Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a condition which is characterized by the onset of severe fatigue, usually between the ages of 20-40. It is often associated with other traits such as impaired memory or concentration, myalgia, arthralgia, headaches and sleep disorders. The cause of CFS is unknown, but viral infection, bacterial infection, genetic disorders and psychological disorders have all been suggested.
A recent study from Colombia University may elucidate the cause of CFS. Noting that about 90% of CFS patients also suffer from irritable bowel syndrome (IBS), these researchers postulated that the gut microbiome may be involved. By analyzing fecal samples they discovered that specific intestinal bacterial species were associated with CFS and that the abundance of these species correlated with disease severity. Surprisingly, using an immune profiling immunoassay to monitory 61 different bloodstream immune markers, they did not find significant correlations between CFS and control patients. This may suggest that all of the CFS patients were chronic. The identification of bacteria involved in CFS allows the ability to sub-type patients based on fecal microbiome and to identify bacterial targets for therapeutics.
This blog has previously highlighted the use of genetically modified bacteria as therapeutics, including a previous post detailing its effectiveness in treating patients impaired in proper nitrogen regulation. Here we focus on recent work from Korea in which a non-virulent form of Salmonella was engineered to express Vibrio vulnificus flagellin B (FlaB). Using human cell culture they demonstrated that this Salmonella resulted in infiltration of tumors with immune cells with activation of M1 macrophages and inhibition of M2 macrophages. Using knockout cell lines, they also showed that this activity required TL4 signaling. Finally, using mice they showed significant decreases in tumor size in about half of the animals treated. This is an exciting step forward in using genetically modified bacteria in cancer immunotherapeutics.
Previous reports have linked the gut microbiome to obesity. A recent study has taken this a step further and provided a mechanism for how this may occur. Scientists at Yale, led by Dr. Gerald Shulman, made the observation that acetate stimulates insulin secretion by activation of the parasympathetic nervous system. They made the complimentary observation that rodents that were fed a high-fat diet produced elevated levels of acetate. Next, they used fecal transplantation from high-fat diet rodents to low-fat diet rodents to demonstrate an increase in acetate, and subsequently in insulin, caused by the gut microbiome. These results suggest the gut microbiome regulates insulin release via acetate activation of the parasympathetic nervous system in a positive feedback loop.
The role the microbiome plays in human disease, such as metabolic, gastrointestinal and neurological disorders, has been well-established. This has led to therapies that, just a few years ago, seemed radical, including fecal transplantation. Currently, several groups are working to design orally-administered “smart” bacteria that can perform deficient enzymatic roles in specific disease.
One example is a genetically-altered E. coli strain designed by Synlogic in Cambridge. This version of E. coli degrades ammonia into arginine in patients unable to regulate their nitrogen level. The strain has been designed to only work in the human gut by requiring low-oxygen, a condition in the gut, and thymidine, which is not found in high levels in the digestive tract. Other uses for “smart” bacteria include anti-cancer therapeutics and food treatment for phenylketonurics.