Posted November 25, 2014
Ashutosh Mangalam, Ph.D., Veena Taneja, Ph.D., Mayo Clinic, Rochester, Minnesota
In a partnering research project funded by the Peer Reviewed Medical Research Program, Drs. Ashutosh Mangalam and Veena Taneja of the Mayo Clinic explored the effects of commensal gut bacteria on inflammatory autoimmune diseases and made the remarkable finding that dietary administration of the commensal gut bacteria Prevotella histicola can prevent or halt disease in mouse models of both rheumatoid arthritis (RA) and multiple sclerosis (MS).
Joint and nerve damage in RA and MS are thought to involve significant contributions from inflammation brought on by an autoimmune reaction, and it has become widely recognized that the gut bacteria play an important role in generating and moderating these inflammatory responses. These researchers therefore reasoned that the moderating influence of these bacteria might be harnessed to control the inflammation involved in these human diseases. Specifically, they found that the P. histicola possesses a potent anti-inflammatory effect and so used it in further testing.
To study this effect, the researchers needed a way to mimic these human diseases in mice, and transgene technology has provided a way. Researchers have long noted that certain human leukocyte antigens (HLA) are found more often in RA and MS patients. Specifically, many MS patients have HLA class II genes called HLA-DR3 and HLA-DQ8. In RA patients, HLA-DQ8 and a different HAL called HLA-DR4 are found more frequently. Using transgenic technology, researchers were able to introduce these human HLA genes into mice and found that the mice bearing these genes were highly susceptible to conditions strongly resembling human RA and MS.
Triggering events cause human disease-like conditions to appear in these transgenic mice. For RA, mice bearing HLA-DR4/DQ8 genes are administered a dose of type II collagen and the resulting condition is called "collagen induced arthritis" (CIA). This condition exhibits many of the hallmarks of the human disease even so far as being more prevalent in females, as is the case with human RA. The MS-like condition is triggered in HLA-DR3/DQ8 mice by administration of a molecule from the central nervous system dubbed PLP91-110. These mice develop an MS-like condition called experimental autoimmune encephalomyelitis (EAE) that is characterized by plaques in the brain and spinal cord.
Using these models of human disease, with Dr. Mangalam working primarily on EAE and Dr. Taneja on CIA, they found that dietary administration of cultures of the gut bacterium P. histicola not only prevented development of the condition if administered before the trigger, but could also halt further deterioration if administered after the trigger when some pathology was already present. Other commensal bacteria were tried as well, but none offered near the response seen with P. histicola. Moreover, live cultures were required to produce the protective effect. Treatment with killed bacteria had no effect.
In addition to examining the effect on organ and tissue pathology, the researchers also assessed the effects on the biochemical pathways and signals involved with the immune inflammatory response. In the EAE model of MS, P. histicola treatment reduced the permeability of the blood-brain barrier and the T cell "recall response" of brain infiltrating cells showed decreased T cell proliferation and lower levels of inflammatory cytokines. In both the CIA model of RA and EAE model of MS, P. histicola administration led to an increase in regulatory T cells and suppressive dendritic cells (both are types of cells that quiet the immune response), a reduction in pro-inflammatory cytokines, and an increase in anti-inflammatory interleukin-10. A molecular receptor called the Toll-Like Receptor (TLR) comes in many types and TLR type 4 is often involved in inflammatory responses. Interestingly, preliminary evidence appears to indicate that TLR-4 is not involved in the quelling of CIA by P. histicola.
While foundations for future research in MS or RA have been laid in this project, anti-inflammatory commensal gut bacteria could provide the basis for treatment of a variety of human diseases possessing significant autoimmune inflammation components. The objective of this research would be to move this treatment out of the laboratory and into clinical trials in human diseases. The next step would be to generate the information that the U.S. Food and Drug Administration (FDA) requires for testing a new therapeutic agent. Such studies would include developing means for the FDA-approved manufacture, toxicity testing, metabolism studies, and calibrated dose/response studies in specific animal disease model, both alone and in combination with existing drugs.