Tremendous advances in next-generation sequencing and omics technologies have catapulted microbiome science into an exciting new frontier in medicine. Emerging data suggest that the microbiome—the rich ecosystem of more than 100 trillion bacteria, fungi, and viruses in and on the human body—is integral in almost all aspects of human health and disease and that analysis of the microbiome one day could play an important role in clinical practice.
“The pendulum has swung from a focus on killing pathogenic bacteria to a focus on healthy, symbiotic, and commensal microbes,” said Melissa Melby, PhD, co-director of the Humans and the Microbiome Program at the Canadian Institute for Advanced Research (CIFAR) in Toronto. “There has been a shift in clinical care as well as the popular consciousness with the realization that microbes are not all bad.”
This deeper appreciation of the microbiome’s power doesn’t mean that clinical labs should expect to be performing omic analyses of the microbiome anytime soon, according to Robert Britton, PhD, professor of molecular virology and microbiology at Baylor College of Medicine in Houston. “I do believe that in five to ten years, we’ll see microbiome-based therapies making it to clinics, but what that’s going to be, who knows,” he said. “We now must do the heavy lifting and find the functions behind…associations showing microbiotas have positive and negative effects on different types of diseases.”
With more than 1 million genes—versus 23,000 in the human genome—the abundance and diversity of the microbiome is staggering; microbiome communities in different body sites have unique profiles, as does each individual, influenced by diet, medications, and other environmental factors.
A Burgeoning Field
Research into the complex and dynamic interactions between microorganisms and their human hosts has taken off in recent years. One of the most promising lines of investigation involves the gut microbiome. Initially thought to have a role limited to digesting complex carbohydrates and synthesizing vitamins and nutrients, this microbiome now is understood to be a structural and functional part of the body. Evidence shows that the gut microbiome globally governs host physiology by regulating metabolism, immunity, and even the gut-brain axis, via signaling of unique microbiome-generated bioactive metabolites.
Disturbances in normal gut microbial profiles have been associated with a range of conditions from cancer to metabolic, inflammatory, cardiovascular, and even neurodegenerative diseases. “Amazing and incredibly large observational studies have shown very clear associations between features of the gut microbiome and clinical outcomes,” said Jonathan Peled, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. “We and others have found associations between perturbations of the gut microbiome and complications of bone marrow transplant.”
Peled and his team profiled fecal samples taken from a large cohort of cancer patients undergoing bone marrow transplants at four geographically distant transplant centers and found that patients with more diverse gut flora had better survival outcomes than those with lower diversity (N Engl J Med 2020;382:822-34). These findings imply that screening gut bacteria or providing interventions to balance the gut ecosystem prior to transplants might enhance patients’ health.
A specific gut bacterial profile also has been reported in people with pulmonary arterial hypertension (PAH) (Hypertension 2020;119:14294). This signature predicted the presence of PAH with 83% accuracy. Although these data are correlative, they suggest that gut microbiome changes eventually could become a way to screen for the disease. However, changes in the microbial ecosystem are what drive changes in microbial function—not merely the presence or absence of specific microbial species, said W.H. Wilson Tang, MD, professor of medicine and research director of heart failure and transplant at the Cleveland Clinic Lerner College of Medicine.
“For a successful clinical transition, we have to go beyond a very pathway-specific manner of looking at things and instead look at how systems interact,” he explained. His team and others have identified metabolites processed by gut microbes that drive the progression of several cardiovascular pathologies like atherosclerosis, hypertension, heart failure, and type 2 diabetes. “These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabo-lites that can directly or indirectly affect host physiology,” wrote Tang in a recent review (Nat Rev Cardiol 2019;16:137-54).
Personalized Nutrition Therapy
In addition to its diagnostic potential, the human microbiome also represents an exciting new target for diet-based disease interventions. Recently, several pivotal studies have revealed new insights into how the diet influences the gut microbiome, with potential implications for disease modification and treatment.
Most notably, a team led by Eran Segal, PhD, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, developed a machine-learning algorithm to integrate microbiome data and evaluate an individual’s glycemic response to identical foods (Cell 2015;163:1079-94).. The investigators discovered not only that each person’s blood glucose levels were different even when they consumed the same food as others but also that microbiome rather than genetic data correctly predicted each person’s blood glucose response to an identical food. Furthermore, the team’s algorithm accurately predicted individual dietary interventions that successfully balanced glucose levels in pre-diabetic people—outperforming the standard-of-care diet.
These unexpected findings portend a whole new era of personalized nutrition in which specific diets based on an individual’s gut microbiome composition could enhance a person’s health outcomes. These findings also validate the idea that integrating microbiome readouts in combination with genetic data offers a more reliable and powerful approach to assessing disease risk. “Deep phenotyping of human cohorts, including the collection of microbiome data, could transform therapy development,” opined Segal.
Gut Over Genetics
The Weizmann Institute team also showed that a host’s genetics has only a “minor role” in the gut microbiome’s composition, suggesting that individualized microbiome alterations aimed at improving clinical outcome can be carried out across people from diverse genetic backgrounds (Nature 2018;555:210-5).
“Understanding and integrating microbiome variability holds potential to promote personalized preventive and therapeutic approaches,” said Eran Elinav, MD, PhD, co-author of both the Cell and Nature papers and a professor of immunology at the Weizmann Institute.
Based on Elinav’s and others’ findings, including his own, Melby’s CIFAR colleague, Brett Finlay, PhD, recently put forth the provocative hypothesis that chronic diseases like obesity, heart disease, and diabetes might be transmissible akin to an infectious disease (Science 2020;367:250-1). “Data increasingly show that the microbiota is dysbiotic (altered) in individuals with various [noncommuni-cable diseases] NCDs … Therefore, we propose that some NCDs could have a microbial component and, if so, might be communicable via the microbiota,” wrote Finlay, co-director of the CIFAR Humans and the Microbiome Program and professor of microbiology and immunology, biochemistry, and molecular biology at the University of British Columbia in Vancouver.
The Road to Interventions
These emerging findings and theories have the microbiome poised to play an integral role in precision medicine. “We are at a point of inflection where we are transitioning from observational studies and some phenomenological mouse work to an era of deeper mechanistic analysis in animal models and to clinically actionable tests and interventions,” said Peled.
The future armamentarium of microbiome diagnostics and therapeutics offers broad and deep possibilities for controlling and treating different diseases—personalized diets, prebiotics, postbiot-ics, microbiota transplantation, engineered bacteriophages, microbial metabolites, microbiota precision editing, and intestinal barrier modulation. So far, however, just one application has advanced clinically—fecal microbiota transplantation (FMT) to treat recurrent Clostridioides difficile infections. “That’s the only example where it has really worked and where there has been actual progress that has been proven,” asserted Peled. Published reports indicate that at least 10,000 FMT procedures take place annually, and FMT is also being investigated in at least 300 clinical trials.
Despite accumulating data about its efficacy, however, this treatment still faces hurdles. In mid-March the Food and Drug Administration issued a safety alert warning about the risk of serious, even life-threatening infections linked to FMT after six patients were infected with Escherichia coli following the procedure, the second such warning within a year.
As the challenges with FMT illustrate, progress is slow going from identifying associations to developing accurate and reliable methods for analyzing the gut microbiome and creating safe and effective clinical treatments.
“Although we are starting to tap into a lot of potential in the gut microbiome space, it is still a long and nebulous road to achieving true clinical impact,” said Braden Tierney, a computational biologist and doctoral candidate at Harvard Medical School. His recent work posted on the preprint server bioRxiv found that the genetic signature of gut microbes was 20% better than their own genes at discriminating between healthy and diseased individuals. The microbiome also outperformed by 50% association studies predicting whether an individual had colorectal cancer.
“A big challenge is getting from correlation to causality and figuring out mechanisms for how microbes are actually affecting our health,” he added.
Melby agreed that metabolomic and proteomic analyses of microbiome function will be key to making this research applicable to clinical settings. “Big data analysis and modeling is also going to be critical as it is not a particular organism or a particular metabolite, but a consortium of organisms that determine health or non-health,” she noted.
Methodological variation poses another challenge. “There are so many different methods and ap-proaches you can take to analyze data that if you put them side-by-side, you could end up with varying results,” said Tierney. Since microbiome cohorts are relatively homogenous and limited in number, it is difficult to decide which observations are generalizable to larger patient populations across different geographical locations, he added.
Despite these hurdles, the promise of microbiome-based clinical tests in predicting, diagnosing, and treating diseases bodes well for the future of personalized medicine.
Pranali P. Pathare, PhD, is a medical writer and editor in St. Louis.
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