The Role of NLRP6 in Stress Induced Intestinal Inflammation

TIBDI blog post 14-01Many inflammatory bowel disease patients know that stress can complicate and worsen their symptoms. Even though this has been generally known for years, the study of the relationship between the gut and the brain is just now gaining popularity. In the most recent issue of Gastroenterology, we finally get a glimpse of how stress leads to intestinal inflammation.

The study, performed by American, Chinese and Taiwanese researchers, investigated the signals induced by stress that lead to inflammation in the small intestine. For this work, they used a stress-induced model of enteritis in mice. The mice were placed on a small platform surrounded by water for one hour each day, for a total of ten days. The resulting disease was characterized by intestinal damage, reduced weight gain and intestinal permeability. Although, IL-17 and IL-6 were found to be increased in the small intestine, there was also striking loss of IL-1β expression, which is what apparently first sparked their interest in inflammasomes.

Inflammasomes are large multi-protein complexes that are needed to activate a family of enzymes known as the caspases, which are involved in cell death and inflammation functions. One of the most well-known caspases is caspase-1. It’s needed to activate IL-1β, which is done by cleaving an inactive precursor of IL-1β. Interestingly, the inflammasomes belong to the (NOD)-like receptor (NLR) family, which many of you might realize also includes NOD2, a receptor that is highly associated with Crohn’s disease.

After some real-time PCR work, they found that the mRNA expression for Nlrp6 was considerably downregulated. They could also eliminate the pathology just by forcing the expression of NLRP6, further supporting its importance.

NLRP6 is an interesting NLR. Previous studies using Nlrp6-/- mice have shown that loss of this inflammasome in colonic epithelial cells disturbs the intestinal flora, which leads to an overgrowth of the bacterial family, Prevotellaceae and the candidate bacterial phylum, TM7. Both of these bacteria types are suspects in IBD, and the knockout mice also displayed a mild intestinal inflammation and extreme susceptibility to chemically induced forms of colitis.

However, other studies with the same knockouts hint that NLRP6 is even more complex. It also seems to have the potential to downregulate signaling via the pro-inflammatory factors NF-κB and ERK making the knockout inherently pro-inflammatory. Which might lead one to believe that the intestinal pathology is only caused by an overactive immune system. However, one most also remember that the microflora community that develops in the knockouts also can induce the same intestinal problems in wild type mice.

In my opinion, these conflicts could be a result of immunological compensation in the knockout. The knockout studies  emphasize the importance of this current study, which was performed in wild type mice and represents what can happen with a normal complement of genes.

The next question of the researchers was how did stress translate into the reduction of NLRP6. They looked at corticotropin-releasing hormone (CRH), an important stress signal in the brain-gut axis. They found that during stress the levels skyrocketed, and the levels were indirectly correlated with NLRP6 expression. More importantly, injecting mice with CRH was enough to mimic the pathology, and blocking it eliminated the stress-induced inflammation.

However, the previous study with the Nlrp6-/- mice indicated that the pathology was caused by the ultimate overgrowth of bad bacteria, which was transmissible by co-housing. Co-housing stressed mice with unstressed mice led to the development of intestinal problems in the unstressed mice. Simple probiotic therapy was enough to protect the co-housed unstressed mice. A detailed investigation of the bacterial populations in the intestines of the stressed mice showed that it, indeed, was changed, and both the small and large intestine had an increased bacterial load.

To sum it up, this study shows that stress can lead to increased CRH, which reduces NLRP6 expression. NLRP6 expression is important for the activation of IL-1β and IL-18. Both of these cytokines are important for the control of bacterial infection, and, thus, loss of NLRP6 could possibly lead to loss of control of bacterial growth. In this study, this appears to be the case, and mice with stress have a changed intestinal flora that, on its own, appears to cause intestinal inflammation in unstressed mice.

This study is intriguing. Could it be that many intestinal pathologies are caused by long-term stress that changes one’s intestinal microbiota? I think it could be the case. However, the chance that this causes inflammatory bowel disease by itself is highly unlikely. One mustn’t forget that there is still a genetic component to inflammatory bowel disease. Yet, it wouldn’t surprise me if it were discovered that those with inflammatory bowel disease have experienced more stress at critical periods in their lives than healthy individuals.

References

Anand, P. K., Malireddi, R. K. S., Lukens, J. R., Vogel, P., Bertin, J., Lamkanfi, M., & Kanneganti, T.-D. (2013). NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature, 488(7411), 389–393.

Elinav, E., Strowig, T., Kau, A. L., Henao-Mejia, J., Thaiss, C. A., Booth, C. J., et al. (2011). NLRP6 Inflammasome Regulates Colonic Microbial Ecologyand Risk for Colitis. Cell, 145(5), 745–757.

Kuehbacher, T., Rehman, A., Lepage, P., Hellmig, S., Folsch, U. R., Schreiber, S., & Ott, S. J. (2008). Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease. Journal of Medical Microbiology, 57(12), 1569–1576.

Sun, Y., Zhang, M., Chen, C. C., Gillilland, M., Sun, X., Zaatari, El, M., et al. (2013). Stress-Induced Corticotropin-Releasing Hormone-Mediated NLRP6 Inflammasome Inhibition and Transmissible Enteritis in Mice. Gastroenterology, 144(7), 1478–1487.e8.

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