30 November 2022

Vaginosis in vitro

A vagina on a chip will help to study dysbiosis

Yulia Panchenko, PCR.news

Recently, a lot of research has been devoted to the microbiome, primarily the intestine. However, bacterial communities of the vagina are attracting more and more attention. Violations of the vaginal microbiome lead to the development of bacterial vaginosis, which affects about 30% of women. Vaginosis increases the risk of contracting sexually transmitted infections, as well as the risk of premature birth. Vaginosis is often accompanied by the accumulation of Gardnerella vaginalis bacteria. Now vaginosis is treated with antibiotics, but there are side effects. I would like to choose an alternative therapy, but researchers are stopped by the lack of a preclinical model — animal models are too different from humans. So, bacteria of the genus Lactobacilli (L.crispatus, L.gasseri and L.jensenii) make up more than 70% of the human vaginal microbiome, and in other mammals — less than 1%.

Researchers from the USA have created a preclinical model — a vagina on a chip (Vagina Chip). To do this, they cultured primary human vaginal epithelial cells on one side of the porous membrane, and primary uterine fibroblasts on the reverse side. After five days of cultivation, several layers of differentiated cells spontaneously developed on the chip, repeating the structure of the vaginal tissues. The authors confirmed the presence of tissue-specific markers.

The vagina on the chip was grown in the presence of β-estradiol — the female sex hormone — in the maximum concentrations characteristic of the female body. Under these conditions, the expression of genes encoding estrogen receptor 1 (ESR1), progesterone receptor (PGR) and claudine 17 (CLDN17) decreased, while the expression of genes encoding PCK1, GCGR, KRT15 and ZO-1 increased. Thus, the resulting organ on the chip can react to sex hormones in the same way as the organ itself.

The authors have shown that L.crispatus consortia consisting of different strains can grow on a chip. The presence of these bacteria did not interfere with maintaining the physiological pH or cell viability.

Both D- and L-lactic acid have antimicrobial activity. However, the vaginal epithelium can only produce L-lactic acid. D-lactic acid is a biomarker of the metabolic activity of L. crispatus. Indeed, both enantiomers were determined on chips colonized by microbial consortia.

It is believed that bacteria of the genus Lactobacillus reduces inflammation. Indeed, when bacteria were present on the chip, the expression of many pro-inflammatory cytokines, such as IL-6, IL-8, IL-1α, IL-1β, IP-10, decreased in cells. This happened even in the absence of immune cells.

Next, the chip was inoculated with bacteria that are not optimal for the human microbiome, such as G.vaginalis, Prevotella bivia and Atopobium vaginae. The bacteria took root well on the chip, while the pH increased. Also, in the presence of these bacteria, cell viability decreased, and the production of proinflammatory cytokines (IL-6, IL-8, IL-1ß and IP-10) increased. This confirms the results obtained in vivo.

Thus, the created chip induces differentiation of the vaginal epithelium, responds to hormones and supports the microbiome. L. crispatus consortia, consisting of different strains, attach to the epithelium, produce D-lactic acid and suppress inflammation. Dysbiosis, on the contrary, damages the epithelium and promotes inflammation. The authors plan to study the role of resident and circulating immune cells on the interaction of the host organism and the microbiome.

Article by Mahajan et al. Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip is published in the journal Microbiome.

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