Despite being a benign condition, endometriosis causes significant morbidity in affected women, 10% of whom are of reproductive age. Endometriosis is characterized by the abnormal growth of tissues resembling that of the uterine lining or endometrium outside of the uterine cavity. Women with advanced endometriosis exhibit gut microbial changes. Previous studies have reported that anti-inflammatory diets may relieve endometriosis-associated pain, which may be achieved by altering bacterial and gut metabolism. The gut microbiome can influence the development of innate immunity and inflammation. In particular, bacterial components or byproducts may inhibit or activate macrophage memory responses. This phenomenon, termed trained immunity, helps these cells respond faster with a stronger inflammatory response. A recent study published in the journal BMC Medicine examined the effects of a Western diet on the development of endometriotic lesions in mice.
After four weeks of life, endometriotic tissue was surgically implanted in female mice, following which the development of endometriotic lesions was monitored by ultrasound. Mice consumed either a control or Western diet (WED) that typically contains more fat and less fiber. Notably, a high-fat diet was avoided to prevent changes due to obesity or overweight. At seven weeks, mice were sacrificed. Both the characteristics of the lesions and the composition of the gut microbiome were analyzed. Mice consuming the control and WED gained weight equally throughout the study period. At the end of the study, the WED group had a mean lesion volume doubled compared to the controls. Despite unchanged inflammatory markers, lesions in the WED group were more likely to be fibrotic and exhibit proliferation. Macrophages were also more active in the WED group lesions despite the same proportion of immune cells present in the lesions in both groups.
The increased lesion size with the WED may reflect WED-linked trained immunity, like that induced by the Bacillus Calmette-Guérin (BCG). Although not discussed in the current study, macrophage polarization may be driven by increased gram-positive bacilli in the gut, similar to the effect produced by BCG. On the other side, investigation of macrophage activation by examining the surface markers CD80, CD206, and MHC-II revealed an increased fluorescence intensity for the markers CD80 and CD206 in the WED mice with endometriosis. Serum glucose levels were reduced in mice with endometriosis as compared to the original endometriosis-free mice, perhaps reflecting higher glucose consumption. WED mice with endometriosis produced more lactate during the anaerobic glucose metabolism than non-endometriotic WED mice; however, no significant differences were observed in the controls.
The higher levels of glucose oxidation may be diet-related and due to activation of the leptin pathway proteins, which lowers glucose levels, thus indicating that leptins are involved in endometriotic lesion development. Many women with endometriosis have functional bowel disorders like irritable bowel syndrome, which dietary changes might alleviate. Some studies suggest that endometriotic lesions are reduced in size after probiotic administration; however, the specific metabolic changes remain unknown. WED causes the intestinal epithelial barrier inflammation (“leaky gut”), allowing bacterial toxic byproducts to enter the bloodstream. This subsequently induces chronic low-grade inflammation, which is also present in endometriosis. Gut microbiome changes were significantly correlated with differences in the dietary pattern. However, after the onset of endometriosis in both groups, gut microbiota in WED mice with the largest lesions was deficient in Akkermansia muciniphila.
Despite this, there was no evidence of visible gut dysbiosis (disrupted Firmicutes/Bacteroidetes ratio). Akkermansia is less abundant in metabolic syndrome and Crohn’s disease. However, supplementation with A. muciniphila as a probiotic reduces low-grade inflammation and promotes intestinal wall integrity. This may depend on the ability of this bacterium to produce large amounts of short-chain fatty acids (SCFAs; e.g. propionate and butyrate), provided with antinflammatory, immuno-modulating and cytoprotective activites on gut mucosa. Despite normal counts in WED mice, the induction of endometriosis was associated with a total depletion of A. muciniphila, thus emphasizing its possible protective function. Endometriosis causes changes in the gut microbiota, with certain alterations in the gut microbial environment promoting lesion progression. Although intestinal dysbiosis was not observed in the current study, other animal and human studies suggest it is present in endometriotic hosts.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Parpex G, Chassaing B et al. BMC Med. 2024 Nov 6; 22(1):513.
Hum Reprod. 2024; 39(10):2259.
BMC Med. 2024 Jul 18; 22(1):294.