Emerging datasets from large human cohorts are dissecting the underlying mechanisms of microbiome–host interactions and accelerating progress in targeted microbiome therapeutics.
The human microbiome was first sequenced in the early 2010s, planting initial ideas that microbiome-targeting therapeutics could be developed. However, it was difficult to determine the direct role of the human microbiome in health and disease because of small datasets, confounding environmental factors and technical limitations. Early clinical trials were unsuccessful, dampening initial enthusiasm, and it was clear that more details about biological links between microbes and disease were needed. Recent years have filled in these links with huge datasets and important biological insights. A recent study used large-scale metagenomic profiling of gut microbiomes and paired host health data from about 34,000 participants in the United States and United Kingdom to define and develop a ranking of bacterial species associated with human health markers, providing links between diet, gut microbiota and health outcomes1. Another study integrated 168,464 publicly available 16S ribosomal RNA gene amplicon sequencing samples from 68 countries to build the Human Microbiome Compendium2. Advances in multi-omic approaches and computational pipelines have defined the healthy human microbiome, highlighted the correlation between gut, vaginal, skin and oral microbiomes and human health, and identified predictive, diagnostic and prognostic markers for various diseases3,4.
However, increasingly large human datasets and multi-omics analyses have shown substantial interindividual variability in microbiome composition, making clinical translation of disease markers slow. Additionally, the complexity of microbial interactions makes predicting outcomes difficult — especially for clinical trials. Microbes have demonstrated that they have unique, constantly evolving mechanisms of antimicrobial resistance when confronted with antibiotics. Additionally, antibiotic use leads to gut, skin and oral microbiome dysbiosis — substantial disruption of the balance between microbiota and the loss of beneficial microbes5,6,7. Providing evidence that modifying the microbiome is associated with a positive, predicted outcome and learning how antimicrobial resistance emerges requires a high-level understanding of biological mechanisms.
In late 2022 and early 2023, the US Food and Drug Administration approved the first microbiome-based therapeutics, both of them to treat recurrent Clostridioides difficile infections8. C. difficile infection mainly happens after heavy and prolonged use of antibiotics and leads to gastrointestinal distress. However, direct causal evidence of the drugs’ activity was, at that time, unknown, limiting their use more broadly. Recently, experiments showed that one of the drugs led to an increased number of Firmicutes species, which produced metabolites to directly inhibit the growth of C. difficile and other opportunistic pathogens9,10.
While there have not been many follow-ups to these early approvals, researchers are now providing evidence for the direct functional effect of the metabolic output of microbial communities, and the insights into host–microbe interactions are poised to lead to breakthroughs. There is now evidence linking microbiome dysbiosis to disease onset and/or severity, and companies are using these data to develop therapeutics to treat and prevent diseases.
For example, microbiome dysbiosis has been linked with atopic diseases (atopic dermatitis, food allergy and allergic asthma). These conditions eventually lead to immune system dysfunction that triggers the production of IgE antibodies and inflammatory responses. Given the recent wealth of infant gut microbiome data, Siolta Therapeutics is combining these data with bioinformatic tools to isolate specific symbiotic organisms from healthy infants that can be manufactured as drugs to treat dysbiosis. Their most promising candidate prevents atopic disease in infants as a preventative, sustainable oral live biotherapeutic. Even a year after taking the drug, it reduced risk of atopic dermatitis by 64% and the risk of food allergy by 77% in an infant population. Whether this sustainability is due to durable engraftment of beneficial microbes or adaptive immune modulation is yet to be established.
Metabolites such as short chain fatty acids (SCFA) and bile acids produced by microbiota can enter circulation and affect human health11. Community-scale metabolic models have now been used to predict individual-specific SCFA production profiles and can help design combinatorial prebiotic, probiotic and dietary interventions in silico12. However, it is yet to be shown whether the direct administration of these metabolites to treat diseases is as efficient as enriching for microbes that produce them, especially in the complex gut ecosystem.
Microbes producing the SCFA butyrate have been shown to support a healthy gut lining and inhibit inflammatory immune cells in the gut13. Maat Pharma has combined a proprietary cryoprotectant for butyrate-producing microbes with a pool of donor-derived microbes from stool to restore the gut ecosystem in gastrointestinal acute graft-versus-host disease. The severity of this disease is associated with a decrease in gram-positive anaerobic bacteria and reduction in the production of butyrate14. Batch-to-batch variability, traditionally a problem when using single-donor stool treatments, is reduced by pooling donor-derived microbes, ensuring consistency15. The company is also developing drugs to improve response to immune checkpoint inhibitor (ICI) therapies in solid tumors, on the basis of previous studies showing that healthy or ICI-responder donor-derived fecal microbial transplants directly improve responses to melanoma therapy16,17,18. By using a co-cultivation system that maintains the full functional diversity of the microbiome, they are more equipped to demonstrate mechanistic details of these host–microbe interactions.
Other small molecules produced by microbes can be identified with computational and experimental approaches and used as therapeutic targets. One such example is curli, a cell surface amyloid protein produced by certain bacteria. CsgA, a major subunit of curli fibers, promotes α‑synuclein pathology in the gut and the brain in mice overexpressing the human amyloid α-synuclein19. Vertero Therapeutics is developing an oral small molecule targeting CsgA in patients with Parkinson’s disease who are positive for its expression to slow disease progression.
Non-gut microbiome datasets are also growing in size and number, with several companies working on skin, oral and vaginal microbiome-targeted therapeutics. Freya Biosciences correlates vaginal microbiome dysbiosis with changes in immune profiles — in particular, increased activation of the immune response20. Increased immune responses could potentially lead to negative reproductive health outcomes, such as preterm birth or infertility. The company created a cell bank for beneficial strains of isolated Lactobacillus communities from donors, which can be grown at scale by fermentation and inserted into capsules for vaginal transplantation. Trials for treatment of women with asymptomatic vaginal dysbiosis are ongoing, in addition to a clinical trial in women undergoing in vitro fertilization to assess how the vaginal microbiome is associated with pregnancy outcomes following frozen embryo transfer.
With all these new attempts to block their activity, microbes will continue to evolve their defense systems. Companies are using datasets to identify and design antimicrobial peptides or small molecules with distinct modes of action to continually combat emerging antimicrobial resistance. Phare Bio uses generative AI to design and develop small molecule antibiotics with novel modes of action, staying one step ahead of microbe evolution. The company predicts it will produce up to 15 novel small molecules by 2030. In a streamlined path to commercialization, once an antibiotic passes preclinical development, large pharma companies have partnered with Phare Bio to move the product into clinical trials.
Researchers have been gathering microbiome data for over 15 years, and now there are tools to process and use it effectively. Even further, combining these data with AI and synthetic engineering technologies will continue to facilitate the generation of therapeutics. Direct engineering of human microbes for therapeutic benefit is in early stages, but it has been accomplished21, and more will come as the biological pathways continue to be teased out.