Standards and technology are now available for microbiome profiling to take personalized medicine to the next level, but prospective trials are needed to realize this possibility, according to a leading expert.
The need for prospective microbiomics trials is increasing with the incidence of immune disorders, many of which have been linked with disturbances in the gut, reported Jöel Doré, PhD, at the annual Gut Microbiota for Health World Summit.
“In spite of considerable progress in medicine, together with hygiene, antibiotics, and vaccination developments, we are still seeing an increasing incidence – uncontrolled, that started over 60 years ago – of immune-mediated conditions,” said Dr. Doré, research director at the French National Research Institute for Agriculture, Food, and the Environment.
According to the World Health Organization, one out of four people will be affected by such a disorder in their lifetime, and the incidence rate of some conditions is accelerating faster than others, with geographical distributions that suggest environmental risk factors.
“The rate of incidence of autism in the U.S.A. is a quite scary exponential curve, where less than 1 birth per 5,000 was [affected] in the 1970s, where today it is 1 birth out of 50,” Dr. Doré said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “Prevention is an urgent need, and possibly if we do not manage to understand what’s going on, human longevity might be at stake.”
Multiple studies have shown that transferring microbiota from humans with immune disorders to healthy mice can induce clinical signs of immune disorders, he said. And between humans, fecal transplants from healthy donors have reduced symptoms in patients with conditions such as inflammatory bowel disease.
While these studies support the link between microbe-host relationships and immune function, most of the underlying mechanisms remain unknown, Dr. Doré said. He highlighted the fact that the complex network of interactions involved separates microbiomics research from conventional approaches to disease.
“I want to stress the fact that clinical trials [in the past] have been designed in the situation where infection was the problem, [but] infection is essentially a linear thing; one agent, one risk, one disease,” Dr. Doré said. “What we are dealing with – with the increasing incidence of immune disorders – is host-microbe interaction at the center of everything, and alteration of host-microbe leading to risk, which may lead to disease. But host-microbe interaction is under the control of a vast number of environmental aspects ... so tools to deal with innovation and translation in a totally different or systemic configuration have yet to be invented.”
According to Dr. Doré, to develop clinical applications, research procedures must first be standardized.
“To be of use for the clinician and general practitioner, microbiome profiling will have to rely on pipelines of standardized preanalytical and analytical procedures,” he said. “This starts from sample collection and shipment.”
For the past 5 years, Dr. Doré and colleagues have been working to standardize procedures with a number of organizations around the world, and progress has been made.
“Today we have very good standards for shotgun sequencing,” he said.
With standards solidifying, microbiomics may lead to new clinical strategies for a range of conditions, even beyond immune disorders, Dr. Doré said. He noted that, as a relatively simple measure, gene richness in the microbiome may be used as a health stratifier. Studies have shown that low gene count has been associated with more severe metabolic and inflammatory traits among overweight patients, a lack of response to low-calorie diets among overweight and obese patients, severity of related conditions and risk of mortality among patients with liver cirrhosis, and poorer responses to immunotherapy among patients with cancer.
Certain patterns of flora may be prognostic, Dr. Doré said, citing a study by Gopalakrishnan et al. that involved 112 melanoma patients, in which those with a high abundance of Faecalibacterium had significantly longer progression-free survival than patients with a low abundance of the same bacteria. Further, a multivariate model showed that a high abundance of Faecalibacterium was the strongest predictor of response to immunotherapy, (hazard ratio, 2.95; P = .03), followed closely by prior immunotherapy (HR, 2.87; P = .03). In contrast, patients with a high abundance of Bacteroidales had shorter progression-free survival than patients with a low abundance of the same bacteria.
Dr. Doré also referred to one of the first interventional microbiomics studies in oncology. Mohty et al. conducted the ODYSSEE phase 1b/2a trial involving 25 patients with acute myeloid leukemia, in which patients were given autologous fecal microbiota transplants after induction chemotherapy and antibiotics. The treatment recovered 90% of original microbiota, and the estimated 1-year overall survival rate was 84%, compared with a historical rate of 70%.
The ODYSSEE study serves as proof of concept that microbiomics may eventually offer the next level of personalized medicine, Dr. Doré said. And now, with standards and technology available, researchers can move forward.
Dr. Doré disclosed relationships with BioFortis, Janssen, Sanofi, and other pharmaceutical companies.