A fascinating study just published in the journal Cell sheds light on how the genetic susceptibility to autoimmune disease can be activated by changes in gut flora, in this case the interaction of a virus with intestinal bacteria. The authors describe their findings:

“Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn’s disease susceptibility gene Atg16L1 induces intestinal pathologies in mice…These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNFα and IFNγ [pro-inflammatory cytokines] and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype [functional expression] of hosts carrying common risk alleles [genotype] for inflammatory disease.”

A perspective on this work published in Science Translational Medicine helps us to appreciate the significance of this research:

“…these findings link host genotype and viral infection with a response to chemical challenge, resulting in Crohn’s-like symptoms, a virus–plus–susceptibility gene interaction. However, the story gets even more complicated, because this interaction was shown to depend not only on the host inflammatory cytokines TNF-α and interferon-γ, but also on the gut microbiome…These findings are consistent with other models of IBD that are clearly dependent on the presence of gut bacteria and can be produced in germ-free mice colonized with defined bacterial consortia in the absence of a viral trigger.”

The practical message for the clinician and patient is that genetic susceptibility to an autoimmune disease can be triggered by alterations in the gut flora with compromise of the intestinal barrier (‘leaky gut’):

“These studies suggest that the microbiota is a key component of colitis; in mouse models, colitis develops in the context of abnormal adaptive or innate immune responses that fail to prevent translocation across the epithelial layer and the presentation of gut bacteria to immune cells ['leaky gut'], or result in excess activation of the adaptive immune system [dysregulated immune response].”

As we know, once these genes are ‘turned on’ they can’t be turned off. Autoimmune disease can be managed with the correct functional approach; the term ‘cure’ is not justified:

“A fascinating observation from Cadwell et al. is that susceptibility to colitis induction can be switched from off to on; mice in a colitis-resistant state before infection with the virus become susceptible to injury-induced colitis after viral infection, and, once the colitis-sensitive state is induced, cannot go back to a colitis-resistant state.”

Rational therapy that offers the chance to manage autoimmune disease for a much higher quality of life must address the microflora and their interactions with the human immune system along with other factors that modify the expression of the autoimmune potential:

“All of these diverse findings suggest that it is necessary to take into account multiple facets of the human microbiome when considering complex diseases such as Crohn’s. Polymorphisms in key susceptibility genes in our human genome, such as ATG16L1, may only serve to weaken the first link in the chain that protects the intestinal epithelia from a combination of viral infection, microbial stimulation of inflammation, and other dietary or xenobiotic factors.”