The beautiful part about science is that different research groups come at problems from different perspectives. In a recent paper looking for biomarkers to differentiate irritable bowel syndrome(IBS) from inflammatory bowel disease(IBD) and healthy controls, researchers found a unique profile of proteins found in the intestinal fluids of people with IBS.
These findings are great for a couple of reasons. First, being able to differentiate between specific disorders is something that needs to be addressed for proper treatment. This is one of the reasons treating gut disorders is so difficult, the symptoms tend to converge so you really don’t know which condition you have.
An additional benefit to biomarker studies is that by painting a clearer picture, we get a little more clarity on what could be causing the problems associated with the disorder. So being able to differentiate between IBS and IBD makes it easier not only to treat the individual, but to also drive research in to potential treatments for either condition.
Gut juice and IBS
One of the big factors causing disturbances in IBS is a hyperactivation of nerves that make up the enteric nervous system. The enteric nervous system is the resident nervous system in the gut and is unique in that it doesn’t require input from the central nervous system to function, although the two are connected via the vagus nerve.
Mucosal biopsy fluid(Supernatant) from either IBS patients or people in remission from ulcerative colitis(UC) causes stimulation of nerves while that of healthy controls does not. So the researchers tried to determine which factors in the intestinal fluid from IBS and UC patients were causing the hyperactivation.
As you can see from the image above, chart A shows us that supernatant from IBS and UC patients causes increased firing of enteric nerves while healthy controls did not. The other charts basically show us that while both are exciting enteric nerves, the IBS supernatant is likely working through a receptor called protease activated receptor-1(PAR-1), or PAR-1. This was not the case for UC supernatant.
What they found was pretty interesting. While the symptoms of the IBS and UC patients were similar and the mechanism for both was hyper-activation of enteric nerves, what was causing the hyperactivation wasn’t. It turns out, 3 protein degrading enzymes, or proteases, were able to predict IBS with an accuracy of 98%. These proteases are elastase 3a, cathepsin L, and proteasome alpha subunit-4.
These proteases work through PAR-1 and are not associated with ulcerative colitis symptoms. So even though people with IBS and in remission from UC experience the same symptoms via the same mechanism, IBS and UC would need to be approached differently to resolve symptoms. But the fun doesn’t end there…
Figuring out how it all works…
Taking their study further, the researchers decided to zero in on elastase 3a to see if they could figure out what was going on. It turns out, elastase 3a works synergistically with histamine and serotonin to activate enteric neurons, causing the hyper-activated state.
In part A of the chart, we can see that elastase 3a when combined with histamine and serotonin increases nerve activation to a much greater extent than histamine and serotonin alone. We also find that elastase 3a on its own doesn’t do anything.
In part B, we find that when combined with SERPINBL, an inhibitor of elastase 3a, histamine, serotonin, and elastase 3a did not lead to increased nerve activation. These results indicate that in people with IBS, elastase 3a amplifies the effects of serotonin and histamine, causing hyper-activation of enteric nerves. Buuuuuttttt…We’re not done.
What’s SERPINBL and how do you get some? Well, SERPIN stands for serine protease inhibitor, but notice the BL on the end? Turns out that BL means something very specific that people with IBS may be lacking. It means Bifidobacterium longum, a beneficial microbe that ferments fiber in our gut. SERPINBL is a serine protease inhibitor generated and secreted in to our gut by our commensal compadre Bifidobacterium longum.
This study moves us a step closer to figuring out a way to help differentiate IBS from people in remission for UC with similar symptoms, towards finding a way to treat IBS, and potentially determining the cause if IBS.
Hacking your gut…
An interesting aspect to this study for me is the role elastase 3a plays in potentiating the effect of histamine on nerve activation. In a previously blog you can find here, I covered the role that histamine plays in regulating inflammation in the gut via the NLRP6 inflammasome.
In that blog, I discuss how a low histamine diet coupled with taurine may be useful in activating the NLRP6 inflammasome. Activating the NLRP6 inflammasome could be useful in managing things like IBS/IBD and SIBO by:
- Decreasing inflammation
- Promoting commensal bacteria
- Increasing antimicrobial peptides against pathogenic bacteria
- Inhibiting bacterial overgrowth
- Promoting mucus secretion
Based on this new data, it seems that promoting Bifidobacterium longum either through probiotic of fiber supplementation may be another useful measure to add to that protocol.