When I developed ulcerative colitis, I had been on several months of treatment as prescribed by Prof Kenny De Meirleir, an myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) researcher and clinician. The treatment included antibiotics to treat a suspected chronic Bartonella infection. I also took a bunch of supplements and injections as part of his protocol.
Prior to treatment I had undergone a barrage of immune system tests, including prostaglandin E2 (PGE2) and interleukin 8 (IL-8) both of which were highly elevated, especially PGE2. I had loads of other markers involved with inflammation that were very high. Over the course of treatment, the others reduced, while PGE2 and IL-8 did not. They went up even further.
One of the supplements I was on was berberine, which has a bunch of effects on the gutflora, which aren’t necessarily all good though it’s often touted as a cure-all (but that’s a whole other topic). Something else that Berberine does is reduce PGE2 synthesis (several studies showing that).
Well it didn’t work for me. Here are my results:
Prostaglandin E2 (normal, 0.17-6.4)
Jan 2013 (prior to any treatment): 28.3
August 2013 (after a few months on treatment): 68.95
Dec 2014 (after eight/nine months of treatment): 37.68
Prior to treatment, and before I developed ulcerative colitis (UC), I had significantly elevated PGE2. I am unaware of anyone measuring PGE2 in ME/CFS patients and reporting it as a finding, though I know others who have been tested and have elevated PGE2 and Maes et al. have reported elevated cyclo-oxygenase-2 (COX-2) in ME/CFS patients (which leads to production of PGE2 – more on that in a minute).
Although the cause of UC is also unknown, several pathogenic bacteria have been put forward as culprits, and some are known to induce the expression on PGE2 during mucosal bacterial infection. (Mallory Agard et al.). I developed UC in September 2013 as a direct result of the antibiotics I was taking which significantly disrupted my gut flora. In November I started taking Pentasa (mesalazine). Although the Dec 2013 result was still very high (higher than pre-treatment, in fact) it did drop between August and Dec 2014. Did the mesalazine cause that drop?
COX enxymes (also known as prostaglandin-endoperoxide synthase) catalyze the conversion of arachidonic acid into prostaglandins, including PGE2. Mesalazine has been shown to down regulate the COX-2/PGE2 axis in inflammatory cells in the colonic mucosa of UC patients (Collier HO et al. and Sharon P et al.) So, mesalazine seems to reduce PGE2 via COX-2 inhibition.
Even now, with my UC much better, if I forget a dose of mesalazine I can feel my bodies inflammation ramp right up and it stays that way until I take the mesalazine and it gets to work (slow release, so often this is up to a day). So maybe this is relevant to some people with ME/CFS, not just UC.
And although I’m not going to focus on it in this blog post, it’s interesting to note that activated B-cells highly express COX-2, and that inhibition of COX-2 dramatically reduces B-cell antibody production (Elizabeth P. Ryan et al). Could this be part of why Rituximab shows such great promise in the treatment of ME/CFS (Fluge Ø et al.) and is now in phase III trials?
Prostaglandin Receptors and Gut Permeability
PGE2 is produced by a bunch of tissues including those of the gastrointestinal tract and it interacts with the epithelial cells via specific cell receptors, namely, EP1, EP2, EP3, EP4, each resulting in different biological consequences. So it is not PGE2 alone that determines the biological effect, the receptor type matters. When the colonic mucosa is inflamed, the EP2 receptor on cells are over-expressed (V. Takafuji et al.) and mucosal PGE2 release appears to increase in correlation with disease activity in UC (DS Rampton et al.).
A new study published in PLoS One by Lejeune M et al. suggests that these prostaglandin cell receptors are involved in gut permeability, with the epithelial layer being more permeable — as measured by transepithelial electrical resistance (TER) — in cells that express less EP2 receptors, resulting in a significant loss of the tight junction protein claudin-4 through proteosomal degradation. The study authors managed to show that it was the receptor that was responsible, not prostaglandin itself (as suggested previously by Rodríguez-Lagunas MJ et al.). Now let me dumb that down for when I’m reading this back to myself in a few day’s time: Loss of EP2 receptors on the colonic epithelium can decrease barrier integrity by degrading a particular protein responsible for tight junctions. But it’s the prostaglandin receptor which is important, not the prostaglandin.
PGE2 is also known to induce IL-8 through its affinity for the EP4 receptor (I Dey et al.). That may explain why my IL-8 also remained high while the others did not, and further demonstrates why PGE2 may be important.
The problem is that PGE2 has all kinds of impacts through these four cell receptor types that it interacts with. We are understanding better what these receptors do thanks in no small part to studies using knock down mice (for which we can thank Nobel Prize winner Mario Capecchi who introduced the concept. Wonderfully, he is now involved in the End ME/CFS Project) but there is still a lot we do not know.
There is some evidence that PGE2 is protective of the intestinal mucosa (Morteau O et al.) but remember, some pathogens are known to induce it’s production, so it clearly isn’t all good. But we’re getting a bit of a mixed message here. PGE2 is also ultimately responsible for inducing fever by acting on the hypothalamus which controls the bodies temperature setting. I don’t get fevers (people with ME/CFS usually don’t get colds/flu when exposed, for some unknown reason) so there must be more to it than just having high PGE2, else my high PGE2 would induce a constantly high temperature… I haven’t looked but I’m guessing this might have something to do with those different cell receptor subtypes again. Maybe a reader knows, and can enlighten me.
But let’s say our COX-2/PGE2 is high when it shouldn’t be (perhaps in ME/CFS and perhaps in IBD when we are in remission) then it may be a reasonable step to try and reduce it. If we wanted to try that then as well as mesalazine, a common but related drug, aspirin, is known to significantly inhibit COX activity, as do other NSAIDs (that’s how they work to reduce pain/inflammation). Generally, nonsteroidal anti-inflammatory drugs are sometimes considered a risk for IBD, both UC and Crohn’s because they are hard on the gut. Though aspirin seems not to have this negative impact in UC (Chan SS et al.)
A number of COX2 inhibitors came on the market and resulted in increased heart attacks and strokes, leading some to be withdrawn, and warnings to be added to traditional NSAIDs. COX2 is actually pretty essential, so drugs that inhibit it can be dangerous.
Mesalazine is generally considered to be very safe though – it’s the front-end treatment for ulcerative colitis and is taken long-term – why is that? I suspect it is because it acts at a very local level; the majority is not absorbed so it stays in the intestines (making it a great drug for treating inflammatory bowel diseases) without having too much systemic impact.
I guess what I’d really like to know is why PGE2 is elevated in UC in the first place (as we’ve known for a long time – Wiercinska-Drapalo A et al.) and seemingly also in some patients with ME/CFS (who commonly suffer gut dysfunctions, including leaky gut). Herpes viruses induce COX-2 (Kaul R et al.) so could it be that herpes viruses, long proposed as the pathogenesis of ME/CFS, are to blame? Who knows.
Speculation aside, I think if we want to reduce COX-2/PGE2 then our aim should not be to potently inhibit it but to lessen it if it is inappropriately high.
Let us take a look at what probiotics might do for us then. This study (Jan-Michel Otte et al.) showed that the probiotics VSL#3 and Mutaflor (E. coli Nissle 1917) “ameliorated induced COX-2 and PGE2 secretion.” That’s nice and might explain why these probiotics have proven helpful in IBD.
The study continues, “Lactobacillus acidophus, however, significantly increased COX-2 expression and PGE2 secretion.” So you want to avoid L. acidophus – something I already do, as it may reduce commensal E.coli. It’s hard to avoid entirely though as it is in many products, including VSL#3 which in this study, on balance, still reduced COX-2 and PGE2 through the other types of bacteria in the product.
Another study (R. Korhonen et al.) suggests that Lactobacillus rhamnosus GG induces COX-2. Maybe best to avoid that one too then. And yes, there are lots of foods and supplements out there which are known to reduce COX-2/PGE2 but that’s a whole other topic. But I can’t resist pointing you to one interesting study comparing the effects of Omega-3 and Omega-6 fatty acids (DiNicolantonio JJ et al.) on Cox-2/PGE2.