“The HLA-selected microbiome is possibly more closely related to the gut microbiota of those rheumatoid arthritis patients carrying the same HLA haplotype than other murine microbiomes,” says Kriegel. “The use of humanized mouse models to study gut microbiota/immune interactions is likely becoming more important for translation of microbiome discoveries to the clinic than previously appreciated, since another recent study by Kasper and colleagues showed that gut immune system maturation depends on colonization with host-specific commensals.
Dr. Kriegel notes that the difference between the susceptible and resistant HLA genes is a single three–amino acid polymorphism. “If the disease-associated, HLA-selected commensals (e.g., Allobaculum) can be causally linked to arthritis development, these findings might have potential implications for the interpretation of genome-wide association studies [GWAS] in autoimmune diseases. A growing body of evidence exists by now that particular commensals in mice can act as disease-promoting ‘pathobionts’ or, vice-versa, as beneficial commensals that prevent or ameliorate established disease.”
He notes that it is tempting to speculate that the low disease risk associated with single-nucleotide polymorphisms identified by GWAS is “due to the fact that patients need also to acquire the ‘wrong bugs’ that are then selected for by the genetically altered immune system, as indirectly suggested by this study.” The microbiome could therefore contribute theoretically to the “missing heritability” problem.
But Dr. Kriegel critiques the study for assaying the microbiome composition only in feces, and not also in various segments of the gut. It would have been nice, he says, “to define the anatomical niche of the different microbes—e.g., Allobaculum—in the tissues. He also suggests that the study should be followed up with immunologic studies of the different compartments of the GI tract, noting, for example, that Th17 cells are predominantly generated in the distal small intestine.
David Holzman is a freelance writer based in Massachusetts.
