To date, Dr. Lipkin has found no strong candidate viruses or bacteria for causing ME/CFS in samples collected in a large, recent study comparing patients and controls. However, the study showed evidence of immune activation in patients that could be driving our symptoms. The question is, what is causing the immune activation?
One possibility is a problem in the microbiome: the ecosystem of bacteria, viruses and fungi that lives in or on our bodies. This system is increasingly being linked to serious illness. Dr. Lipkin’s team has already found microbiome abnormalities in colon cancer, stillbirth and autism and this is also a promising area for ME/CFS. Given that most of the immune system is in the gut and that many patients have gut symptoms, the cause of our disease could well lie within our gut microbiome.
The study design
The study will take place at Dr. Lipkin’s 60-strong Center for Infection and Immunity at Columbia University in New York, the world’s largest and most advanced academic center in microbe discovery and diagnosis. His team will use high-throughput DNA sequencing to identify viruses, bacteria and fungi in fecal samples from 100 ME/CFS patients and 100 carefully matched controls and will determine the amounts of each microbe using highly accurate real-time PCR assays that are specific for that microbe.
Levels of cytokines (immune-system messenger molecules) will be measured in the blood to generate an immune profile for each patient. Biostatisticians will then analyze the cytokine and microbiome profiles to identify a potential link to ME/CFS and to define the relationship between immune markers and candidate microbes. In addition, the team will develop antibody tests for any microbes that appear to be related to immune dysfunction.
The patients and controls have already been selected as part of an earlier US National Institutes of Health study in which well-known ME/CFS specialists from sites across the US – Drs. Klimas, Levine, Bateman, Peterson, Montoya, and Komaroff – identified patients who each fulfilled both the Fukuda and Canadian Consensus diagnostic criteria.
The next step
Gut microbes that are consistently associated with immune (cytokine) dysfunction will be further evaluated as candidates for causing ME/CFS. The next step will be to find out whether they are the cause of the disease or simply an effect of it.
One possibility is to use an “animal model” – that is, to introduce any suspect microbes into the gut microbiome of animals to see if they develop the same symptoms and pattern of immune activation seen in humans.
Another option is to go straight to “proof of concept” placebo-controlled clinical trials using treatments likely to target the microbes in question. If patients receiving the intervention did better than placebo patients, and if the gut composition of these patients also showed changes that did not appear in the gut of patients receiving the placebo, that would lend support to the idea that gut microbes were playing a role. Certain gut composition patterns may also serve as a predictive biomarker or indicator that an individual patient will respond positively to a particular type of microbe-focused treatment.
If a microbiome problem can be identified, Dr. Lipkin wants to establish clinical trials of treatments that could include probiotics, antibiotics followed by probiotics, restriction diets and possibly even fecal transplants. Such transplants have been shown to be extremely effective in treating potentially fatal infections with the bacterium C. difficile. There is also anecdotal evidence of their efficacy in treating a wide range of chronic conditions, including rheumatoid arthritis, IBS, coeliac disease and metabolic syndrome.
Dr. Lipkin believes it unlikely that there will be just one microbiome problem that causes ME/CFS. Rather, it is probably the result of different types and combinations of microbes – possibly bacterial, fungal or viral – producing different types of immune dysfunction. If so, the treatment for any patient would be personalized and refined according to their specific microbiome problem.
Of course, ME/CFS is believed to have multiple causes and the microbiome might not be the answer for all patients. However, identifying patients who have microbiome-related immune disturbances within the larger population of individuals with ME/CFS is a critical first step toward improved understanding and effective treatment of the disease.