Female Gut and Genital Tract Microbiota-Induced Crosstalk and Differential Effects of Short-Chain Fatty Acids on Immune Sequelae

Abstract

The gut and genital tract microbiota of females represent very complex biological ecosystems that are in continuous communication with each other. The crosstalk between these two ecosystems impacts host physiological, immunological and metabolic homeostasis and vice versa. The vaginal microbiota evolved through a continuous translocation of species from the gut to the vagina or through a mother-to-child transfer during delivery. Though the organisms retain their physio-biochemical characteristics while in the vagina, the immune responses elicited by their metabolic by-products appear to be at variance with those in the gut. This has critical implications for the gynecological, reproductive as well as overall wellbeing of the host and by extension her offspring. The homeostatic and immunomodulatory effects of the bacterial fermentation products (short chain fatty acids, SCFAs) in the gut are better understood compared to the genital tract. While gut SCFAs prevent a leakage of bacteria and bacterial products from the gut in to circulation (leaky gut) and consequent systemic inflammation (anti-inflammatory/protective role); they have been shown to exhibit dysbiotic and proinflammatory effects in the genital tract that can lead to unfavorable gynecological and reproductive outcomes. Therefore, this review was conceived to critically examine the correlation between the female gut and genital tract microbiota. Secondly, we explored the metabolic patterns of the respective microbiota niches; and thirdly, we described the diverse effects of products of bacterial fermentation on immunological responses in the vaginal and rectal ecosystems.

Keywords: SCFA; dysbiosis; gut; inflammation; metabolite; microbiota; vagina.

FIGURE 1

Vaginal microbiota composition from periparturition to postmenopause. The menstrual cycle comprise of uterine and ovarian cycle. The proliferative phase of the uterine cycle coincides with the follicular phase of the ovarian cycle, which overlaps menstruation. +, increase; –, decrease; *cyclical change in intracellular glycogen content (2, 26, 27, 31, 51).

FIGURE 2

Saccharolytic fermentation of dietary non-digestible carbohydrates into short chain fatty acids (SCFAs) by gut microbiota. A cross feeding of intermediate metabolites between species exists. Acetate produced by Bifidobacterium spp. is utilized by Firmicutes (F. prausnitzii, Roseburia, Anaerostipes, Eubacterium) to produce butyrate (56). Lactate, succinate and 1, 2-propanediol do not usually accumulate to high levels in the colon of healthy adult humans due to their utilization by the propionate and butyrate-producing species (78, 82). Deficiency of these species and their metabolic by-products permits a “leaky gut” with transfer of bacteria and lipopolysaccharide to systemic circulation. A plausible hematogenous spread of these pathogen-associated molecular patterns to the genital tract or global induction of systemic inflammation can lead to genital tract infection/inflammation and unfavorable gynecological/reproductive outcomes (59). Furthermore, translocation of gut microbial species to the vagina and consequent high levels of vaginal SCFA production alters the vaginal microbiota leading to infection (94). AP, acrylate pathway; bat, butyryl-CoA:acetyl-CoA transferase; bk, butyrate kinase; DHAP, dihydroxyacetone phosphate; EMP, glycolytic Embden-Meyerhof-Parnas pathway; PEP, phosphoenolpyruvate; PP, propandiol pathway; PPP, pentose-phosphate pathway; SP, succinate pathway; WLP, Wood–Ljungdahl pathway. Adapted with permission from: Tungland (77).

FIGURE 3

Immunomodulatory roles of gut and vaginal microbiota-generated short chain fatty acids (SCFAs). SCFAs promote eubiosis (including increase in Lactobacillus spp. and low pH), tolerance and homeostasis in the gut by suppressing bacterial and lipopolysaccharide (LPS) translocation in to systemic circulation, inhibiting pro-inflammatory chemocytokine production and increase PGE₂, IL-10, and Foxp3⁺ T cells. In contrast, SCFAs mostly promote dysbiosis (including decrease in Lactobacillus spp. and high pH) and inflammation in the vagina. AMPs, antimicrobial peptides; CXCL, Chemokine (C-X-C motif) ligand; Foxp3⁺, forkhead box P3 positive; IFN-γ, interferon gamma; IL, interleukin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PGE₂, prostaglandin E₂; TNF-α, tumor necrosis factor alpha.

FIGURE 4

Cervicovaginal fluid metabolite profile in healthy condition (eubiosis) and infection (bacterial vaginosis, BV). Lac, lactate; Ace, acetate; But, butyrate; Prop, propionate; Succ, succinate. Data Source: Aldunate et al. (92). ****p < 0.0001 (χ² test).