The article was originally published on the IPA website (International Probiotics Association) in April 2024 Melissa, 28, is the mother of two beautiful children, Zachary and Sara-Jeanne. She is the commercial director of a company marketing natural health products based on plant extracts grown in a fair trade and eco-responsible manner. She works out, takes care of her parents, and has a rich and fulfilling social life. In short, everything is going well. Um… not everything. For the last two years, every month, the week before her period, she has been going through hell. Melissa’s abdomen is bulgy like a balloon, she has intestinal cramps, her breasts are swollen and tender. She doesn’t sleep nor recover well. On top of that, she also suffers from constipation very often. All of this obviously makes her irritable, which greatly affects her quality of life. And then, suddenly, a few days after the start of her period, everything goes back to normal. This story is unfortunately shared by many women on the planet. Premenstrual disorders (PMD), as its name suggests, occurs 2 to 7 days (and sometimes more) before period and stops when it begins or on the following days. PMD affects millions of women of all backgrounds. Recent studies establish that approximately 90% of women of childbearing age experience at least one mild symptom and that between 20 and 40%, the symptoms interfere with their daily activities (1). The most common symptoms of PMD include many manifestations, both physical and emotional. These symptoms are sore or tender breasts, headache, fatigue, skin changes, acne, irritability, mood swings, food cravings, and depression. There are also gastrointestinal (GI) symptoms such as intestinal pain and bloating, diarrhea or constipation (2). PMD is not associated with age, educational level, or revenue (3). What is the pathophysiology of PMD? It is not clear, but experts link PMD with hormonal changes, serotonergic dysfunction, impaired gamma-aminobutyric acid (GABA) function (GABA is a neurotransmitter and disorder in GABA signalling to be implicated in a multitude of neurologic and psychiatric conditions), stress, and poor lifestyle habits such as longer duration of internet use and shorter sleep duration. Treatment of PMD includes prescribed drugs, such as oral contraceptives or serotonin reuptake inhibitors (commonly prescribed antidepressants with some adverse effects), lifestyle modifications (meditation, exercise, diet…). Dietary changes include consuming soy isoflavones and soy products, although not every woman is responsive to these natural compounds. A recent review concluded that diet is an essential modulating factor to manage PMD symptoms, although clear and specific conclusions can hardly be drawn. It was mentioned that calcium, magnesium, vitamins B & D, and some herbal supplements can be useful and effective to support quality of life and help to control some PMD symptoms (3). Role of Gut Microbiome in PMD The gut microbiome comprises trillions of microorganisms residing in the gastrointestinal tract, including bacteria, viruses, fungi, eukaryotic parasites, and archaea (4). These microbes play a crucial role in host physiology, influencing nutrient metabolism, immune function, and neurological signalling. The composition and diversity of the gut microbiome are influenced by various factors, including diet, lifestyle, medications, and hormonal fluctuations. An increasing number of studies are now linking PMD with an imbalance of the gut microbiome. Dysbiosis, characterized by an imbalance in microbial composition and function, has been associated with increased inflammatory markers, hormonal imbalances, and neurotransmitter disturbances—all of which are implicated in PMD symptomatology. Moreover, dysbiosis can disrupt intestinal barrier integrity, leading to the translocation of microbial products and triggering systemic inflammation, further exacerbating PMD symptoms. A study published in 2022 (Takeda et al. (2022)) compared the structure of the fecal microbiome of women experiencing PMD that negatively affect their daily activities to women with no serious PMD (controls). Slight differences in the microbiome were observed, and the authors concluded that two bacterial genera, Parabacteroides and Megasphaera, were negatively associated with more severe symptoms of PMD (5). In another study comparing 24 Japanese women experiencing PMD with 144 healthy women, it was observed that the composition of the fecal microbiome differs between women with PMD vs controls (6). But it is not just about who is there, i.e., what type of microorganism are part of the gut microbiome. The gut microbiome plays a pivotal role in the production of various metabolites, including S-(-)equol, short-chain fatty acids (SCFAs), neurotransmitters, and hormones. Interestingly, it has been shown that only about 30-60% of people have a gut microbiome able to produce S-(-)equol, a metabolite biotransformed from isoflavones (isoflavones act as phytoestrogens, a plant-derived compounds with estrogen-like properties) by certain gut microbes. S-(-)equol mimicking estrogen effects, sometimes enhancing and other times reducing them, which contributes to the improvement of PMD symptoms (7). SCFAs (butyrate, acetate, and propionate), have anti-inflammatory properties and exert regulatory effects on immune function and synthesis of neurotransmitters. Furthermore, certain gut bacteria can produce neurotransmitters like serotonin, dopamine, and GABA, which modulate mood, cognition, and behaviour (8). Dysregulation of these microbial metabolites may contribute to the mood disturbances and cognitive changes observed in PMD. PMD and Probiotics Some probiotics have been shown to synthesize metabolites such as SCFAs, neurotransmitters, and hormones. Probiotics have also been evaluated to alleviate symptoms of PMD. Many decades ago, in 1996, a study on sixteen women administered 3 capsules daily of a probiotic containing 1 billion of L. acidophilus NCDO 1748 and 1 billion Bifidobacterium bifidum NCDO 2203 strains in combination with antidepressant drugs (S-adenosyl-L-methionine) revealed modulation of their gut microbiome, normalization of enzymatic activities of fecal enzymes and relief of PMD symptoms, as observed in most participants (9). More recently, in a study on 80 women experiencing PMD, women receiving 10 billion L. paragasseri OLL2809 daily had less irritability and greater change in premenstrual arousal score compared to placebo after three menstrual cycles (10). Tablets of L. gasseri CP2305 was administered daily to 56 women over the course of 6 cycles. Overall, the probiotic group reported fewer PMD symptoms than placebo, including depressed mood and anxiety (11). Unfortunately, the exact mechanism of action (MoA) of probiotics to alleviate symptoms of PMD is not clearly known. Action on the mucosal barriers and immune system to modulate gut inflammation, antimicrobial activity against pathogenic microbes, secretion of gut hormones, and neurotransmitters are some MoAs that have been associated with probiotics in this context. Lactobacilli and Bifidobacteria have been shown to biotransform dietary isoflavones into S-(-)equol or dietary fibres into SCFA, two types of metabolites that have been associated with better outcomes in PMD. Conclusion The gut microbiome exerts profound effects on various aspects of women’s health, including the pathophysiology of PMD. Dysbiosis-driven inflammation, hormonal dysregulation, and alterations in neurotransmitter signalling contribute to the complex symptomatology of PMD. Obviously, more research in this field is needed to fully explain these complicated interactions so optimal treatments are available to relieve the symptoms of PMD. Meanwhile, Melissa can add micronutrients (calcium, vitamins B & D), fibres, fermented soy products, and probiotics to her diet to manage the symptoms of PMD and enjoy life every day with her family and friends. References 1) Cary, E. and P. Simpson. 2024. Premenstrual disorders and PMDD – a review. Best Practice & Research Clinical Endocrinology & Metabolism. 38(1):101858. 2) Bernstein, M.T., L.A. Graff, L. Avery, C. Palatnick, K. Parnerowski, L.E. Targownik. 2014. Gastrointestinal symptoms before and during menses in healthy women. BMC Womens Health. 14:14. 3) Siminiuc, R., D. Turcanu. 2023. Impact of nutritional diet therapy on premenstrual syndrome. Frontiers in Nutrition. 10:1079417. 4) Matijašić, M., T. Meštrović, H.C. Paljetak, M. Perić, A. Barešić, and D. Verbanac. 2020. Gut Microbiota beyond Bacteria—Mycobiome, Virome, Archaeome, and Eukaryotic Parasites in IBD. International Journal of Molecular Sciences. 21(8):2668. 5) Takeda, T., K. Yoshimi, S. Kai, G. Ozawa, K. Yamada, K. Hiramatsu. 2022. Characteristics of the gut microbiota in women with premenstrual symptoms: A cross-sectional study. PLoS One. 17(5):e0268466. 6) Okuma, K., K. Kono, M. Otaka, A. Ebara, A. Odachi, H. Tokuno, H. Masuyama. 2022. International Journal of Womens Health. 14:1435-1445. 7) Takeda, T. and Y. Chiba. 2022. Evaluation of a natural S-equol supplement in treating premenstrual symptoms and the effect of the gut microbiota: An open-label pilot study. Neuropharmacology Reports. 42(2):127-134. 8) Miri, S., J. Yeo, S. Abubaker, R. Hammami. 2023. Neuromicrobiology, an emerging neurometabolic facet of the gut microbiome? Frontiers in Microbiology. 14:1098412. 9) Minelli, E.B., A. Benini, L. Vicentini, E. Andreoli, M. Oselladore, R. Cerutti. 1996. Effect of Lactobacillus acidophilus and Bifidobacterium bifidum Administration on Colonic Microbiota and its Metabolic Activity in Premenstrual Syndrome. Microbial Ecology in Health and Disease. 9:6, 247-260 10) Sato, A. A. Fukawa-Nagira, T. Sashihira. 2023. Lactobacillus paragasseri OLL2809 Improves Premenstrual Psychological Symptoms in Healthy Women: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients. 15(23):4985. 11) Nishida, K., D. Sawada, T. Yasui, Y. Kuwano, K. Rokutan. 2021. Daily intake of Lactobacillus gasseriCP2305 ameliorates psychological premenstrual symptoms in young women: A randomized, double-blinded, placebo-controlled study. Journal of Functional Foods. 80:104426.
