Thousands of species of microbes—bacteria, viruses, fungi, and protozoa—inhabit every internal and external surface of the human body. Collectively, these microbes, known as the microbiome, outnumber the body’s human cells by about 10 to 1 and include more than 1,000 species of microorganisms and several million genes residing in the skin, respiratory system, urogenital, and gastrointestinal tracts. The microbiome’s complicated relationship with its human host is increasingly considered so crucial to health that researchers sometimes call it “the forgotten organ.”
Disturbances to the microbiome can arise from nutritional deficiencies, antibiotic use, and antiseptic modern life. Imbalances in the microbiome’s diverse microbial communities, which interact constantly with cells in the human body, may contribute to chronic health conditions, including diabetes, asthma and allergies, obesity and the metabolic syndrome, digestive disorders including irritable bowel syndrome (IBS), and autoimmune disorders like multiple sclerosis and rheumatoid arthritis, research shows.
While study of the microbiome is a growing research enterprise that has attracted enthusiastic media attention and venture capital, its findings are largely preliminary. But some laboratorians are already developing a greater appreciation for the microbiome’s contributions to human biochemistry and are considering a future in which they expect to measure changes in the microbiome to monitor disease and inform clinical practice.
Pivot Toward the Microbiome
Following the National Institutes of Health (NIH) Human Genome Project, many scientists noted the considerable genetic signal from microbes in the body and the existence of technology to analyze these microorganisms. That realization led NIH to establish the Human Microbiome Project in 2007, said Lita Proctor, PhD, its program director. In the project’s first phase, researchers studied healthy adults to produce a reference set of microbiomes and a resource of metagenomic sequences of bacteria in the airways, skin, oral cavities, and the gastrointestinal and vaginal tracts, plus a catalog of microbial genome sequences of reference strains. Researchers also evaluated specific diseases associated with disturbances in the microbiome, including gastrointestinal diseases such as Crohn’s disease, ulcerative colitis, IBS, and obesity, as well as urogenital conditions, those that involve the reproductive system, and skin diseases like eczema, psoriasis, and acne.
Phase 1 studies determined the composition of many parts of the microbiome, but did not define how that composition affects health or specific disease. The project’s second phase aims to “answer the question of what microbes actually do,” explained Proctor. Researchers are now examining properties of the microbiome including gene expression, protein, and human and microbial metabolite profiles in studies of pregnant women at risk for preterm birth, the gut hormones of patients at risk for IBS, and nasal microbiomes of patients at risk for type 2 diabetes.
Promising Lines of Research
Cystic fibrosis and microbiology investigator Michael Surette, PhD, sees promising microbiome research not just in terms of evidence of its effects on specific diseases, but also in what drives changes in the microbiome. Surette is Canada research chair in interdisciplinary microbiome research in the Farncombe Family Digestive Health Research Institute at McMaster University
in Hamilton, Ontario.
One type of study on factors driving microbiome change examines how alterations in composition and imbalances in individual patients relate to improving or worsening disease. “IBS, cystic fibrosis, and chronic obstructive pulmonary disease all have periods of instability or exacerbation,” he noted. Surette hopes that one day, tests will provide clinicians the ability to monitor changes in microbial composition over time and even predict when a patient’s condition is about to deteriorate. Monitoring perturbations to the gut microbiome might also help minimize collateral damage to the microbiome during aggressive antibiotic therapy for hospitalized patients, he added.
Monitoring changes to the microbiome also might be helpful for “culture negative” patients, who now may receive multiple, unsuccessful courses of different antibiotics that drive antibiotic resistance. Frustration with standard clinical biology diagnosis of lung infections in cystic fibrosis patients first sparked Surette’s investigations into the microbiome. He hopes that future tests involving the microbiome might also help asthma patients with neutrophilia, community-acquired pneumonia patients who harbor complex microbial lung communities lacking obvious pathogens, and hospitalized patients with pneumonia or sepsis. He envisions microbiome testing that would look for short-term changes indicating whether or not a drug is effective.
Companion Diagnostics
Daniel Peterson, MD, PhD, an assistant professor of pathology at Johns Hopkins University School of Medicine in Baltimore, believes the future of clinical testing involving the microbiome lies in companion diagnostics for novel treatments, and points to companies that are already developing and marketing tests that will require such assays.
Examples of microbiome-focused enterprises abound, including Genetic Analysis, based in Oslo, Norway, with its high-throughput test that uses 54 probes targeted to specific bacteria to measure intestinal gut flora imbalances in inflammatory bowel disease and irritable bowel syndrome patients. Paris, France-based Enterome is developing both novel drugs and companion diagnostics for microbiome-related diseases such as IBS and some metabolic diseases. Second Genome, based in South San Francisco, has developed an experimental drug, SGM-1019, that the company says blocks damaging activity of the microbiome in the intestine. Cambridge, Massachusetts-based Seres Therapeutics has received Food and Drug Administration orphan drug designation for SER-109, an oral therapeutic intended to correct microbial imbalances to prevent recurrent Clostridium difficile infection in adults.
One promising clinical use of the microbiome is fecal transplantation, which both prospective and retrospective studies have shown to be effective in patients with C. difficile infections who do not respond to front-line therapies, said James Versalovic, MD, PhD, director of Texas Children’s Hospital Microbiome Center and professor of pathology at Baylor College of Medicine in Houston. “Fecal transplants and other microbiome replacement strategies can radically change the composition of the microbiome in hours to days,” he explained.
But NIH’s Proctor discourages too much enthusiasm about fecal transplant. “Natural products like stool can have [side] effects,” she pointed out. “The [microbiome research] field needs to mature and we need to verify outcomes before anything becomes routine.”
Hurdles for Lab Testing
While he is hopeful that labs someday will use the microbiome to produce clinically useful information, Surette pointed to several problems that must be solved beforehand. First, molecular methods commonly used right now should be more quantitative and accurate. Additionally, research on the microbiome encompasses a wide variety of protocols, some of which are better at extracting particular types of bacteria and therefore can give biased views of communities living in the body. Also, tests may need to distinguish between dead and live microbes. Another hurdle is that labs using varied bioinfomatic methods may produce different results from the same sample, a problem that Surette sees as ripe for a solution from clinical laboratorians, who have expertise in standardizing robust protocols and in automating tests.
One way laboratorians can prepare for future, routine microbiome testing is to expand their notion of clinical chemistry to include both microbial and human biochemistry. “The line between microbiome science and clinical science is blurring,” said Versalovic. “When developing future assays to detect biochemical changes in disease states, we must consider the contributions of microbial metabolites and proteins and how to tailor tests to detect them.” In the future, clinical labs may test for uniquely microbial metabolites in various disease states, he predicted.
Deborah Levenson is a freelance writer in College Park, Maryland. +Email: [email protected]