P < 0.001) smaller in volume than those from vehicle-treated mice. Finally, oral gavage of faeces from mice with endometriosis restored the endometriotic lesion growth and inflammation (P < 0.05 and P < 0.01, respectively) in metronidazole-treated mice. LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: These findings are from a mouse model of surgically-induced endometriosis. Further studies are needed to determine the mechanism by which gut bacteria promote inflammation, identify bacterial genera or species that promote disease progression and assess the translatability of these findings to humans. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that gut bacteria promote endometriosis progression in mice. This finding if translated to humans, could aid in the development of improved diagnostic tools and personalised treatment strategies. STUDY FUNDING AND COMPETING INTEREST(S): This work was funded, in part, by: a National Institutes of Health (NIH)/ National Institute of Child Health and Human Development (NICHD) grant (R00HD080742) to RK; Washington University School of Medicine start-up funds to RK; an Endometriosis Foundation of America Research Award to R.K.; and an NIH/NICHD grant (R01HD091218) to IUM. The authors report no conflict of interest.

Experiment 1

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Reviewed Marked as Reviewed by Claregrieve1 on 2022/07/8

Curated date: 2021/08/09

Curator: Samara.Khan

Revision editor(s): Samara.Khan, Claregrieve1, WikiWorks, Peace Sandy

Subjects

Location of subjects: United States of America

Host species Species from which microbiome was sampled. Contact us to have more species added.: Mus musculus

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Endometriosis endometriosis,Endometriosis (clinical),endometriosis (disease),Endometriosis (disorder),Endometriosis (morphologic abnormality),ENDOMETRIOSIS NEC,Endometriosis NOS,Endometriosis NOS (disorder),Endometriosis of other specified sites,Endometriosis, site unspecified,Endometriosis

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Non-endo mice

Group 1 name Corresponds to the case (exposed) group for case-control studies: Endo mice

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Uterine tissue was transplanted onto the peritoneal wall in order to induce endometriosis in these mice.

Group 0 sample size Number of subjects in the control (unexposed) group: 5

Group 1 sample size Number of subjects in the case (exposed) group: 5

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): Mice had never been given antibiotics prior to the start of the experiment

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: T-Test

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: No

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: increased

Signature 1

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Reviewed Marked as Reviewed by Claregrieve1 on 2022/07/8

Curated date: 2021/08/09

Curator: Samara.Khan

Revision editor(s): Samara.Khan, Claregrieve1

Source: Figure 3

Description: Differential microbial abundance between non-endo and endo mice: fecal samples from mice with simulated endometriosis had higher levels of Bacteroidetes and Firmicutes than non-endo mice. The bacteroides genera was absent in non-endo mice but present in endo mice.

Abundance in Group 1: increased abundance in Endo mice

NCBI	Quality Control	Links
Bacteroides

Revision editor(s): Samara.Khan, Claregrieve1