As a first-year student taking microbiology, my class was asked to culture our own fecal samples. This taught us to identify bacteria by their growth on culture plates. There were more than we could identify. In fact, there may be more bacterial cells in our gastrointestinal (GI) tract than the rest of the cells in our bodies. Other than GI infections and some concept that they were there in that massive amount for some form of symbiosis with the rest of our cellular composition, not much about their role made its way to our curriculum.
My endocrinology fellowship taught me a lot of chemistry. People had diabetes, thyroid problems, and adrenal disorders because their chemicals weren't right. Bacterial infection wasn't a primary concern, but all sorts of chemicals changed when bacterial invaders appeared. We also learned that DNA and RNA could serve as great fingerprints for a variety of cells, including bacteria, although identifying and obtaining measurable amounts was a tedious project. But an endocrine disorder as an infectious disease?
By fellowship time, we had pretty much forgotten all the antibiotics we learned about as residents. Then someone figured out that duodenal ulcers might be an infectious disease. Now the possibility that what we thought was a chemical issue could relate to microbes served as a demarcation point. If anatomical findings could be related to those overwhelming gut bacteria, what about systemic conditions?
As medical capabilities advanced to the current age, interest in gut microbial composition and its role in health, disease, and therapy has accelerated. Moreover, the capacity to determine DNA and RNA sequences efficiently has made the exploration of microbiota more realistic. As an added incentive, there remains an ample list of diseases that need more effective treatments. Endocrinology has its fair share of these conditions.
Recent studies and review articles have addressed the relationship of microbiota to type 2 diabetes, thyroid autoimmunity, and ovarian function. Moreover, our internal flora may even function as an aggregate endocrine organ, performing its own metabolic inputs. Polycystic ovary syndrome (PCOS) may serve as a suitable prototype for where our understanding has come and perhaps where this new opportunity for rethinking endocrine disorders is headed. A wonderful overview appeared in the Journal of the Endocrine Society in 2021.
Studies on this connection include comparisons of patients with matched controls and also rodent models with microflora that can be manipulated or provided chemicals to induce hyperandrogenism or reproductive difficulties they would not otherwise have. This can help establish whether the clinical phenotype generates the flora or whether the flora creates the clinical presentations.
In some studies, particularly larger ones in premenopausal women, those with PCOS often show a less diverse bacterial distribution in their fecal samples, known as alpha diversity. This has also been found in several autoimmune disorders and perhaps obesity and type 2 diabetes. There are many confounders, including geography, where customary diets differ drastically between countries. Most studies are done within a single geographical area. But this loss of diversity does not mean that it is a cause or consequence of the metabolic derangement.
Beta diversity, the distribution of microbiome elements between populations, also has a suggestive difference among women with PCOS in their early or prime reproduction years. When given to lab rodents, the aromatase inhibitor letrozole induced hyperandrogenism in some animals and then compared with rodents with similar genetics and environment. In pubertal animals, the alpha diversity differed but the beta did not. In adult animals treated with letrozole, the hyperandrogenism had less effect on bacterial diversity.
A group in Finland took advantage of vital statistics collected there to try to ascertain whether the microbiome and its impact on PCOS persisted past the prime reproductive years. The Finnish government recorded all births in the northern provinces in 1966 with the intent of creating prospective health data. At age 31, all women still registered as residents of Finland received health questionnaires, which included responses regarding oligomenorrhea and hirsutism. At age 46, as they approached menopause, the questionnaire asked if they had PCOS. Measurements of testosterone and glucose metabolism were taken at ages 31 and 46 to compare mid- and late reproductive years, with fecal sampling at age 46. The national database also logged prescriptions, to exclude those women on medicines to regulate their cycles or who were pregnant at one of the assessments. In this study, the alpha and beta diversity did not differ on the basis of a known diagnosis of PCOS. However, other indices did shift with certain clinical measurements commonly obtained, particularly body mass index, fasting insulin levels, and sex hormone–binding globulin.
As data on gut microflora accumulate, and as animal models allow the creation of specific lab components of a disease, interventions can become more targeted. At present, these potentially include selected fecal transplants, dietary modifications such as probiotics, and drugs such as metformin that do not change the flora but may mitigate some of the deleterious effects of dysbiosis. For now, as challenging as this seems to the creativity of study design, as tantalizing as this avenue may appear therapeutically, we have more science to pursue than therapeutic certainties to offer.
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Cite this: Bacterial Infections and the Link to PCOS - Medscape - Dec 20, 2022.