Fatty acids restore normalcy to the vaginal microbiome

Itchiness, weird discharge, an unmistakable stinky smell — these are all hallmarks of bacterial vaginosis (BV), one of the most common vaginal infections worldwide. For some people, a quick course of antibiotics — typically metronidazole — can rid the infection. For over half, however, the infection can return within a year.

Bacterial vaginosis occurs when bacteria that don’t use oxygen dominate the vaginal microbiome over “healthy” species of bacteria, like Lactobacillus. Because metronidazole aggressively nukes many different bacteria, it is difficult to reestablish a microbial balance. Many people can get stuck in a seemingly unending cycle of infection, then antibiotics, then another infection, then more antibiotics — and repeat. “It’s a real clinical problem,” said Douglas Kwon, an infectious disease physician at the Ragon Institute.

Kwon and his team wanted to see if there were other ways, besides antibiotics, to help reestablish this microbial balance. In a study recently published in Cell, the scientists found that a certain type of fatty acid called oleic acid encouraged the growth of a specific type of Lactobacillus bacteria that is associated with a non-BV microbiome (1). This approach, the scientists said, could open the door to more specific, non-antibiotic strategies to treat BV while potentially reducing the risk of recurrence.

There’s a constant back-and-forth communication, but we actually don’t understand the language between the host and the bacteria.
- Douglas Kwon, Ragon Institute

According to Kwon, different species of Lactobacillus can have varying effects on the vaginal microbiome. A microbiome that has lots of Lactobacillus crispatus is associated with better health outcomes. A microbiome that has lots of Lactobacillus iners, however, is more likely to turn into BV. “Lactobacillus iners seems to be unique in that it has this sort of promiscuity and facilitates transition to these non-optimal states,” said Kwon.

When a patient takes metronidazole for BV, Kwon and his team noticed that the microbiome became dominated by L. iners, not L. crispatus. And because an L. iners-dominated microbiome can quickly lead to BV, this could explain the high rate of recurrence for these patients. To combat this, the scientists wondered if there was a compound that could selectively encourage the growth of L. crispatus as opposed to L. iners.

Inspiration for this compound struck from an everyday product in the laboratory: detergents. Kwon and the team noticed that one of these detergents had a different effect on the growth of L. crispatus compared to L. iners. Within the detergent was a long-chain fatty acid. When the scientists added different long-chain fatty acids to bacterial cultures containing either L. crispatus or L. iners, they found that one of these fatty acids — oleic acid — would inhibit the growth of L. iners, but not that of L. crispatus.

To figure out why this was happening, the scientists looked at the genes that each bacterial species activated in response to the addition of oleic acid. They found that L. crispatus expressed an efflux pump that enabled them to uptake the oleic acid as well as oleate hydratase, an enzyme that can convert the compound into something useful. L. iners, on the other hand, “cannot utilize oleic acid as a metabolic substrate because it doesn’t have the same mechanism,” Kwon said. “Those genetic mechanisms are completely and uniquely absent within iners.”

Kwon and the team saw that these findings were recapitulated in real-life women. Over a decade ago, Kwon had established a longitudinal study with South African women who would provide vaginal fluid samples over time, while also learning about health maintenance, research, and job skills. When the team looked at the fluid samples of women whose vaginal microbiomes were dominated by non-iners Lactobacillus, they found the metabolites of oleate hydratase — meaning that the enzyme was active and working. “This gave us more reassurance that this is real and probably important,” Kwon said. “The enzyme is very active not just in the bacteria when you grow them in the lab but is active in people.”

When the scientists went back to the lab, they tested to see if oleic acid could help promote the dominance of L. crispatus in a lab dish model of the vaginal microbiome. They saw that, as expected, treating with metronidazole caused L. iners to become the dominant bacteria. However, when using oleic acid alone or in conjunction with metronidazole, L. crispatus became dominant. This meant that even in a more complex model, the fatty acid could help bring the distribution of bacteria to a “healthier” state.

This work has “really advanced the field,” said Gilda Tachedjian, a virologist at the Burnet Institute who has studied the vaginal microbiome. She notes that a critical next step would be seeing if, in women, oleic acid could shift the microbiome out of a BV-like state.

It’s a goal shared by Kwon and his team, who are interested in starting a clinical trial with oleic acid for BV treatment. “There’s a constant back-and-forth communication, but we actually don’t understand the language between the host and the bacteria,” he said. “Understanding that in greater detail will help us better intervene to leverage the vaginal microbiome to improve women’s health outcomes globally.”