The educational content in this post, elaborated in collaboration with Lesaffre, was independently developed and approved by the GMFH publishing team and editorial board.
How is gut microbiome linked to reproductive tract health?
Endometriosis is a common gynecological estrogen-dependent inflammatory disorder that affects approximately 10% of women in reproductive age. It can go unnoticed for several years before the onset of the symptoms, which include impaired reproductive function, psychological changes, and pain in the reproductive system or adjacent to it. For instance, up to 23% of patients experience gastrointestinal symptoms that can overlap with those of irritable bowel syndrome.
Both conditions can cause abdominal pain, cramping, and diarrhea, with women with endometriosis having a threefold increased risk of developing IBS (here).
One hypothesis that explains the development of this disease includes frequent retrograde menstruation, common in around 80% of women, which can evolve into endometriosis in the presence of multifactorial dysregulation. This includes the reproductive and gut microbiota interaction as well as immunological, metabolic, genetic, and hormonal factors.
Endometriosis: cause or consequence of gut microbiome dysbiosis?
This pathological condition was first characterized by hormonal dysregulation. Further assessments showed the presence of damage-associated molecular patterns (endogenous signals released with the damage, such as DNA) in endometrial cell fragments shed during menstruation. These patterns trigger inflammation to promote the removal of these fragments, but in persistent immune stimuli, it promotes endometrium implantation and growth.
In endometriosis, chronic inflammatory signals have been correlated with increased circulating estrogens and bacterial dysbiosis in the gut and reproductive system. Indeed, the hygiene hypothesis suggests reduced commensal microbial diversity could be behind the higher prevalence of chronic inflammatory diseases, such as endometriosis, in high-income countries.
Several studies in animal models and humans have shed new light on the gut microbiome and endometriosis interactions, but the cause-consequence directionality is still unclear. Some of the changes associated with endometriosis include reduced Lactobacillus, higher opportunistic pathogens in the reproductive tract microbiome, and reduced Bacteroidetes and Actinobacteria and increased Firmicutes in the gut microbiome.
The bidirectional interaction between these two microbiotas and the gut-immune-brain axis is becoming increasingly clear. This altered composition of both microbiomes can alter the immune state and the intestinal barrier integrity:
- The higher abundance of pathogenic bacteria causes a chronic inflammatory response that contributes to the endometriosis pathogenesis, as shown in mice, rhesus macaques, and humans. For instance, antibiotic treatment helps to reduce symptoms.
- Gut dysbiosis may increase gut permeability through disruption of tight junctions, relevant in the permeability of intestinal epithelial cells in humans, allowing harmful substances to enter the bloodstream, leading to a chronic inflammatory state.
- Estrogen regulation by the genes encoding enzymes capable of metabolizing estrogens in the gut microbiota, known as estrobolome. For example, increased β-glucoronidase-producing bacteria, such as Escherichia coli, generate more circulating estrogens in women.
Recently, a research group from Guangzhou (China) showed that the predictive value of gut microbiota in endometriosis may be more important than vaginal microbiota. For instance, researchers are analyzing Ruminococcus and Pseudomonas, present in intestinal and peritoneal fluids, as potential biomarkers for diagnosis of endometriosis.
Can dietary interventions complement the treatment of endometriosis?
Considering the increasing evidence of the gut and reproductive health connection, non-pharmacological interventions have emerged as a promising complement to medical treatments for diseases such as bacterial vaginosis or vulvovaginal candidiasis. For this, researchers have analyzed the diet of women with endometriosis and the impact of dietary changes on symptoms or disease regression.
Some of the first attempts include studies that only compared symptoms before and after the intervention:
- Gluten-free diet: only 50% of the 295 patients reported improvement in painful symptoms, and 30% withdrew due to side effects (here).
- Low nickel diet to assess the prevalence of Ni-allergic contact mucositis in patients with endometriosis. This study showed that 90% of the 31 patients experienced a reduction in the intensity of gastrointestinal symptoms after 3 months (here).
- The Mediterranean diet has been related to the reduction in general pain and an improvement in the overall condition of over 50% of the women on the study after 5 months (here).
However, the lack of properly controlled groups limits the impact of these results. To overcome this limitation, controlled studies have analyzed the effect of other nutrition-based interventions, including antioxidants, probiotics, vitamins ( B6, A, C, E), mineral salts, fiber intake, dairy products, and many more. For instance, in some of these studies scientists observed a decrease in oxidative stress markers and pain symptoms. Nevertheless, the diversity of endometriosis patients and the complexity of dietary interventions still limit the extraction of practical outcomes.
Researchers have given particular attention to diets low in fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) due to their role in intestinal luminal distension and, thus, gut motility and pain. Some studies have evaluated this diet in women with endometriosis within a group of patients with gastrointestinal disorders:
- In 2017, Moore et al. showed that 72% of the 59 patients with endometriosis and IBS saw an improvement in symptoms over 50% after 4 weeks (here).
- At the DDW 2024 Congress, Varney et al. showed preliminary results from a single blind crossover feeding trial of low FODMAP diet vs Australian diet in women aged 18 to menopause with endometriosis and poorly controlled gastrointestinal symptoms: up to 70% of the patients exhibited a reduction in the severity of gastrointestinal symptoms compared to 32% in participants following Australian diet (here).
In summary, several dietary studies on endometriosis have found a positive effect, but some patients experienced side effects such as abdominal symptoms. Additionally, the high heterogeneity of the interventions and measured outcomes results in a moderate or high-risk bias, limiting the validity of the results.
To ensure the safety, effectiveness, and clear definition of consensus guidelines, further clinical trials must evaluate their potential, among others, to relieve endometriosis-associated pain, decrease endometriotic lesion size, and prevent disease pathogenesis or recurrence.
Take-home messages
- The gut microbiota is linked to reproductive tract health through the gut-reproductive tract axis.
- Recent studies show a higher predictive value of gut microbiota in endometriosis diagnosis than that of the vaginal microbiota.
- Further research is needed to establish a causal relationship between gut microbiome dysbiosis and endometriosis.
- The potential use of probiotics and other dietary interventions, such as the low nickel diet, could be explored as complementary treatments for endometriosis.
REFERENCES
Nirgianakis, K., Egger, K., Kalaitzopoulos, D.R. et al. Effectiveness of Dietary Interventions in the Treatment of Endometriosis: a Systematic Review. Reprod. Sci.2022. 29, 26–42. doi:10.1007/s43032-020-00418-w
Qin R., Tian G., Liu J., et al. The gut microbiota and endometriosis: From pathogenesis to diagnosis and treatment. Front Cell Infect Microbiol. 2022. 24;12:1069557. doi: 10.3389/fcimb.2022.1069557.
Kobayashi H. Gut and reproductive tract microbiota: Insights into the pathogenesis of endometriosis (Review). Biomed Rep. 2023. 29;19(1):43. doi: 10.3892/br.2023.1626.
Xholli A., Cremonini F., Perugi I., et al. Gut Microbiota and Endometriosis: Exploring the Relationship and Therapeutic Implications. Pharmaceuticals. 2023; 16(12):1696. doi: 10.3390/ph16121696
Philips C.A., Theruvath A.H., Ravindran R., et al. Complementary and alternative medicines and liver disease. Hepatol Commun. 2024. 3;8(4):e0417. doi: 10.1097/HC9.0000000000000417
Huang L., Liu B., Liu Z., et al. Gut Microbiota Exceeds Cervical Microbiota for Early Diagnosis of Endometriosis. Front Cell Infect Microbiol. 2021 Dec 7;11:788836. doi: 10.3389/fcimb.2021.788836.
Moore, J.S., Gibson, P.R., Perry, R.E. et al. Endometriosis in patients with irritable bowel syndrome: Specific symptomatic and demographic profile, and response to the low FODMAP diet. Aust N Z J Obstet Gynaecol. 2017. 57: 201-205. doi: 10.1111/ajo.12594
Nabi M.Y., Nauhria S., Reel M. et al. Endometriosis and irritable bowel syndrome: A systematic review and meta-analyses. Front Med (Lausanne). 2022 Jul 25;9:914356. doi: 10.3389/fmed.2022.914356.
Marziali M., Venza M., Lazzaro S., et al. Gluten-free diet: a new strategy for management of painful endometriosis related symptoms? Minerva Chir. 2012 Dec;67(6):499-504. PMID: 23334113.
Borghini R., Porpora M.G., Casale R., et al. Irritable Bowel Syndrome-Like Disorders in Endometriosis: Prevalence of Nickel Sensitivity and Effects of a Low-Nickel Diet. Nutrients. 2020. An Open-Label Pilot Study.; 12(2):341. doi: 10.3390/nu12020341
Ott J., Nouri K., Hrebacka D., et al. Endometriosis and nutrition-recommending a Mediterranean diet decreases endometriosis-associated pain: an experimental observational study. J Aging Res Clin Practice. 2012;1:162–6. doi:
Moore J.S., Gibson P.R., Perry R.E., et al. Endometriosis in patients with irritable bowel syndrome: specific symptomatic and demographic profile, and response to the low FODMAP diet. Aust N Z J Obstet Gynaecol. 2017;57(2):201–5. doi: 10.1111/ajo.12594.
[This article was originally published in July 2024.]
