INCREASED IMPORTANCE OF PREBIOTICS LIKE FOS IN WOMEN’S HEALTH

1. Health benefits of FOS

2. I Increased importance of ncreased importance of prebiotics like FOS IN WOMEN prebiotics like FOS IN WOMEN’’S HEALTH S HEALTH The continuum of a woman’s life can be divided into several life stages, each characterized by certain features that are accompanied by considerable hormonal changes. In addition to pregnancy, these are usually divided into infancy, puberty, reproductive age, climacteric period, and elderly years. 1 Different health issues may arise at each stage affecting the quality of life of women, such as menstrual cramps, mood swings, acne, uro -genital infections, hot flashes, weight gain, osteoporosis and typical aging-related conditions that affect the elderly such as frailty, decline in immunity, and cognitive ability. For a good quality of life, attention is required on interventions that can help manage these conditions mentioned. In this pursuit, the human gut seems to play a significant role. Role of gut health in women Role of gut health in women Recent research has thrown light on the role of the gut in maintaining overall health indicating a relationship between diet, microbiota and health status.2 Connections have also been found between the gut and skin microbiome 3; as well as the gut and vaginal microbiome.4 Many conditions, such as bone health, obesity, constipation, uro-genital infections are closely correlated with disturbances in the gut microbiome composition and functions. 5 These can be examined in the context of the different phases in a woman’s life. Modulation of gut health for better health in women  Puberty-associated health (Adolescence)  Obesity during adolescence  Acne in adolescents  Vaginal infections  Urinary tract infections (UTIs)  Pregnancy and infertility  Constipation  Gestational Diabetes (GDM)  Bone health  Potential Areas of Research Modulation of gut Modulation of gut health for better health in women health for better health in women With the effects of dysbiosis on various aspects of health at different stages in a woman ’s life, it seems imperative to pay attention to the modulation of gut health in women. Such modulation is possible with a dietary intervention using probiotics and prebiotics which therefore prove to be promising for the promotion and maintenance of health in women. Prebiotics like FOS have been shown to positively modify the gut microbiota composition. 6, 7 Puberty Puberty- -associated health associated health (Adolescence) (Adolescence) Page 1 1 of 9 9

3. Puberty in a young girl’s body brings about the increased production of certain hormones, leading to physical, emotional changes and finally the start of menstrual periods. Along with this, the skin becomes oily and acne may develop. The beginning of vaginal discharge causes a change in the vaginal environment that can lead to infections. Weight gain during this period can be rapid, requiring careful attention to diet. Additionally, adolescence is a time to build bone mass to reduce osteoporosis related adverse impact on health later in life. Obesity during adolescence Obesity during adolescence There is a growing appreciation that adolescents are at increasing risk for type 2 diabetes mellitus (DM) and the metabolic syndrome (MBS) as the prevalence of obesity increases in this age. 8, 9, 10 The prevalence of the MBS increases with obesity, reaching prevalence rates as high as 50% among morbidly obese adolescents. 10 Central obesity and insulin resistance also seem to play significant roles in PCOS. 11, 12 Polycystic ovary syndrome (PCOS) affects an estimated 5–10% of women of reproductive age; and typically presents during adolescence. The increasing incidence of childhood obesity has resulted in an alarming Increase not only in distressing symptoms but also impaired glucose tolerance and even diabetes among adolescent girls with PCOS. 13 Studies have reported that an increased intake of dietary fibre is associated with lower body weight14, 15 or less weight gain. 16 While limited studies are available reporting the efficacy of short chain FOS on satiety and weight management, increasing dietary fiber intake by using prebiotics has been shown to stimulate satiety hormones and enhance appetite control, thereby helping to manage body weight. 17 The consumption of a low calorie diet along with oligofructose has shown to result in significant decrease in body mass index and body fat percentage in adolescents. In girls and women, the rate of insulin resistance was also significantly reduced. 18 Acne in adolescents Acne in adolescents Acne represents the eighth most common medical disorder worldwide with 85% of adolescents and young adults in the age group of 12 and 25 being affected. 19 , 20, 21, 22 It is now also known that the skin microbiome changes at various phases of life. Before puberty, there is a majority of Firmicutes, Bacteroidetes, and Proteobacteria, whereas in puberty, more lipophilic species such as Propionibacteriaceae and Cornebacteriaceae dominate.23, 24 The skin microbiome prefers a relatively acidic environment (pH is around 5.0), which helps inhibit the growth of pathogens; and the gut microbiome appears to influence the skin microbiome. 25 SCFAs produced from fiber fermentation in the gut (propionate, acetate, and butyrate) are believed to play a central role in determining the predominance of specific skin microbiomic profiles. For example, Propionibacterium genus is capable of producing SCFAs, mainly propionic acid and acetate. Reportedly, propionic acid can exhibit a profound antimicrobial effect against USA300, the most prevailing community-acquired methicillin-resistant Staphylococcus aureus. 26, 27, 28 Such findings provide supportive evidence for a functional interactive mechanism between gut and skin. 25 Modulation of this microbiome through prebiotic consumption such as FOS therefore holds promise. Pre- and probiotic beneficial effects can be delivered topically or systemically (by ingestion). Nutritional products containing prebiotics and/or probiotics have already been shown to have a positive effect on skin by modulating the immune system and by providing therapeutic benefits for atopic diseases. 29 Vaginal infections Vaginal infections Page 2 2 of 9 9

4. Cervicovaginal infections are common, and one of the most important causes of illness in women of reproductive age. They can lead to mortality and complications such as miscarriage, cervical cancer, preterm delivery, and infertility. 1 If the vaginal microbiome becomes disrupted by antibiotics or other factors, the incidence o f bacterial vaginosis or candidal vulvovaginitis increases. 30 It has been noted that in bacterial vaginosis, there is a reduction in Lactobacillus and an increase in the abundance of other bacteria such as Prevotella. 31 In postmenopausal women, vaginal infections including bacterial vaginosis (BV) and vulvo-vaginal candidiasis (VVC) are caused by changes in the intravaginal environment, which are closely related to imbalances in vaginal microflora composition due to decreased estrogen. 32 Modulation of the vaginal microbial ecosystem with the use of probiotics has shown an effect in preventing vaginal infections in postmenopausal women. They also reduce the symptoms of vaginal infections (e.g., vaginal discharge, odor, etc.), and are thus helpful for the treatment and prevention of BV and VVC. 25 In-vitro studies have indicated that prebiotics like FOS promote the growth of Lactobacilli. Lactobacilli generated lactic acid to lower the vaginal pH and secreted antibacterial substances that inhibited the adhesion and replication of the pathogenic bacteria. FOS and GOS have shown potential prebiotic property for selected Lactobacilli strains 33. Urinary tract infections (UTIs) Urinary tract infections (UTIs) Urinary tract infections (UTIs) are particularly common among the female population with an incidence of about one percent of school aged girls and four percent of women through child bearing age. 34 Women are vulnerable due to their anatomy and reproductive physiology and the prevalence increases with advancing age, catheterization, sexual activity and menopause. 35 In premenopausal women, 90% of the vaginal flora is Lactobacilli, which protect the system against colonization with uropathogens such as E. coli. Biological changes due to menopause put these women at particular risk of contracting both primary and recurring UTIs because with estrogen loss, the walls of the urinary tract become weak and as such it reduces its ability to resist bacterial colonization. 36 Prebiotics such as FOS can be beneficial since any effects of prebiotics in the gut are reflected in/ on other parts of the body, such as the skin, vagina or bladder. 29, 37, 38 Pregnancy and infertility Pregnancy and infertility Studies have highlighted the adverse role that pathogenic microorganisms can have in preventing conception and birth of a healthy baby, but recently has there been an appreciation for the role of non-pathogens in a positive outcome. 39 The vagina, cervix, and uterus are exposed to bacteria, and the trillions of organisms in the intestine have access to the reproductive tract via the rectum and perineum. Thus, there is daily exposure of microbes to the reproductive tract, that can influence the reproductive process from conception to the end of gestation. A pilot study published in The Australian and New Zealand Journal of Obstetrics and Gynaecology has identified trends in the microbiome of the female reproductive tract in women experiencing infertility, wherein infertile women more often had Ureaplasma in the vagina and Gardnerella in the cervix. 40 Page 3 3 of 9 9

5. Scientific studies have suggested that a vaginal microbiome plays a role in preterm birth41 and that a vaginal microbiome rich in lactobacilli reduces its incidence.42, 43 Prior studies have reported associations between Lactobacillus-deficient genital microbiota and other poor reproductive outcomes such as preterm delivery, late miscarriage44, 45 and cervicitis. 46 Though not clinically proven yet, it appears that the modulation of gut microbiota with interventions such as consumption of probiotics and prebiotics may have promise in further modulation of the vaginal microbiome. Constipation Constipation The prevalence of constipation in pregnancy ranges from 11% to 44%. 47 In pregnant women, FOS ingestion alleviates constipation. 48 There is an increase in stool frequency which suggets that dietary FOS helps alleviate the gastrointestinal discomfort in pregnant women49. In old age too, constipation can affect the quality of life significantly. Interventions with consumption of prebiotic fibers help by modulating the gut microflora. A cross-over study50 performed in elderly CAPD patients with chronic constipation proved that FOS supplementation was both effective and well-tolerated in this population. Furthermore, increased production of SCFAs in the gut by pre and probiotics, reduces the pH in the colon and this lower pH enhances peristalsis in the colon. 51 These microbe-derived SCFAs have been shown to stimulate host receptors for gut motility. 52 Gestational Diabetes (GDM) GDM affects 5–20% of pregnancies and the prevalence seems to be rising53, 54 and is associated with many adverse maternal and neonatal outcomes. 55, 56 20-50% of GDM women are expected to develop type 2 diabetes within 10 to 20 years. described in pregnancies either before the onset of GDM or after its diagnosis. 59, 60 57, 58 Change in gut microbiota composition have been While certain subgroups have been found in the GDM patients, the subgroup with a higher relative abundance of Bacteroides, the bifidogenic prebiotic fibers such as FOS and GOS have been postulated to be beneficial to control the gestational weight gain. 61 Bone health Bone health Bone health is of utmost importance to women, especially postmenopausal, since osteoporosis sets in rapidly after this phase. Prebiotics have been demonstrated to increase mineral absorption, particularly that of calcium and magnesium and to reduce bone loss in post-menopausal women. In a double-blind, placebo-controlled cross-over study, 6 weeks of treatment with FOS increased calcium and magnesium absorption in postmenopausal women (average age 72 years old). 62 While not all subjects responded to treatment, the ones with a lower bone density (DEXA T -score of −1.7) absorbed more calcium and magnesium than subjects who had an average Tscore of 0.2. GOS was also shown to modestly increase calcium absorption in postmenopausal women. 63 Similarly, 1 year of short chain FOS treatment reduced bone loss in postmenopausal women with reduced serum and urine bone turnover markers. 64 Studies conducted on post-menopausal women have also shown that FOS improved the Mg2+ absorption, and the overall retention was higher than in the placebo group. 65 There is clear evidence that prebiotics such as lactulose, FOS, and GOS, when given in large doses (10–40 g per day) can have beneficial effects of calcium bioavailability 66. The underlying Page 4 4 of 9 9

6. mechanisms are related to the increased bacterial production of short-chain fatty acids, which is promoted by the greater supply of prebiotic substrate. 67 Potential Areas of Research Potential Areas of Research Cancer Cancer Recently, potential links have been identified between the microbiome and gynaecological cancers.3 A healthy vaginal microbiome dominated by Lactobacillus species may have a protective effect and therapeutic potential. In the Lactobacillus-dominated microbiomes, the pH is typically < 4.5. Such a pH is well tolerated by Lactobacillus, but inhibitory to several other types of bacteria. Cervical cancer Cervical cancer The imbalance of vaginal flora leads to multiple gynecological diseases, such as high -grade cervical intraepithelial neoplasia (CIN), and cervical cancer. 68 A decline in the quantity and activity of Lactobacillus leads to an overgrowth of anaerobic bacteria. 69 Deleterious metabolites such as nitrous acid can be produced by these organisms, and the risk of HPV infection also increases. 70 Persistent infection of oncogenic HPV is a cause of cervical cancer. 71 Breast cancer Breast cancer One in eight women will be diagnosed with breast cancer in their lifetime. 72 While prevention of cancer is still being investigated, one study73 found a relationship between breast cancer and gut health. The authors stated that “microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. Our findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications.” Similarly, another study found that bacterial genes living in the intestines can play a significant role in metabolizing estrogen. This can affect a woman’s risk of developing postmenopausal estrogen receptor-positive breast cancer. 74 Colo Colo- -rectal cancer rectal cancer Considered the second deadliest form of cancer after lung cancer, colorectal cancer is one of the most preventable, as there are various dietary factors that seem to play a protective role against the disease. It has previously been shown that prebiotics plus probiotics added to the diet of animals can reduce the development of cancer dramatically. In one study, 80 human subjects who either had intestinal polyps (precancerous lesions) removed or had been treated for colon cancer were given placebo or prebiotics plus probiotics combined (synbiotic) daily for 12 weeks. The treated group showed significantly decreased damage to the cell’s DNA, improved DNA repair and reduced cell proliferation rate. 75 Conclusion Conclusion Since the growth of Lactobacilli in the gut is stimulated by prebiotics, and since this can help influence the vaginal and skin microbiome, dietary supplementation with FOS seems a promising strategy to enhance the quality of life in women through different phases of their life. 1 Makvandi S, Zargar Shoushtari SH. The Relationship of Cervicovaginal Infections in PAP Smear Sampels with Some Factors In Ahvaz, IRAN; An Epidemiological Study. Jundishapur Journal Of Chronic Disease Care. 2012;1(1):55-61. Page 5 5 of 9 9

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