The microbiome has broad and deep effects on pretty much all aspects of health. So broad and so deep, in fact, that how to best translate those effects into medical interventions remains an open question.

At one extreme of the spectrum, the most reductionist approach would be to identify individual bacteria, or even individual metabolites, that are correlated with a health outcome, and administer them as treatments.

That approach, though, risks being ineffective through oversimplification, in much the way that taking vitamin supplements is almost universally useless for health, though the foods containing those same vitamins improve health.

At the other end of the spectrum, fecal transplants are showing promise in combating intractable C. difficile infections. But they pose regulatory challenges as well as potential risks precisely because the microbiome's effects are so far reaching. The gut microbiome affects multiple organs, including the brain, and in a worst-case scenario, "you might also be transplanting Parkinson's into someone," Raja Dhir told BioWorld.

Dhir is co-CEO, with Luba Greenwood, of Luca Biologics, a startup that is aiming for the middle of the spectrum. The company plans to use "rational consortia" of commensal bacteria to treat women's health indications.

Aiming for that middle ground, he added, gives the treatments "the advantages of a living medicine," but focusing on narrower bacterial communities rather than a whole transplant results in "more manageable of an ecosystem," and ensures that "safety is paramount."

The company, which focuses on what it calls "live biotherapeutics for widespread, unmet medical needs in women's health," plans to start clinical trials in its first indication, urinary tract infections, in the third quarter of 2019. Luca is also developing treatments for bacterial vaginosis, preterm birth and infertility.

The company is tight-lipped about its funding. Business Insider has reported the company had raised $2.8 million, but Dhir and Greenwood would not disclose how much funding the company had.

Dhir said that "the research that the technology is emerging from had over $40 million of funding," including from the NIH and the Bill & Melinda Gates Foundation.

Those years and that funding has been used to repeatedly sequence the metagenome of the female reproductive and urogenital tracts. At this point, 3,000 different women have been sequenced, 1,000 of them have been followed and repeatedly sequenced for a period of more than five years.

The resulting data have allowed scientists to look at healthy vs. diseased states, as well as stable and unstable members of those commensal communities, and "identify core features within those genomes" that are associated with health, and with specific disease states.

Some commensals, including E. coli, Staphylococcus epidermidis and S. lugdunensis, and commensal Neisseria strains, help fight infection by directly killing, competing with or killing their pathogenic relatives.

The commensals Luca is focusing on work more indirectly.

"Certain strains can have an effect on host response," Dhir said. The presence of specific strains of lactobacilli, for example, "can change the entire host response to an infection."

Those lactobacilli can produce lactic acid in the vagina, which leads to an environment that is hostile to infections both due to its acidic pH and the production of mucus that is a physical barrier to infectious agents.

However, a significant fraction of women have microbiomes that are not characterized by the dominancy of lactobacilli. Such women are at increased risk of bacterial and viral infections, including urinary tract infections, bacterial vaginosis and HIV.

Even beyond infections, immunity plays a role in many conditions not classically considered immunological. Cancer research's biggest successes of the past decade have been the development of effective immune oncology treatments.

In pregnancy, too, the immune system plays multiple roles. The ability of the maternal immune system to tolerate a fetus that is genetically distinct from the mother during pregnancy is an obvious intersection between pregnancy and immunity.

Earlier this year, Luca co-founder Jacques Ravel, who is a professor of microbiology and immunology at the University of Maryland School of Medicine, published research in Nature Communications showing that both the composition of the cervicovaginal microbiome – including the presence of lactobacilli – and the maternal immunological profile, specifically levels of the antimicrobial peptide beta-defensin 2, affected the risk of spontaneous preterm birth. The effects of the microbiome were more pronounced in African American women, who have a higher risk of preterm birth than Caucasian women.