Akkermansia muciniphila is permissive to arthritis in the K/BxN mouse model of arthritis

Abstract

Studies have identified abnormalities in the microbiota of patients with arthritis. To evaluate the pathogenicity of human microbiota, we performed fecal microbial transplantation from children with spondyloarthritis and controls to germ-free KRN/B6xNOD mice. Ankle swelling was equivalent in those that received patient vs control microbiota. Principal coordinates analysis revealed incomplete uptake of the human microbiota with over-representation of two genera (Bacteroides and Akkermansia) among the transplanted mice. The microbiota predicted the extent of ankle swelling (R2 = 0.185, p = 0.018). The abundances of Bacteroides (r = −0.510, p = 0.010) inversely and Akkermansia.(r = 0.367, p = 0.078) directly correlated with ankle swelling. Addition of A. muciniphila to Altered Schaedler’s Flora (ASF) resulted in small but statistically significant increased ankle swelling as compared to mice that received ASF alone (4.0 mm, 3.9 – 4.1 versus 3.9 mm, IQR 3.6 – 4.0, p = 0.041), as did addition of A. muciniphila cultures to transplanted human microbiota as compared to mice that received transplanted human microbiota alone (4.5 mm, IQR 4.3 – 5.5 versus 4.1 mm, IQR 3.9 – 4.3, p = 0.019). This study supports previous findings of an association between Akkermansia muciniphila and arthritis.

Patterns of ‘Analytical Irreproducibility’ in Multimodal Diseases

“…Assessing the effect of random sampling at various N, and also as N accumulated, we were able to illustrate that pairwise trio-trio comparisons between the simulated datasets almost always produce non-significant results when iterative trios were compared (due to large SD overlapping; see bars in Figure 1D representing 21 sets of pairwise trio-trio p-values). However, as N increases by the cumulative addition of all (mostly ‘non-significant’) donor trios ( i.e ., N increases in multiples of 3, for a range of N between 3 and 63 donors/group; [3, 6, 9, 12…63]), pairwise statistical comparisons between the simulated datasets did not produce consistent results (see line plots in Figure 1D representing p-value for cumulative addition of donors when sampling iterations were simulated).…”

Microbial orchestra in juvenile idiopathic arthritis: Sounds of disarray?

“…Asquith and colleagues reported increased cecal abundance of A muciniphila in HLA‐B27‐transgenic rats corresponding to onset of intestinal inflammation and arthritis . Finally, Stoll demonstrated that while monocolonization of A muciniphila in an arthritis model did not result in a demonstrable increase in arthritis severity, the addition of this organism to an otherwise normal microbiota obtained from a healthy child did increase arthritis severity accompanied by diminished intestinal mucin content.…”

“…In contrast, in the world of inflammatory diseases, there are not for the most part “good guys” or “bad guys.” Rather, the impact of a specific organism is likely to depend on the age of exposure, other community members, host genetics, the host's immune response against the organism, and myriads of other factors. Thus, species that emerge as pathogenic in one condition (eg, Prevotella and RA may be reduced in another; pediatric exposure to Bacteroides may predispose to JIA while adult exposure may be protective; and mucin‐degrading organisms such as A muciniphila and Ruminococcus may be harmless in isolation but harmful in the right setting . Furthermore, many of the organisms identified as potentially relevant to JIA pathogenesis may be beneficial for other reasons, and their obliteration even if technically possible may have downstream effects that would need to be monitored.…”

“…Thus, species that emerge as pathogenic in one condition (eg, Prevotella and RA 108 may be reduced in another 7 ; pediatric exposure to Bacteroides may predispose to JIA [6][7][8]93 while adult exposure may be protective 93,108 ; and mucin-degrading organisms such as A muciniphila and Ruminococcus may be harmless in isolation but harmful in the right setting. 93,104,108,115 Furthermore, many of the organisms identified as potentially relevant to JIA pathogenesis may be beneficial for other reasons, and their obliteration even if technically possible may have downstream effects that would need to be monitored.…”

Juvenile Idiopathic Arthritis and the Gut Microbiome: More Clues, More Questions

“…We have started to see tantalizing hints of answers to these tough questions, including studies on the pathogenic role of Akkermansia mucinophila in juvenile spondyloarthritis and the potential benefits of elemental formula in children with active JIA . Still, these are early days of microbiome research in JIA, and causal interpretations of the published evidence would be premature.…”