A growing understanding of the thousands of bacteria living inside the human body has held out the promise of treating diseases based on changes in the composition of the microbiome.
That research progress has also led researchers and companies to hunt for news tests to better diagnose the health of gut microbiota.
While the microbiome-based diagnostics field is very young, it looks set to emerge quickly. Transparency Market Research, a research firm, predicts the sector could increase in value to $700 million by 2024, driven by the completion of the National Institutes of Health Human Microbiome Project.
Reflective of the still emerging field, Research and Markets estimates only about 25 microbiome diagnostics were in development as of 2017.
Growth expectations are fueled, in part, by advancing clinical development from biopharmaceutical companies, especially in gastrointestinal diseases. In order to design and run those trials, better diagnostics will be needed to determine what a "healthy" microbiome really means.
Gut feeling: Focusing on the GI tract
Bacteria are the most common microorganisms found in the human microbiota, and most of these are in the colon. In total, a healthy adult's gut contains somewhere around five pounds of bacteria. However, an imbalance in these bacteria, known as dysbiosis, has been linked with a range of gastrointestinal disorders. Screening the genomes of the microbiota can help to understand what is going on.
Several companies are taking up the challenge of giving physicians and researchers a better look.
uBiome Inc. describes its SmartGut as "the first sequencing-based clinical microbiome screening test," looking at the balance of microorganisms associated with inflammatory bowel disease and irritable bowel syndrome, including ulcerative colitis and Crohn's disease. The test is available through physicians.
In contrast, U.K.-based HolistX Ltd. describes its stool analysis as "lifestyle microbiome testing." Not yet launched, the tool will be available as an individual test or a monthly subscription, allowing subscribers to look at and track their own microbiota, assess its diversity and see what difference lifestyle changes could make. The company uses its own data, along with data from publications, and will continue to incorporate new information as it becomes available.
"This is still a new area, and interventions, such as probiotics and prebiotics, are not yet fully up to scratch. Research is moving fast, and standards and validation will boost confidence in these kinds of approaches," said Alex Knight, CEO of HolistX.
Larger companies are testing the waters, too. Nestlé Health Science SA has created a joint venture with Enterome SA, known as Microbiome Diagnostic Partners, which develops microbiome-based stool/serum diagnostics in areas including inflammatory bowel disease and non-alcoholic steatohepatitis.
One challenge facing all companies in this space: How to turn complex information into a clear and relevant message for the patient.
"The profiles we produce are likely to be most useful where we can make clear links, for example, there is good evidence that a diverse microbiota is good, and there are clear ways to rebalance certain groups through diet," said Knight. "We try not to talk about 'good' and 'bad' bugs, but about balance."
The microbiota-gut-brain axis
The role of the gut microbiota is related to more than just gastrointestinal disorders, however; it also plays an important role in the immune response.
"Around two-thirds of our immune system resides in our gut," said Craig Shimasaki, president & CEO of Moleculera Labs Inc. "The gut microbiota produce different chemical signals that help to maintain homeostasis and health, while our immune system helps our bodies to recognize self and non-self."
Perhaps more surprisingly, the gut microbiota is being linked with neurological, neuropsychiatric and neurodegenerative diseases, though it's not entirely clear how.
"Some studies have shown that the diversity of the microbiota in individuals with autism is less diverse than those without the disorder, but it's not clear whether this is cause or effect," said Shimasaki.
The microbiota also includes opportunistic pathogens. In some individuals, bacterial infections, including streptococci, can lead to infection-induced autoimmune disorders. This in turn may trigger neurologic and psychiatric symptoms, which can mimic obsessive-compulsive disorder, eating disorders, attention deficit hyperactivity disorders and others.
Two such infection-triggered autoimmune disorders are known as PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) and PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection).
Moleculera Labs is working on a test panel that examines the presence of auto-antibody levels in patients with these and related disorders, aiming to help direct treatment toward the underlying condition rather than the symptoms.
"Rather than looking at the microbiota or offending organisms that may have triggered these types of disorders, our diagnostic tool examines the effect — the presence of the auto-antibodies directed against various parts of the brain that is a root cause," said Shimasaki.
The microbiota in cancer
There are also increasing signs of a link between changes in gut microbiota and cancer, suggestive of an effect on the immune system. While work in this part of the field is still early, research points to a link between microbiota health and the risk of colon cancer.
These types of findings could help fuel further work on diagnostic approaches. Metabiomic Corp., for example, is developing a non-invasive test, now in clinical development, which will use changes in the microbiome to detect colon polyps and early-stage colorectal cancer. In theory, this could help prevent cancer development through polyp removal and facilitate early treatment of tumors.
Currently available screening methods include colonoscopy, which is accurate but invasive, costly and unpleasant for patients. Fecal occult blood tests and fecal immunochemical tests are noninvasive and highly specific for blood in the stool. Both are not as sensitive, however, not always picking up pre-cancerous polyps, for example. Metabiomics claims its test has the potential to detect even small, early-stage polyps.
To develop the test, the researchers will use next-generation sequencing and phylogenetic analysis of stool samples of patients from gastroenterology clinics, comparing the microbiome of patients with positive and negative results from colonoscopies to create microbiome signatures. Metabiomics hopes to be able to provide a screening service in the next two to three years.
"Microbiomics is still a new area, and to gain acceptance we know we will need robust and well-controlled studies, which are benchmarked against colonoscopy, the gold standard in this field," said Metabiomics Chief Operating Officer Greg Kuehn. "We are very excited about the potential of this tool in diagnosis and prognosis."
One area where the test could provide cost savings, as well as clinical benefit, is in patients with Lynch syndrome (hereditary non-polyposis colorectal cancer), who have to endure colonoscopies every one or two years from their twenties on.
"As a tool, our approach has potential in any disorder that has an effect on the gut microbiota. We expect the next big breakthrough to be in the diagnosis and monitoring of inflammatory bowel disease, and in predicting flare-ups," said Kuehn.
The microbiota may also have an impact on cancer therapy, by affecting drug absorption, bioavailability and metabolism, pharmacokinetics, anticancer effect and toxicity. Creating microbiota profiles, then, might be a useful way to personalize drug regimens down the road.
It's more than just about the gut
It's not just the gut biota. Other parts of the body have their own characteristic microbiota, and tipping the balance can have an impact.
In the pharynx, otherwise pathogenic bacteria — such as Streptococcus pneumonia or Mycoplasma pneumonia — may become part of the normal biota and kept in equilibrium. However, disruptions, such as damage to the respiratory tract lining can lead to the pathogenic bacteria becoming problematic.
In the vagina, an imbalance in the microbiota has been linked with the infection bacterial vaginosis. uBiome's SmartJane sequencing-based clinical microbiome screening test looks at the balance of the vaginal microbiota, as well as testing for the herpes papilloma virus (HPV) and sexually transmitted infections.
Outside lifestyle gut microbiota testing, HolistX is also looking at a genetic test to predict a patient’s wound healing prognosis, and metagenomics-based microbiome profiling for diabetic foot ulcers.
The microbiome is a growing field, but more research is essential to translate promise into clinical reality for patients. Regulation and compliance will also have to keep up — for example standardization of tests is likely to be crucial to retain their relevance, particularly for healthcare providers.
"We are learning more, and it's all possible through advances in next-generation sequencing, computational tools, machine learning and data analysis," said Kuehn.