Antibiotic Therapy With Metronidazole Reduces Endometriosis Disease Progression in Mice

A Potential Role for Gut Microbiota

Sangappa B. Chadchan; Meng Cheng; Lindsay A. Parnell; Yin Yin; Andrew Schriefer; Indira U. Mysorekar; Ramakrishna Kommagani

Disclosures

Hum Reprod. 2019;34(6):1106-1116. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Endometriosis causes pain in the pelvis and lower abdomen and afflicts up to 10% of women between the ages of 25 and 40, ~5 million women in the USA. Nearly, half of these women experience chronic pelvic pain that significantly diminishes their quality of life (Giudice, 2010). Factors implicated in establishment and expansion of endometriotic lesions include hormonal imbalance, immune dysfunction, epigenetic modifications triggered by environmental toxicants (Rier and Foster, 2003; Hsiao et al., 2017) and unopposed estrogen action coupled with progesterone resistance. The current treatments for endometriosis, principally hormone therapy and surgery, have negative side effects and do not prevent recurrences. Therefore, a new approach is needed to combat this disease (Falcone and Flyckt, 2018).

A well-accepted theory is that endometriosis is caused by endometrial tissue which enters the peritoneal cavity via retrograde menstruation and implants onto pelvic organs and peritoneal surfaces. However, up to 90% of women experience retrograde menstruation, yet only 10% of women develop endometriosis. This suggests that other factors contribute to the onset of endometriosis onset (Sourial et al., 2014). It is thought that the immune system usually clears the cells that enter the peritoneal cavity during retrograde menstruation, but when it is unable to do so, the lesions spread as a result of inflammation brought about by macrophages releasing pro-inflammatory cytokines and growth factors into the peritoneal cavity (Ahn et al., 2015b). This hypothesis is supported by findings in mouse models of endometriosis (Lin et al., 2006; Han et al., 2015). For example, macrophages drive lesion growth and vascularisation (Lin et al., 2006; Bacci et al., 2009; Capobianco et al., 2011) and enhance IL-1β signalling in response to inflammasome activation, which also promotes endometriotic angiogenesis (Lebovic et al., 2000; Bullon and Navarro, 2017).

Endometriosis may also be influenced by the microbiome. Distinct microbial communities have been identified in the reproductive tracts of reproductive-age women (Moreno et al., 2016; Chen et al., 2017), and some microbial compositions appear to correlate with reproductive pathologies such as preterm birth and infertility (Parnell et al., 2017b). Additionally, Cregger et al. (3–6) identified differences in the cervical and uterine microbiome communities between women with and without endometriosis (Cregger et al., 2017). Here, we tested the hypothesis that the gut microbiome, which encodes 150 times more genes than the host genome (O'Hara and Shanahan, 2006; Ursell et al., 2014), influences endometriosis disease progression. We demonstrate that treating mice with broad-spectrum antibiotics greatly curtailes the early growth and progression of endometriotic lesions. Whereas metronidazole treatment reduced endometriotic lesion growth, oral gavage of bacteria from mice with endometriosis restored endometriotic lesion growth and associated inflammatory responses. These results suggest that gut bacteria promote endometriosis disease progression and have implications for microbiota-based therapies to combat this painful disease.

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