Microbiome and Probiotics: Link to Arthritis

Mohamed K. Bedaiwi; Robert D. Inman


Curr Opin Rheumatol. 2014;26(4):410-415. 

In This Article

Microbiome in Spondyloarthritis

The term 'spondyloarthritis' (SpA) refers to a group of disorders that includes AS, undifferentiated SpA, reactive arthritis, and the arthritis accompanying psoriasis and inflammatory bowel diseases. For the SpA group as a whole, there is a strong genetic relation with HLA-B27, especially for AS. However, the strongest genetic association (HLA-B27) accounts for only 30% of the heritability, thus a large part of the genetic susceptibility remains unknown and this has led to an intense effort to identify additional predisposing factors.[21]

In studying a possible role for microbiota in the pathogenesis of AS, it has been observed that active AS patients have a higher serum IgA Klebsiella pneumoniae in comparison with RA and healthy controls, whereas inactive AS patients had no such antibody elevation,[22] with possible flare of anterior uveitis in relation to Klebsiella colonization in bowel flora.[23] In these studies, it was noted that serum antibodies could be detected against pullulanase-D peptide, which contains a sequence having homology with HLA-B27.[22] However, subsequent studies did not provide confirmation of the specificity of anti-Klebsiella antibodies in AS.[24]

HLA-B27 may indirectly alter the bacterial flora. It has been demonstrated that transfected monocytes with HLAB-27 showed reduced proliferative response to endotoxin.[25,26]

Initial studies[27,28] of animal models which might link the genetic component of SpA to environmental factors found no spontaneous development of inflammatory process in HLA-B27 transgenic mice. On the other hand, rats transgenic for human HLA-B27 and β2-microglobulin spontaneously develop an inflammatory response in the form of nail changes, hair loss, and arthritis, thus mimicking the spectrum of clinical manifestations seen in SpA. These studies indicated the need for gut colonization with conventional bacterial flora in concert with genetic predisposition to initiate the inflammatory response.[29] Recently, an RA-like arthritis accompanied by a positive autoantibody profile has been developed in SKG mice.[30] SKG mice raised in a specific pathogen-free environment stayed healthy until exposed to curdlan (a β-1,3-glucan derived from the cell wall of yeast, fungi, and bacteria). Thereafter, the mice developed peripheral and axial arthritis associated with extra-articular manifestations similar to SpA.[1]

Inflammatory bowel disease (IBD) shares a wide spectrum of manifestations with HLA-B27-related SpA. There is now mounting evidence that certain bowel flora play a causative agent in IBD,[31,32] in concert with numerous genetic factors like NOD2 and CARD9 to initiate the immune response.[33,34] Many observational studies have supported the notion of subclinical gut inflammation commonly occurring in SpA, with as many as two-thirds of SpA patients demonstrating this phenomenon. In a recent study,[35] the absence of CD14+ macrophages and a large increase in CD163+ (M2) macrophages were observed in AS, supporting the concept of subclinical ileal inflammation in the AS patient. It has been observed that the eventual development of symptomatic IBD occurs in approximately 6.5% of SpA patients presenting without symptoms of IBD.[36]

The prevalence of gut inflammation in nonradiographic axial SpA and AS was comparable in one study[37] which addressed this question, although other parameters including male sex, high disease activity, restricted spinal mobility, and younger age were independently associated with gut involvement.

In a recently published observational study,[38] the results showed higher antiflagellin antibody-positivity rates and acute-phase reactants in AS patients compared with mechanical back pain patients.

In one recent report, a cohort of 68 patients with AS had an ileocolonoscopy and MRI of the sacroiliac joints, and the result showed higher radiological inflammatory MRI scores in axial SpA patients with chronic gut inflammation compared with axial SpA patients showing normal gut histology. These findings indicated that greater Sacroiliac joint bone marrow edema was correlated with chronic gut inflammation.[39]

Although there have been numerous studies suggesting a link between microbiome and SpA, the precise mechanism by which those environmental factors initiate the immune response still needs further investigation.