Paradoxical Inflammation

Anti-inflammatory Treatments Cause Inflammation in Some Diseases, e.g. Rosacea

I thought that the anti-inflammatory diet and lifestyle I outlined on this blog would be a general purpose starting point for the treatment of all diseases. Inflammation is the foundation for allergies, autoimmune diseases and cancer. Inflammation is a basic defense against infectious diseases and many tissues require signaling components integral to inflammation for their normal function, so it is possible to overdo anti-inflammatory treatment and produce immuno-suppression. But that is unusual. What I am talking about here is inflammation caused by vitamin D, omega-3 oils, potentially low carbs and inhibitors of NFkB, such as tumeric. This is Paradoxical Inflammation.

Rosacean Inflammation Is Paradoxical

The obvious example of a paradoxical inflammatory disease is rosacea. Rosacea seems to be a large group of diseases that manifest in facial inflammation. Excessive flushing of the face can become persistent and form pustules and swelling. The triggers for rosacean inflammation are legion and idiosyncratic. They include mundane social interactions, numerous foods, temperature extremes and, paradoxically, just about everything that I recommend to decrease chronic inflammation.

Bacteria in Tissue and Gut Biofilms Are Candidates

Why do otherwise anti-inflammatory foods and exercise make rosaceans red in the face? Even vagal stimulation that is uniformly calming to inflammation, can make a rosacean flush. This is very inconvenient. I can only invoke the typical players: cryptic bacteria, biofilms, vagus nerve stimulation and response, lymphocytes/macrophages, cytokines and neurotransmitters.

All rosaceans have demonstrated facial inflammation and have had long term exposure to antibiotics and NSAIDs. That combination suggests that bacteria have been transported from a leaky gut (NSAIDs) to the site of inflammation (the face). It is likely that cryptic bacteria inhabit the dermis near the blood vessels and resident lymphocytes/mast cells. This is also the location for axons from vagus nerves. Thus, vagus stimulation may result in the release of neurotransmitter acetylcholine to stimulate lymphocytes/mast cells with subsequent release of cytokines. In this case the cytokines are inflammatory.

Other sources of inflammatory cytokines are lymphocytes/mast cells activated by endotoxin release from cryptic bacteria triggered by immunological attack. In this case, the immunological attack can be initiated by disruption of the stasis invoked by the cryptic bacteria.

Activated Cryptic Bacteria Are Source of Inflammation

It is hypothesized that the cryptic bacteria remain in tissue, because they are able to induce a hibernation-like physiology in the tissue. Disruption of the hibernation would initiate an immunological assault. Disrupting agents typically include vagal stimulators, such as activators of the hot or cold sensors, e.g. capsaicin, castor oil or menthol. Interestingly, the cryptic bacteria require a residual level of inflammation to acquire nutrients from the host. Anti-inflammatories that inhibit NFkB may destabilize the bacterial/host interaction and result in an immunological attack on the bacteria. All of the attacks on the cryptic bacteria release inflammatory endotoxin.

Gut Biofilms Store Bacteria Recruited to Become Cryptic in Inflamed Tissue

During the course of the disease and following numerous antibacterial treatments, bacteria can be continually recruited from safe havens, such as gut biofilms. Antibiotic treatment of biofilms converts the biofilm community to antibiotic resistance through activated horizontal gene transfer. Moreover, harsh treatment of biofilm communities initiates shedding of bacteria that could migrate across the leaky gut adjacent to the gut biofilms and provide new emigrants into the inflamed face tissue. A likely resident would be Chlamydia pneumonia, which has been demonstrated to be carried by macrophages and offloaded at distant sites of inflammation.

How the Vagus Becomes Inflammatory

This brings up the question of why vagal stimulation shifts from anti-inflammatory to inflammatory in rosaceans. I don’t think that the vagus nerves change in either their activation or in the neurotransmitters that are released as a result of stimulation. This means that the cells that respond to the vagal acetylcholine must be changed. I think that the change is a depletion of Treg cells and the result is that acetylcholine receptors on the remaining T cells cause a release of inflammatory cytokines. These cytokines cause the release of NO by endothelial cells and vasodilation. Leaking of endotoxin from the resident cryptic bacteria causes persistent dilation and restructuring of the vasculature.

Helminth and Il-2 Therapy Reestablish Tolerance and Reverse Vagal Inflammation

Since I have been forced to explain paradoxical inflammatory diseases, I might as well speculate on exotic approaches that already suggest potential treatments. Ingesting parasitic worm eggs (helminth therapy) has proven successful in the treatment of inflammatory diseases such as asthma, allergies and IBDs. Interleukin 2 (Il-2), usually used as a complex with an anti-Il2 antibody, is also a productive treatment. In both of these cases, the treatment stimulates the proliferation of Treg cells, which appear to be deficient in many of the inflammatory diseases. These treatments should also lead to a lowering of inflammation in the gut and suppression of inflammation as a result of vagal stimulation. Inhibitors of acetylcholine receptors, e.g. scopolamine patches, might also be interesting to test to see if they inhibit rosacean flushes in response to typical vagal stimulants such as castor oil or menthol.

Addendum:  Another possibility associated with the heavy use of antibiotics by rosaceans is intestinal (biofilm?) candidiasis.  Yeast infections are common after prolonged antibiotic treatment.  Interestingly, Candida produces resolvins from omega-3 fatty acids and the resolvins suppress neutrophil activity that would attack the yeast.  Thus, many of the anti-inflammatory treatments would actually aggravate yeast infections and contribute to rosacea.  Treatment for candidiasis (keeping in mind that yeast may be protected by biofilms) helps many rosaceans.  Stripping biofilms may be useful if pro- and pre-biotics are used to displace Candida.