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

Discussion

Given that their ability to influence systemic and peritoneal inflammation and estrogen regulation, gut microbiota could contribute to endometriosis. Here, we showed that antibiotic treatment reduced endometriotic lesions in a mouse model of endometriosis. Additionally, mice with endometriosis had more Bacteroidetes and less Firmicutes in their guts than mice without endometriosis. Finally, metronidazole, which targets Bacteroides genus, reduced endometriotic lesion growth, but lesion growth was restored in mice gavaged with faeces from mice with endometriosis, suggesting that gut bacteria promote endometriotic lesion progression.

Once an initial endometriotic lesion is established, pro-inflammatory cytokines and growth factors are released into the peritoneal cavity, and the resulting inflammation promotes lesion spread (Ahn et al., 2015a,b). Additionally, macrophages drive lesion growth and vascularisation in a mouse model of endometriosis (Lin et al., 2006; Bacci et al., 2009; Capobianco et al., 2011). Inflammasomes and IL-1β also contribute to endometriotic lesion growth (Snider et al., 2010; Goncalves et al., 2017). We showed that mice treated with VNMA or metronidazole alone had fewer macrophages in their lesions and lower peritoneal IL-1β concentration than vehicle-treated mice. Additionally, metronidazole-treated mice that were orally gavaged with faeces from mice with endometriosis had a similar number of lesion macrophages and peritoneal IL-1β concentration as vehicle-treated mice. Gut bacteria can modulate systemic inflammatory responses (Borody and Khoruts, 2011; Ellekilde et al., 2014; Rose et al., 2015), and release of bacterial products into the peritoneal cavity promotes auto-immunity (Luckey et al., 2013). Thus, we suggest that gut bacteria promote endometriosis by promoting inflammation. Future work should further test this model and define the mechanism by which this occurs.

We found that microbial diversity was altered in faeces from mice with endometriotic lesions and that mice with endometriosis had a higher abundance of Bacteroidetes and lower abundance of Firmicutes in their guts than mice without endometriosis. Our results differ somewhat from those of Yuan et al. (2018), who reported that, along with changes in Firmicutes and Bacteroidetes, Bifidobacterium was altered in mice with endometriosis. This difference perhaps reflects the origin of the mice and differences in diet.

In summary, our findings suggest that gut bacteria promote endometriosis disease progression in mice. If our findings are translated to humans, they may lead to new diagnostic strategies and microbiota-based therapies to treat this debilitating disease.

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