According to Transparency Market Research, the Human Microbiome Market is set to be worth US$3.2 billion by 2024. North America is the biggest market followed by Europe. France is notably leading the charge there, with companies such as VC firm Seventure Partners (who had one of the first investment funds in the world to focus mainly on the microbiome) and biotechs Enterome and Eligo Biosciences.
In 2012 Elizabeth Grice and Julia Segre described the microbiome as being the “second genome” and predicted that “in the future, analyzing genetic variation and risk of human disease will sometimes necessitate the integration of human and microbial genomic data sets”. That future may already be here with 796 clinical trials “that have microbiome analysis as some component of the trial*” and over 37,000 publications tagged "microbiome" in Pubmed data. Recent studies include the microbiome’s affect on: HIV, cancer, autoimmune disorders, antibiotic resistance, bacterial infections and degenerative brain diseases such as Alzheimers’.
I reached out to eleven researchers and healthcare professionals - with expertise ranging from genomics to chemical engineering - to ask them what they think the most important contribution that analysis of this “second genome” will bring to human health. Will it be research on: Alzheimers’, HIV, immunotherapy treatments for cancer, autoimmune disorders, antibiotic resistance, bacterial infections or something else entirely? While the overwhelming consensus was “all of them”, there were some favorites. Their answers follow.
Jack Gilbert, Faculty Director, The Microbiome Center; Professor Department of Surgery, The University of Chicago; Author, Dirt is Good. @GilbertJackA
“This would be a very long answer. I wrote an article last year for Nature that encapsulates some of the promise in each area. However, the basic areas are: (1) Biomarker discovery, which can help to stratify the patient populations, and to enable prediction of endpoint consequences of treatment, e.g. likelihood of developing an infection during surgery, which we may be able to predict based on the patients microbiome (among other vitals) at the first visit; (2) Combinatorial Therapy - where we use microbial organisms or their products to facilitate positive outcomes for an existing treatment - such as the work (in mice) on alpha-PDL1 immune blockade therapy and Bifidobacteria as a probiotic - providing a significant decrease in tumor volume compared to either by themselves; (3) Ecosystem restoration - whereby we shape the gut microbiome, the ecosystem, to prevent the onset of diseases, especially in the young, but also in the old. These three strategies have applications across the range of diseases you highlighted.”
(*Thanks to Dr. Gilbert for bringing to my attention to the number of microbiome clinical trials in the US.)
Maria J.G.T Vehreschild, Clinical Microbiome Research Group and Clinical Trials Unit II Infectious Diseases at University Hospital Cologne @UniCologne
"Clinical practice of all the topics you mention may be changed by microbiota-based treatment approaches. Which topic and product may turn out to be clinically relevant will depend on the following factors: 1) Completion of basic and clinical research that allows for the identification of effector strains or strain consortia; 2) Overcoming challenges in culturing these strains; 3) Building a functional interaction between academia and industry for conduct of successful clinical trials."
David Kyle, Chairman and CSO, Evolve Biosystems @EvolveBio
"I think we will find microbiome research helpful in all the health areas you mention. We are just taking the first steps into an area that will revolutionize our concept of health and medicine. With the recognition for the first time that our lives are not just controlled by our own genes but also the activities of trillions of microorganisms and their genetic contributions, we are starting to shift our view of where to target therapies. That said, I believe that there will be an even greater impact on long term morbidity that will be uncovered as we look to the deflection of certain developmental milestones early in life by an altered gut microbiome and that this deflection could result in physiological and neurological consequences later."
"Being more specific, over 20 years of research at the University of California at Davis has established that the natural microbiome of the human infant is dominated by a single commensal species (Bifidobacterium longum ssp infantis) through its unique and dominant ability to consume Human Milk Oligosaccharides (HMOs). Astonishingly, we have now discovered that this natural microbiome has changed slowly, but extensively, over the past 100 years resulting in the near extinction of this keystone commensal species in most developed nations around the world through the unintended consequences of extensive infant formula use, the multigenerational use of antibiotics, and recent increases in the C-section rate. Through research and clinical studies, we have now established that this pandemic dysbiosis in gut of infants can be returned to the natural state simply through the reintroduction of this natural dominant commensal into the population along with breast-feeding or otherwise supplying HMOs to the infant. This new data now sets the path forward to a major worldwide reestablishment of the natural infant microbiome over the next few years and this journey started just 4 months ago here in the US with the introduction of EVIVO and will shortly expand into Canada and beyond."
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"This represents a novel approach to the translation of the wealth of information we are generating on the microbiome. It is more of an understanding of how food and nutrition changes (has changed) or remodels the gut microbiome and, for the first time, we have identified a “healthy microbiome” in infants and how this can, and has been disrupted. With this understanding, I believe we will be able to implement mechanistic-based changes that will have a significant impact of long term health and morbidity, long before we will be able to institute microbiome remodeling strategies to treat symptoms or cure disease. Simply put, a prevention model may be closer to market and possibly more impactful than a treatment model. I have summarized this latter case in a Speed Round Blog from the Microbiome Consortium."
Peter Embley, Senior Director Regulatory & Health Economic Science at Voisin Consulting Life Sciences
"All of them! I think we should continue to keep an open-mind for Microbiome research, as an internal ecosystem, since we are still trying to truly understand its mechanism of action and therapeutic effects. At this point, we should not shut-down on any discovery research, especially in chronic disease areas."
Sarkis K. Mazmanian, Luis & Nelly Soux Professor of Microbiology; Investigator, Heritage Medical Research Institute, Division of Biology and Biological Engineering,California Institute of Technology @Caltech
"Though the microbiome holds great promise to help patients with various ailments, microbiome-based therapeutics will likely first impact people with recurrent Clostridium difficile infections. Research, in particular human studies, are most advanced in this indication compared to other disorders, such as inflammation, autoimmunity, obesity, cancer, neurological conditions, etc. Further, the biological mechanisms for how the microbiome may ameliorate C. difficile infections appears more straightforward than for other diseases. This being said, research into how gut bacteria can be harnessed for treatment of numerous immunological, metabolic and neurological disorders is rapidly advancing and the notion of validated therapies emerging from the microbiome is very exciting."
Robert S. Langer, David H. Koch Institute Professor, Massachusetts Institute of Technology. @MITChemE
"Manipulation of the microbiome may be helpful in all of these areas of human health. Bacterial infections and control of the spread of antibiotic resistance are two areas where we are already seeing clinical success. Fecal transplantation has been tested in randomized, placebo-controlled trials with success in the treatment of C. difficile infections and in open-label studies for the treatment of antibiotic-resistant bacteria. Second-generation approaches based on rationally-defined bacterial consortia drugs by companies like Vedanta Biosciences are now entering the clinic, too. Rebiotix, along with several academic clinical sites including University of Minnesota (Dr. Alex Khoruts), Brown University (Dr. Colleen Kelly), and Albert Einstein College of Medicine (Dr. Larry Brandt), are also doing work with fecal transplants. Autoimmune disorders of the gut, particularly inflammatory bowel diseases (IBD), have also seen clinical successes with fecal transplantation, with two randomized, double-blinded, placebo-controlled studies recently published by academic groups in Australia and Canada. Janssen is also beginning the first microbiome trial in IBD of a defined consortium drug in 2018 (in collaboration with Vedanta). Autoimmune disorders distal to the gut, such as Rheumatoid Arthritis, Multiple Sclerosis or lupus could follow, but have not yet progressed to the clinic. Many autoimmune and inflammatory diseases (Type 1 Diabetes, asthma, food allergies) are developed early in infancy. Early childhood is increasingly seen as an area where there might be traction and companies like Commense are now pursuing manipulation of the infant microbiome. A recent Nature paper showed a symbiotic combination of fiber and probiotic could decrease sepsis and death in a neonatal population. This is some of the earliest data showing the benefit of microbiome-based interventions."
"Potentiation of cancer immunotherapy is now seeing a lot of attention because of recent high-impact publications suggesting that the baseline microbiome of cancer patients may determine how they respond to checkpoint inhibitors. This work will likely progress to clinical testing in 2018. Companies and institutions pursuing microbiome approaches to cancer include Vedanta, MD Anderson/Parker Institute, Institute Gustave Roussy, Synlogic, and Enterome, among others. HIV, neurodegeneration and aging are areas where the evidence that the microbiome plays a role in the disease is weaker, although preclinical data is accumulating. Groups doing leading work in HIV and microbiome include IrsiCaixa in Barcelona and the University of Colorado. UCSF has done leading work in the microbiome and multiple sclerosis. Axial Biotherapeutics is also working on microbiome-based therapeutics for CNS diseases."
"Another area worth mentioning is the role of the microbiome in obesity and related diseases such as Type 2 Diabetes and Nonalcoholic steatohepatitis (NASH), which is being explored by Gelesis with the University of Copenhagen and the European Institute of Oncology."
Pierre Belichard, CEO, Enterome. @pbelichard
"I would say that the area in which microbiome research has the most promise right now is boosting the immune system. Enterome is developing new drugs to fight against gut microbiome defects associated with immune disorders like IBD or IO – in the case of IBD, the immune system is overactive against gut bacteria leading to a profound modification of its composition associated with invasion of a subset of bacteria inducing chronic inflammation. We are developing a drug (not a probiotic or a LBT) that is specifically disarming the virulent bacteria without killing it as an antibiotic could do. In IO, we are developing ways to use the gut microbiome to boost the immune system against tumor genesis."
Joseph Maxwell, IBD Program Director at Finch Therapeutics, @Finch_TX
"Microbiome therapy is clearly effective for infectious conditions such as C. diff, and I believe there is likely to be additional opportunity in other infectious conditions, including those driven by antibiotic resistant microbes. There has been growing evidence for microbiome therapy in metabolic and inflammatory diseases of the digestive tract, and that will be the next frontier that is tested with such therapies. Beyond that, data associating changes in the microbiome with response to cancer immunotherapy is very compelling, as is the surprising association with neurodegenerative diseases. These are all highly impactful indications that can serve patients in need, but each is a large commitment on its own. A lot for small microbiome companies to do alone, so expect plenty of collaborations with large pharma companies to drive research into these areas. The company that can find the right niche first will be very successful. "
JC Gutiérrez-Ramos, Ph.D., President and CEO, Synlogic, Inc. @Synlogic_tx
“At Synlogic, we believe that the microbiome will be the next frontier of drug development. We are developing Synthetic BioticTM medicines using synthetic biology to engineer probiotics to enable them to carry out metabolic functions that are defective or missing in disease. We engineer potency and design our Synthetic Biotic medicines so that we can reliably manufacture them and achieve a dose response, as with other medicines. Initially we are focused on inborn errors of metabolism, such as urea cycle disorders and phenylketonuria, that reduce the ability of the liver to deal with metabolites, including ammonia and certain amino acids, and can be treated from the gut. However, we believe that the platform has much broader applications including liver disease, inflammatory and immune disorders, and cancer. There is also strong scientific evidence that neurologic conditions can be modulated by taking advantages of the natural cross talk between gut and the brain (the gut-brain axis), a conversation that involves hundreds of well-characterized metabolites. Top-line data from our first-in-man study to treat hyperammonemia demonstrated a pharmacological effect and dose responses in systemic metabolites with a Synthetic Biotic medicine that acts from the gut. As we also observed this effect in non-human primates in our phenylketonuria program, we now have two examples of Synthetic Biotic medicines modifying metabolites through their programmed mechanisms while acting in different regions of the gut in human and non-human primates. Our mission is to unlock the broad potential of these medicines and bring them to patients.”
Gitte Pedersen, CEO and Co-founder Genomic Expression, Board Member at ExpreS2ion Biotechnologies @DNABarcode
"All of the areas you mention. They are all diseases which course are greatly impacted by the immune system. The microbiome is an external organ that plays a key role in our immune system. We don’t understand all the details yet but we have the tools to figure it out so it’s just a matter of time."
Miguel Toribio-Matteas, Editor in Chief Nutrition Evidence; Chairman, British Association for Applied Nutrition and Nutritional Therapy (BANT) @MiguelMateas
“The last 5 years have seen an explosion of research in gut microorganisms brought about by gene testing of the microbes using stool samples to assess the thousands of different species. These microbes are collectively called gut microbiota. The term microbiome refers to the microbiota and its metabolites, and it varies between individuals far more than our genes do because our gut microbes are influenced by our health status and our diet, i.e. the microbiota of a person with diabetes, cancer or Alzheimer’s is likely to be different from that of a person who doesn’t have any of those conditions. Indeed, increasingly it looks like you can assess a person’s health far better by a single microbiome test than a genome screen and major disruptions are seen in allergy, obesity, colitis and irritable bowel syndrome, diabetes or even cancer. The ‘Western diet’, rich in animal protein, fats and artificial additives, and lacking in fibre, beneficial microbes, plant phytochemicals, vitamins and minerals, is thought to drive these conditions by encouraging gut dysbiosis. While gut microbiota / microbiome tests are not diagnostic in nature, and can vary from day to day, the reports and accuracy will continue to improve with time and larger datasets. Importantly, they are useful in motivating the patient and providing a holistic snapshot of gut health and diversity.”
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