• Posted by admin

Arthritis and Brain-Gut Dynamic: Autoimmunity and the Human Microbiome

The relationship between microbial infection and development of arthritis has been recognized for several decades in rheumatoid arthritis (RA) and spondyloarthritis (SpA).  The latter is significantly higher in Caucasian individuals with the human leukocyte antigen (HLA) B27 gene. SpA consists of diverse disorders of inflammatory arthritis including ankylosing spondylitis (AS), reactive arthritis, arthritis and spondylitis associated with psoriasis and inflammatory bowel disease (IBD).  Chronic low back pain or joint pain is often the first manifestation of SpA.  Such patients may be seen by a rheumatologists, orthopedic surgeons, physiatrists, and general practitioners before SpA is correctly diagnosed.  It differs from mechanical back pain by its insidious onset, history of morning stiffness, pain at night, improvement with exercise, and favorable response to non-steroidal anti-inflammatory drugs (NSAIDs). Magnetic resonance imaging (MRI) has an important role in detecting the earliest phase of the illness in demonstrating synovitis and associated inflammation and bone marrow edema which may be absent on standard bone radiographs, and visible only in the later stages of disease. Documentation of HLA B27 is key in such people.
    Experimentally-induced SpA occurs in mice with a striking resemblance to humans when HLA B27 components are introduced into genetically susceptible animals. Certain genetically prone mice develop colitis and later SpA when colonized with Bacterioides flora along with increased colonic cytokine expression compared to germ-free uncolonized animals suggesting a critical role of immune activation in relation to bacterial colonization. This story became more interesting when the same animals showed activation of T-helper cells (Th17) and HLA-B27 misfolding with a further heightened immune response to interleukin (IL)-23 protein production. Taken together, these findings suggest that genetically predisposed animals react to a microbial imbalance by altering their immune system in the intestinal compartment toward a more inflammatory state. The process is mediated by T-cell and IL production which ultimately leads to local and systemic clinical disease manifested as an aSpA-like human illness 

Investigators have incorporated insights into the microbiome to advance therapy for SpA and other autoimmune arthritides.  Empiric broad-spectrum antibiotics do not appear to have a therapeutic role and may select species with even more pathogenic potential. However bacterial modulation through alternative methods drawing from innate benefits of the microbiota include donor fecal microbial transplantation (FMT) to restore a healthier intestinal microbiome. FMT was significantly more effective for the treatment of recurrent Clostridium difficile infection than vancomycin antibiotics. However, its role in SpA is unclear and should probably only be considered when there is concomitant IBD or another refractory colitis. Probiotic therapy for SpA have a theoretical rationale, however benefit was not been observed in several randomized-control studies (RCT).  Bacteroides fragilis protects animals from experimental colitis induced by the commensal bacterium, Helicobacter hepaticus. This beneficial activity requires a single microbial molecule (polysaccharide A [PSA]).  In fact, animals harboring Bacteroides fragilis not expressing PSA, and colonized with Helicobacter hepaticus, develop colitis and pro-inflammatory cytokine production in colonic tissues. A randomized double-blind placebo-controlled pilot study of probiotics in active RA, led to functional improvement in active RA compared to placebo. 

The gut microbiota has been shown to play an essential role in central nervous system (CNS) disorders. This relationship termed the gut-brain connection, postulates a close association or triggering of brain autoimmune disease by commensal gut bacteria. In transgenic studies of spontaneous experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis (MS), the autoimmune attack against the CNS requires the presence of an intact commensal gut flora, and the concurrence of 3 factors: a permissive genetic disposition, a pro-inflammatory intestinal microbial profile, and the presence of autoreactive T-cells in gut-associated lymphatic tissue.  The gut bacteria act on the organism via different targets placed in the intestinal wall, such as along epithelia lining the lumen, the immune cells forming gut-associated lymphatic tissues and at sites of the enteric nervous system.  

The therapeutic implications of the gut microbiome suggests that their manipulation might reduce pathogenic stimulation of the immune system components or conversely to redirect it toward an anti-inflammatory or pro-regulatory status. The use of long-term chronic antibiotics to eliminate populations of the gut flora is likely to be complicated however there was some anecdotal benefit in MS with minocycline. A more selective approach might employ bacteriophage methods to specifically target microbial species.