Rosacea, Brain Cooling and Niacin Flush

Other players include:  Cathelicidins, Prostaglandins, Cryptic Bacteria, Nerves, Gut

What does it take to make your face red?  Excessive solar exposure can lead to apoptosis of skin cells overloaded with DNA damage and trigger inflammation: vasodilation, recruitment of neutrophils, swelling, etc.  Similarly, a local infection can cause inflammation and the accumulation of neutrophils (see The Inner Life/Extravasation for slide show), lymphocytes, etc., that is observed as pus.  These are general responses that occur in skin anywhere, but the face also blushes in response to emotional cues and flushes with exercise.  Rosacea seems to involve all of these reactions to produce a variety of symptoms of wide severity.  Here I try to provide an overview of the complex physiological interactions involved in rosacea.

Rosacea is Persistent Vasodilation of the Face with Accumulation of Neutrophils

The nervous and circulatory systems of the face are unique and provide numerous triggers for inflammation.  Emotional blushing is a common trait among those who progress to rosacea, even though this type of vasodilation is not easily observed with some facial characteristics.  Thus, many rosaceans claim to have never flushed before their first outbreak, but tests of skin circulation indicate that these individuals had skin types that prohibited display of the blushing.  The face is also adapted to control brain temperature, so changes in body temperature, physical activity, etc. can also trigger flushing.

Facial Blood Circulation to Cool the Brain

The cooling of the blood as it traverses the facial skin is used to cool the brain during extensive exercise or in warm environments.  This unique adaptation also means that control of facial vasodilation can potentially be disrupted in disease and cause symptoms of pathology.  In rosacea,  the brain cooling response is disturbed (see reference below), resulting in persistent vasodilation and suggesting that the unique control of inflammation in the face is why rosacea is limited to the face.  The pattern of blood circulation in the face, however, only roughly approximates the inflammation pattern in rosacea.

Nerves to the Face

The face receives sensory branching from the trigeminal nerve.  The enervation pattern of the branches matches emotional blushing, but they also appear to approximate the pattern of reddening in rosacea.  It makes sense that rosacea involves nerve-triggered dilation of the blood vessels of the face.  One contrast between emotional blushing and rosacea is that emotional blushing does not lead to the offloading of lymphocytes, whereas rosacea produces localization of neutrophils that exacerbate and prolong inflammation.

Cathelicidin, Vitamin D Receptor, DNA Complexes, Autoinflammation

A major component of the innate immune system is the group of basic antimicrobial peptides, cathelicidins.  Cathelicidins are effective against bacteria and they are produced during inflammation and are partially controlled by the vitamin D receptor acting as a transcription factor.  Thus, part of the action of vitamin D in providing protection against disease is by enhancing cathelicidin production.  Cathelicidin action in the skin parallels the control of intestinal villi development by defensins, that are also basic antimicrobial peptides under the control of vitamin D.  Cathelicidins also form complexes with host DNA from damaged cells.  These cathelicin/DNA complexes bind to toll-like receptors (TLRs) and trigger inflammation.  This reaction has been associated with psoriasis and may explain how neutrophil damage can perpetuate inflammation in rosacea.

Niacin Flushing Implicates Arrestins

The unique circulatory system of the face also makes it susceptible to flushing with niacin, a.k.a. nicotinic acid or vitamin B3.  Niacin is cheaper and much more effective at raising HDL and lowering triglycerides and LDL than statins, but is not fully utilized because it also produces intense facial flushes.  A recent article (below) has demonstrated that the lipid benefits can be separated from the flushing and implicated beta-arrestin 1 activation by niacin binding to GPR109A (G-protein-coupled receptor) as the triggering event.  Arrestin, which is involved in clathrin-mediated endocytosis, activates phospholipase A2 that in turn releases arachidonic acid (ARA) from phospholipids.  The ARA (that got into the phospholipids as the omega-6 fatty acid in vegetable oils) is converted by COX-2 into the inflammatory prostaglandin D2.  This prostaglandin is what stimulates vasodilation.  It is possible to produce chemicals that will stimulate the lipid metabolism alterations of niacin, without producing the arrestin activation and inflammation.  Aspirin can be used to inhibit COX-2 and other parts of NFkB-mediated inflammation and eliminate the niacin flush.  It is also interesting that the modified lipid metabolism of schizophrenics also eliminates niacin flushing.  Salicylic acid, the same as the acetylsalicylic acid of Aspirin without the acetate, is also used in some topical applications to quiet the symptoms of rosacea.  Arrestin activation may be involved in rosacea.

Gut Flora, Biofilms and Cryptic Bacteria

The gut is probably involved in most cases of rosacea and bacteria are also implicated by the modification of rosacea symptoms by antibiotics.  This area has not been explored, but I suspect that gut flora controlled by diet, as well as pathogenic biofilms and cryptic bacteria, e.g. Clamydia pneumoneae, in facial tissue are involved in varying degrees in the panoply of pathologies called collectively, rosacea.  Since the bacteria in contact with the gut determine the development of the lymphocytes in the lining of the gut, e.g. Tregs vs. T cells that fight infections, pathogenic gut biofilms may disrupt the normal function of the immune system and support rosacea.  Die off and release of cell wall endotoxin from cryptic bacteria could explain the paradoxical inflammation in response to many treatments that are normally anti-inflammatory.  I have discussed in another article potential approaches to strip off biofilms.

Treatment with Anti-Inflammatory Diet

The Anti-Inflammatory Diet (AID) and Lifestyle that I advocate on this blog would seem to be a natural cure for rosacea.  It should eliminate the inflammatory background that supports rosacea and was probably essential for its development.  This diet also eliminates acne, which is directly related to the accumulation of lymphocytes to make pus.  Inflammation is also needed for the offloading of neutrophils that exacerbate inflammation in rosacea.  Vitamin D is instrumental in cathelicidin production to eliminate cryptic bacteria. 

In most cases of rosacea, the AID should be helpful.  Eliminating dietary sources of inflammation, especially vegetable oils (the source of omega-6 fatty acids that are converted into inflammatory prostaglandins), should reduce rosacea symptoms.

In advanced, severe cases, however, it appears that maintenance of the suppression of the response to cryptic bacteria is required to prevent endotoxin-based inflammation.  Thus, most treatments that decrease inflammation, e.g. omega-3 oils, vitamin D3, Vagal maneuvers, can paradoxically produce elevated inflammation.  These treatments may also inadvertantly contribute to inflammation by upsetting pathogenic interactions between bacteria and intestinal cells.  I have discussed these paradoxical ramifications in another article.

references:
Brinnel H, Friedel J, Caputa M, Cabanac M, Grosshans E.  1989.  Rosacea: disturbed defense against brain overheating.  Arch Dermatol Res. 281(1):66-72.
Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ.  2009.  Beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.  J Clin Invest. 119(5):1312-21.

Heparin, Growth Factors and Rosacea

Knock-out Mice and FGF Receptor Inhibitors Mimic Rosacea
Heparin Nanofibers Loaded with VEGF and FGF Mimic Stem Cells

In previous articles, I have emphasized the mediation of extracellular signaling by heparan sulfate proteoglycans (HSPGs, polysaccharides attached to proteins) and heparin (HS fragments, oligosaccharides) and the sensitivity of HSPG expression and HS degradation by inflammation.  I return to that subject, spurred on by reading two articles that together show both the significance of heparin-mediated growth factors in general and in the specific case of symptom development in rosacea.

FGF Receptor Inhibitors Cause Symptoms Like Rosacea
Fibroblast growth factors stimulate the development of cancers, and antibodies against FGF receptors block cancer growth (see ref.)  FGF receptor inhibiting antibodies are now being used to stop cancers.  Unfortunately,  FGFR antibodies (e.g. cetuximab, panitumumab) also cause symptoms in the skin (telangiectasia, acneiform eruption) similar to the facial inflammation of rosacea.  Similarly, in knock-out mice, that lack the ability to produce FGFR, there are related symptoms.  It appears that lack of some FGF signaling may produce the symptoms of visible blood vessels and pus-filled (though lacking bacteria) follicles of rosacea.

FGF Mediated by HSPG
FGF binds to the heparan sulfate of membrane bound HSPG in pairs and these FGF dimer/heparan sulfate complexes activate a pair of FGF receptors.  The result is activation of protein phosphorylation activity (tyrosine kinase) and normal skin development.  HSPG synthesis is modified by inflammation and heparanase activity is increased.  This suggests that inflammation will decrease FGF signaling and could lead to symptoms of rosacea.

Growth Factors (VEGF, FGF) Bind to Heparin Nanofibers that Mimic Stem Cells
Stem cells produce lots of different growth factors and when stem cells are introduced into damaged cardiovascular tissue, more healing results (see ref.)  To determine if the growth factors produced by the transplanted stem cells was sufficient for the improved healing, fibers made of heparin were dipped into stem cell cultures and the resulting growth factor-coated fibers were injected into damaged tissue.  The heparin-binding growth factors were just as effective at enhancing healing as were the stem cells in previous experiments.  This demonstrated that heparin-binding growth factors were the key to normal repair/revascularization and function.

Rosacea Results from Inflammation and Aberrant Vascularization
Rosacea is poorly understood and is probably numerous diseases that have related symptoms and complex development.  As I indicated in previous articles, neurotransmitters from stimulated facial nerves, enzymes (kallikrein) and cytokines from intestinal interactions with gut flora, mast cell products (heparin, protease) and modified antimicrobial peptides (cathelicidins), as well as cryptic bacteria in facial tissues, may all be involved.  Inflammation in the skin of the face and in the intestines is involved.  Vitamin D, omega-3 fatty acids and anti-oxidants have a variety of responses (sometimes paradoxical) that differ from individual to individual and at different stages in the development of the disease.  Facial inflammation leads to abnormal development of blood vessels (telangiectasia) and in accumulation of lymphocytes and neutrophils (papulopustular rosacea).

Facial Inflammation May Depress HSPG Production and Disrupt FGF Function
One of the key ramifications of persistent facial inflammation may be the depletion of of HSPGs that normally coat cells.  HSPGs are continually produced, reabsorbed and degraded.  The half-life for HSPGs, even those that surround the cells that produce cartilage in connective tissue, is six hours.  HSPGs are also the source of heparin, that is produced as a counter ion bound to histamine and proteases in the secretory granules released by activated mast cells.  Thus, inflammation-based depression of HSPG production, which is also accompanied by heparanase activation, will remove the HSPG coating of cells.  This HSPG coating is needed for normal growth factor function.  Lack of an HSPG matrix on the surface of cells will also result in the migration of growth factors away from where they are normally functional and into adjacent tissue where they may stimulate aberrant development of blood vessels.  This may explain telangiectasia.

Is Topical Heparin a Rosacea Treatment?
Topical heparin does penetrate the skin.  It would appear to be a logical treatment, if HSPG depletion is contributing to symptom development in rosacea.  The length of the heparin fragments may be important.  I am unaware if anyone has tried the heparin lotions that are available for treatment of wounds to minimize scarring, on rosacea.  Heparin may be useful in combination with vitamin D3 and remediation of gut flora in a general scheme to treat rosacea.

refs:
Segaert S, Van Cutsem E.  Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors.  Ann Oncol. 2005 Sep;16(9):1425-33. Epub 2005 Jul 12.

Webber MJ, Han X, Prasanna Murthy SN, Rajangam K, Stupp SI, Lomasney JW.  Capturing the stem cell paracrine effect using heparin-presenting nanofibres to treat cardiovascular diseases.  J Tissue Eng Regen Med. 2010 Mar 10. [Epub ahead of print]

Rosacea: Alzheimer’s of the Face

Is Rosacea Caused by Amyloid LL-37, as Alzheimer’s Is Caused by Anti-microbial Abeta?
A recent article in PLoS One (Thanks Daniel!) suggests that the amyloid beta (Abeta) proteins that aggregate to form fibrous plaques in the brain tissue of Alzheimer victims, function as typical defensive anti-microbial peptides (AMPs), similar to the LL-37 cathelicidin implicated in facial tissue in rosacea.  The structural and functional similarities of Abeta and LL-37 suggest to me that Alzheimer’s and rosacea may also be similar in initiation and treatment.  Let’s compare amyloids and AMPs.

[The figure shows a model protein (from ref.) used to examine stain binding to amyloids.  The stains appear to bind to aromatic amino acids spaced evenly between adjacent proteins, but adjacent basic amino acids (blue) are spaced the same way and provide sites for heparin binding.]

Amyloids:

• Amyloid proteins/peptides align into stacks and fibers
• Stacked beta sheets bind amyloid stains: Congo Red, Thioflavin-T
• Fibers form on anionic polymers: heparin, DNA
• Short amyloid stacks are toxic to cells
• Proteases produce multiple sizes of amyloid peptides

Anti-microbial Peptides:

• AMPS typically contain heparin-binding domains -- basic peptides/ plus charge
• Some AMPs, e.g. LL-37, form fibers on DNA, heparin (stain with amyloid stains)
• Toxic to cell membranes
• Kallikrein stimulated by gut flora migrates to face and clips LL-37 to a smaller peptide that binds to host DNA and stimulates the TLR receptor to produce inflammation
• Stomach pepsin hydrolyzes dietary proteins into anti-microbial peptides (heparin is secreted by mast cells onto to the intestinal surface to protect from any amyloid-like effects)
• Defensins, cathelicidins and other AMPs are under transcriptional control of vitamin D receptor

Abeta Is Anti-microbial Like LL-37

Amyloid beta is the well-known source of the fibrous plaques forming brain lesions in Alzheimer’s disease.  The normal function of Abeta has not been firmly established.  The recent article shows data to support Abeta as an anti-microbial peptide comparable to LL-37 against several pathogenic bacteria and yeast.  Knock-out mice deprived of a gene corresponding to Abeta are susceptible to bacterial infections.  The anti-microbial activity present in extracts from Alzheimer’s disease brains was inactivated by anti-Abeta antibodies.

Implications of Abeta as an AMP Like LL-37

The similarities between AMPs and amyloid peptides suggest some implications for both Alzheimer’s disease and rosacea.  Vitamin D is a hormone that binds to a cytoplasmic receptor and the vitD/receptor complex then acts as a transcription factor that controls the expression of defensins in the intestines, LL-37 in facial skin and perhaps Abeta in brains.

Amyloids form fibers on a scaffolding of heparan sulfate (HS).  There is usually an excess of HS on the surface of cells and the HS is rapidly recycled back into cells.  During inflammation, mast cells release heparin, short fragments of HS, that should also inhibit amyloid fiber formation on HS.   Chronic inflammation, however, reduces HS production and may set the stage for amyloid fiber formation.  HS metabolism of the brain may be vitally important to the development of Alzheimer’s disease, especially since the increasing chronic inflammation of aging people should deplete brain HS.

LL-37 forms complexes with DNA from damaged host cells in rosacea skin.  The LL-37/DNA complexes trigger TLRs and inflammation.  LL-37 may normally bind to cell surface HS and chronic inflammation of the skin may cause the shift to pathogenic autoinflammation.  Topical application or perhaps low dose IV heparin may be effective in disrupting the autoinflammation due to LL-37.  Part of the toxicity of LL-37 in the skin may be due to amyloid like structures that could form with inadequate HS and overabundant LL-37 production.  Vitamin D metabolism should also be very important, since LL-37 synthesis is controlled by vitamin D.  This is consistent with the benefits that some rosaceans observe with high doses of vitamin D3 supplements.

references:
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD.  The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.  PLoS One. 2010 Mar 3;5(3):e9505.

Abedini A, Tracz SM, Cho JH, Raleigh DP.  Characterization of the heparin binding site in the N-terminus of human pro-islet amyloid polypeptide: implications for amyloid formation.  Biochemistry. 2006 Aug 1;45(30):9228-37.

Biancalana M, Makabe K, Koide A, Koide S. Molecular mechanism of thioflavin-T binding to the surface of beta-rich peptide self-assemblies.  J Mol Biol. 2009 Jan 30;385(4):1052-63. Epub 2008 Nov 14.

Erectile Dysfunction Diet

Inflammation Leads to Hypertension, Nitric Oxide Inadequacy and Impotence

Drugs for erectile dysfunction (ED), e.g. sidenafil (Viagra), compensate for inadequate nitric oxide (NO) production from arginine by inhibiting the enzyme, phosphodiesterase (PDE5), that hydrolyzes the cyclic GMP that mediates the NO-triggered process of vascular dilation.

Inflammation Is the Core of ED

Drug treatment to compensate for inadequate NO production is a multibillion dollar industry that avoids curing the underlying cause of the ED.  All of the physiological predispositions to ED result in or derive from chronic inflammation.  The major cause of ED, hypertension, frequently as a result of kidney disease, diabetes or metabolic syndrome, can be treated with diet and exercise.  Of course the typically recommended diet is essentially the Anti-Inflammatory Diet, compromised by the unenlightened persistence in the counterproductive use of grain starches, high fructose corn syrup, omega-6 polyunsaturated fatty acids and low saturated fat.

Decreasing Testosterone Results from Declining Health -- not Age

Recent studies also indicate that testosterone levels do not normally decline with age, but rather with declining health.  Healthy men have higher testosterone levels.  I would suggest that reduction in serum testosterone could be used as a measure of chronic inflammation in men.  This also suggests that many of the symptoms associated with aging in men actually reflect increasing chronic inflammation and reduced testosterone.

ED Diets Are Just the Anti-Inflammatory Diet Plus Veggies

A chronic high starch/sugar/HFCS diet with omega-6 oils in place of saturated fats, leads to chronic inflammation, high triglycerides, risk of metabolic syndrome and obesity.  Of course, diabetics have an even lower tolerance for this type of diet.  This diet, which is rather typical in many modern cultures, also provides a high risk of damage to endothelial cells lining the circulatory system and to ED.  The opposite of the inflammatory diet is the low carb, high omega-3 fish oil, no vegetable oil, meat/fish/dairy, Anti-Inflammatory Diet.  This is supplemented with exercise and high vitamin D.  Foods labeled as beneficial to ED also include specific herbs, spices and leafy vegetables, because these contain organic chemicals that inhibit components of the inflammation system or are anti-oxidants.
 
ED and Biofilms

I would suspect that men with ED suffer from chronic dietary inflammation and one of the consequences of this type of diet is the accumulation of pathogenic biofilms.  Hypertension, which is a contributor to ED and a consequence of chronic inflammation, is also associated with periodontal biofilms and kidney disease (aggravated by renal biofilms.)  I suspect that endothelial cells of capillaries are compromised by biofilm-derived endotoxins that ultimately contribute to apoptosis, decrease in capillary beds and elevation of blood pressure.  All of these assaults on endothelial cells undermine penile vasculature and contribute to ED.

Viagra Can Lead to Rosacea

Men taking Viagra or other PDE5 inhibitors typically have compromised vascular systems that are the basis for ED.  Increasing the response to NO in men with ED produces an increased risk of rosacea.  Withdrawal from PDE5 inhibitors stops the rosacea, which returns if the PDE5 inhibitor use is reinitiated.  Thus, the flush that is the goal of Viagra therapy, leaves some redfaced.

ref:
Ioannides, D. et al. (2009) Phosphodiesterase-5 inhibitors and rosacea: report of 10 cases. Br. J. Dermatol. 160: 719-20.

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.

Health Diagrams III — Inflammation from Cell to Tissue

---All 200 Posts---

I have explained my perspective in diagrams of the relationship between diet, gut flora and disease:

Health Diagrams I — Gut Flora and Diet

and of the interaction between gut flora, the immune system and autoimmunity:

Health Diagrams II — Curing Autoimmunity and Allergies

Now I am discussing how inflammation, the foundation of most chronic diseases, begins at the cellular level and results in the classic symptoms of tissue inflammation: redness, heat, swelling and pain.

NF-kB is the Transcription Factor that Controls Inflammation Genes

Of the 23,000 human genes, about 1,000 on each of 23 chromosomes, five dozen, e.g. enzymes involved in nitric oxide (vasodilation and erection hormone), synthesis of heparin sulfate and prostaglandin synthesis from omega-6 fatty acids or cytokines (IL-1, IL-6, TNFa), are associated with inflammation.  These inflammatory genes are turned on or expressed in individual cells, when the inflammation transcription factor, NF-kB, is activated by any of numerous external signals, including inflammatory cytokines, bacterial or fungal cell wall materials (LPS or beta-glucan), advanced glycation end products (AGE, e.g. HgA1C, resulting from high blood sugar) or reactive oxygen species (ROS, e.g. super oxide, from insulin resistance).

NF-kB and Inflammation
Superoxid Causes Insulin Resistance

Inflammation is the Foundation of Growth, Birth, Cancer and Pain

We think of inflammation as the sum of physical symptoms, and our purpose in responding to inflammation is typically to limit its impact.  We try to stop swelling by applying cold or hot, and we take aspirin to lower fevers and stop pain.  We fail to realize that inflammation is essential to the growth and development of many different tissues, and that inflammation is a cycle that leads back to normal function.  

Body tissues, such as the lining of the intestines or the uterus, continually produce new cells to replace the old that are sloughed off.  NF-kB must be turned on for these growth and attrition cycles.  Taking aspirin blocks NF-kB in the gut and stops local development of the lining, resulting in weak areas that bleed.  That is why doctors encourage patients to drink a half glass of water before and after swallowing aspirin tablets. 

Another more dramatic example of control of inflammation is conception, gestation and birth.  Conception and gestation require inhibition of inflammation, to permit growth of a foreign organism (a fetus is half sperm genes) in the uterus.  Chronic inflammation limits the ability of the uterus to suppress immune attack and can produce infertility, which is treated by aspirin and heparin, which suppress chronic inflammation.  The return of inflammation at the end of gestation precipitates labor and birth.  Excess Inflammation produces high levels of circulating inflammatory cytokines, which causes postpartum depression.  Depression and chronic inflammation have the same cytokine profiles, i.e. depression is a symptom of chronic inflammation.

Birth and Inflammation

Proliferation, or enhanced cell division, is another aspect of inflammation and is also the foundation for cancer.  That is the reason that some doctors recommend low dose aspirin to reduce colon cancer.  Similarly, since inflammation is the basis for coronary artery disease, doctors sometimes recommend low dose aspirin, although this is controversial.  Doctors also use aspirin as a so called blood thinner, since it blocks inflammatory signaling in platelets and discourages clotting.  Inflammation of nerve cells is experienced by the brain as pain.  

When it is understood that inflammation is an essential feature of many normal, healthy cell and tissue functions, then “inflammation," with its negative connotations, becomes a misnomer.

NSAIDs Inhibit Inflammatory Prostaglandin Production

Aspirin directly inhibits NF-kB activation inside the cell, but it also chemically modifies COX, the enzyme that converts omega-6 polyunsaturated fatty acids (common in polyunsaturated vegetable oils) into inflammatory prostaglandins.  Other NSAIDS (Non-Steroidal Anti-Inflammatory Drugs) just inhibit COX, but Aspirin transfers its acetyl group to make acetyl-COX, which has a new activity that converts omega-6 fatty acids into anti-inflammatory prostaglandins.  The high omega-6 fatty acid content of vegetable/seed oils, such as corn, soy, canola, etc. is why these oils, in contrast to olive oil or butter, are inflammatory.  Omega-3 fish oil is anti-inflammatory, because it is converted to anti-inflammatory prostaglandins.  Plant omega-3 fatty acids are shorter and are not converted to prostaglandins, but inhibit omega-6 conversion.

Aspirin

Nitric Oxide, Vasodilation and Viagra

Swelling is caused by vasodilation, the relaxation of blood vessels, and accumulation of serum in the tissue.  This vasodilation also makes the tissue red and warm from the increased amount of warm blood in the capillaries.  Vasodilation is caused by nitric oxide, NO, that is produced by an enzyme under the control of NF-kB, which takes the nitrogen from arginine (or nitroglycerine).  The NO diffuses easily and binds to receptors that produce an amplified signal, cyclic GMP, that relaxes the muscle cells surrounding blood vessels.  [Viagra is potentially dangerous, because it just exaggerates the amplified signal and obscures the underlying vascular damage, e.g. hypertension, that causes erectile dysfunction by blocking normal vasodilation.]

Nitric Oxide and Erectile Dysfunction

Hot/Cold and Endorphins

The dilemma of whether to use hot or cold therapy to block inflammation is based on a misunderstanding of what the temperature changes are actually doing.  Changing the temperature of the skin alters the structure of sensory proteins in nerves of the skin and triggers signals to the brain that register as hot or cold.  Chemicals, e.g. capsaicin or menthol, can have the same effect without changing skin temperature.  The important response for inflammation control, is return signals from the brain that release neurohormones, e.g. endorphins, from different nerves that reach not only some of the skin that was hot or cold, but also deeper tissue.  The endorphins block inflammation and all of its symptoms.  That is why chemically treated pads are more effective than icing or changing from hot to cold, because "hot" and "cold" signaling chemicals can be applied simultaneously.  None of the treatments is more than skin deep.  Actually chilling or heating tissue below the skin is damaging and causes more inflammation.  Low dose Naltrexone may be effective in some cases of chronic inflammation, by stimulating systemic rebound endorphin production.

Dr. Oz, Pain, Hot/Cold Receptors

Lymphocyte Offloading, Mast Cells, Heparin

Rosacea is a group of diseases that involve inflammation of the face in an exaggerated blush.  Any of the signals that would lead to blushing cause intense vasodilation.  A blush is fleeting, but rosacea is made chronic by another aspect of inflammation, offloading of lymphocytes.  Large numbers of lymphocytes accumulating in response to a local infection would produce pus.  In the case of rosacea, the distributed leucocytes, including neutrophils, respond to the blushing signals by producing inflammatory signals, such as P protein.  The result is cycles of inflammation, autoinflammation.

Mast cells can also be offloaded from blood vessels and provide a link between the immune system and inflammation.  Mast cells display IgE receptors on their surfaces, which bind antigens and trigger release of histamine, heparin and protease.  Histamine is a neurotransmitter that binds to receptors on blood vessels and nerve cells.  In the gut, histamine mediates many digestive processes.  Heparin released along with  histamine, coats the gut and prevents attachment of pathogens by competing for binding to the heparan sulfate proteoglycans (HSPGs) that form the surface of cells that line the gut.  [Heparin is the most common drug used in hospitals and is produced from intestines of cattle and hogs in the meat industry.]  Heparin also binds and inactivates the proteases released from mast cells.  Upon release, the now active proteases attack and activate receptors on nerves and immune cells.

Mast Cells and Heparin

Heparin is Anti-Inflammatory

Heparin is the most negatively charged polysaccharide, mediates most of the receptor/hormone interactions at cell surfaces; facilitates amyloid plaque formation, e.g. in Alzheimer's, atherosclerosis, diabetes, dementia; and controls numerous protease reactions in the complement system and clotting, etc.  There are hundreds of heparin-binding proteins.  Heparin is produced in secretory granules of mast cells by the action of heparanase on heparan sulfate proteoglycans. Heparin is a mixture of small fragments, oligosaccharides of heparan sulfate polysaccharides.  Heparin is anti-inflammatory and is administered to facilitate conception and gestation.  Inflammation also inhibits the genes involved in heparan sulfate proteoglycan production and since HSPGs are a major component of basement membranes of tissues and provide the barrier function of blood vessels in kidneys and brain, inflammation leads to proteinuria and loss of the blood brain barrier.  Since HSPGs have a short half life of six hours and are rapidly recycled, heparin added to the blood is rapidly absorbed by vessels, and heparin taken orally is absorbed by intestinal cells, but does not reach the blood.  HSPGs and heparin are central components of immunity and inflammation.

Heparin and Inflammation

Inflammation Blocks Skin Synthesis of Vitamin D from Cholesterol

Inflammation blocks solar synthesis of vitamin D in the skin and is more important than skin pigmentation, use of sunblock or latitude in producing vitamin D deficiency.  The vitamin D content of food is negligible compared to solar production in the skin.  It is not surprising that rising chronic inflammation is also accompanied by rising vitamin D deficiency.  Vitamin D supplementation is usually ineffective in curing vitamin D deficiency, because the supplements are too low and very high levels of supplemental vitamin D are required to reverse underlying chronic inflammation.  Statins are very effective at blocking cholesterol synthesis and although reducing cholesterol has minimal impact on the target, cardiovascular disease, it dramatically reduces vitamin D causing muscle pain, etc.

Most vitamins are enzyme cofactors synthesized by gut bacteria and used as quorum sensing signals during formation of biofilms.  Vitamin D, in contrast, is a steroid hormone and receptors for vitamin D are inside cells.  The receptor/vitamin D complex is transported into the nucleus where it acts as a transcription factor to control the expression of genes.  Vitamin D controls the expression of defensins in the crypts of the villi of the small intestines.  The antimicrobial activity of defensins is based on the basic amino acids (arginine and lysine) of its heparin binding domains.  Vitamin D also interacts with NF-kB in the nucleus and modulates inflammation.

Inflammation and Vitamin D

Bacteria and LPS

Lipopolysaccharide is a wall component that is indicative of bacteria, just as beta-glucan is indicative of fungi, and both are intense activators of NF-kB and inflammation.  LPS is released from damaged bacteria, e.g. by antibiotic treatment, binds to receptors on the surface of intestines and stimulates inflammation with release of NO, which produces diarrhea.  Food intolerances, which are based on incomplete digestion of food components, because of an incomplete gut flora (immunological responses/food allergies are rare) are probably also the result of LPS release from gut flora and inflammation.

Innate Immunity is also Triggered by LPS

The basic defenses of humans against microorganisms are mediated at the cellular level by triggering molecules common to all microorganisms, e.g. LPS for bacteria.  The responses are equally general: lysozyme to digest bacterial wall peptidylglycan, lactoferrin that binds iron and yields antibacterial peptides.  LPS (and inflammatory cytokines) also stimulates the liver to produce CRP (C Reactive Protein) that binds to choline on bacteria as the first step in phagocytosis and DNAse I that digests NETs (neutrophil extracellular traps) that are the DNA and histones released by triggered neutrophil cells that enmesh bacteria for engulfment by phagocytic cells.  [NETS plug peripheral catheters and can be cleared with probiotics that stimulate DNAse I release from the liver.]  NETs are also present at sites of inflammation and the accompanying nuclear proteins have the basic triplets that stimulate immune presentation and act as autoantigens, i. e. produce anti-nuclear antibodies, in the absence of adequate Tregs.

Diet and Inflammation

The diagram outlines the interactions that produce the tissue symptoms of inflammation.  Many components of modern diet can trigger inflammation:

Sugars and high glycemic starches raise blood sugar and enhance AGE/HgA1C.

Vegetable oils high in omega-6 oils are converted into inflammatory prostaglandins.

Wheat and other grains have high glycemic starch and insoluble fiber that is inflammatory.  Gluten is inflammatory.

Antibiotics damage the gut flora and produce vitamin deficiencies, autoimmunity and allergies.

Food intolerances result from damaged gut flora and produce gut inflammation.

Fish high in omega-3 EPA and DHA are anti-inflammatory.

The Anti-Inflammatory Diet

Health Results from a Balance of:

Diet (meat, fish, eggs, dairy, vegetables), containing macronutrients of protein, starch 30-100 g/d and fat (low omega 6/3 and saturated fat for most calories), and micronutrients

Soluble Fiber, e.g. resistant starch (consult Free the Animal), inulin, pectin, (plant polysaccharides, animal GAGs)

Gut Flora, diverse and adapted to dietary soluble fiber,

Exercise

Resistant Starch, Panacea, but Why?

Mark’s Daily Apple provides an authoritative diet guide (except for the gut flora).

Transglutaminase, Gluten, Celiac, Inflammation, Autoimmunity

The point of this post is that the intestines produce an enzyme, transglutaminase (TG) that normally protects the gut from toxic plant proteins, such as grain gluten, but modern food processing and antibiotics corrupt digestion of gluten to produce intestinal inflammation and a series of related autoimmune diseases including celiac, thyroiditis, diabetes, baldness and atherosclerosis. 

Transglutaminase Links Proteins Enzymatically

Transglutaminase is a ubiquitous enzyme produced in the intestines, thyroid, heart, skin, hair follicles, etc.  This enzyme attaches to a protein (TG + ProA ~~> TG-ProA) via amino groups extending from some of the protein's amino acids, e.g. lysine or glutamine, and then the enzyme replaces itself by another protein leaving the two proteins crosslinked (TG-ProA + ProB ~~> TG + ProA-ProB).  Another alternative reaction is to leave the original glutamine without its amino group to yield glutamic acid residues.

Linking Proteins Makes Connective Tissue Tough

Transglutaminase is useful to crosslink the proteins in connective tissue.  Proteins in basement membranes form a matrix by binding to the heparan sulfate sidechains of another basement protein, perlecan.  The heparin-binding domains consist of basic amino acids that TG can react with to crosslink the proteins.

Linking Pathogen Proteins

Transglutaminase is also produced to crosslink the DNA/heparin/matrix polysaccharide-binding domains of pathogenic bacteria leading to aggregation, localization and death of the bacteria.  Inflammation resulting from activation of the inflammatory transcription factor, NFkB, stimulates production of TG.

Gluten is a Plant's Way of Saying "Don't Eat Me!"

Gliadin is a protein component of gluten that contains long stretches of glutamine residues, i.e. it is a polyglutamine protein similar to the protein that causes Huntington's disease.  Gliadin is an advantage as a storage protein for grain, because it is aggregated by the TG that protects the lining of the intestines of herbivores, such as humans, makes the animal sick and thereby discourages eating the grain.  Aggregation of gliadin/gluten inhibits digestion of the grain protein and can leave TG bound to gliadin.  Conversion of the polyglutamine stretches to polyglutamic acid stretches that are negatively charged, produces proteins that will bind to the positively charged heparan sulfates that circulate along the surface of intestinal cells leading to damage and inflammation.

Basic Triplet Leads to Antibody Production

Transglutaminase is also transported into cells, because it contains a region with a triplet of basic amino acids (...EPKQKRKLVA...).  This internalization probably contributes to enhanced presentation of TG to the immune system for subsequent antibody production.

Transglutaminase is Inflammatory

Transglutaminase interaction on the surface of cells also activates, NFkB, the transcription factor responsible for inflammation. Thus, TG turns on inflammation and part of inflammation is the activation of the innate immune system that includes production of TG.  This circular activation may produce autoinflammation that is associated with various forms of inflammatory bowel diseases.

Gluten Sensitivity is Normally Controlled By Gut Flora

Gluten sensitivity expressed by most people, is the intestinal response to the toxicity of gluten as it interacts with TG and causes inflammation.  This inflammation will also result in immune presentation of both gliadin and TG, and production of antibodies to both. Antibody production will normally be controlled by regulatory T cells of the immune system, unless spreading inflammation in the gut and/or antibiotics destabilizes the gut flora and compromises regulatory T cell development in the intestines.  

Anti-Glutaminase Antibodies Attack the Gut

Celiac results from uncontrolled production of antibodies to gliadin and TG with attack by the immune system on the aggregated gliadin/TG on the surface of the intestinal epithelium.  Celiac flare ups in response to eating even small quantities of gluten lead to further inflammation of the gut and further disruption and simplification of gut flora.

Celiac Leads to Thyroiditis and Much More

Transglutaminase is also produced by the thyroid and celiac will develop into a more generalized autoimmune disease that results in Hashimoto's thyroiditis.   TG production in the skin can result in skin rashes and may contribute to rosacea.  The base of hair follicles contains TG involved in hair production, and may contribute to some forms of hair loss.  Another substantial worry about the sequelae of celiac and gluten intolerance is the presence of TG in coronary arteries.

Antibiotics are Part of the Gluten Problem

Celiac and gluten sensitivity seem to be increasing with modern processing of grains and increased use of antibiotics.  Wheat has been gradually changed by traditional breeding, but genetic engineering has not yet been developed for wheat.  So, at least in this case, GM wheat cannot be part of the problem.  Many recent studies show that antibiotics profoundly and permanently alter gut flora.  As a result, the immune system, which is dependent on gut flora diversity is compromised, and various forms of autoimmunity and allergies develop.

Super Fine Flour Damages Gut Flora

Germ and bran are removed from all wheat before it is ground.  This is true even for whole grain flours, which have some of the germ and bran added back after milling.  Modern milling may be part of the gluten problem, because the flour is ground so fine that the grains of starch are broken.  Broken starch grains are digested by pancreatic amylases in the upper intestines, whereas some of the starch from intact grains is digested by gut flora in the colon.  Thus, modern wheat flour fails to feed gut flora like soluble fiber to produce short chain fatty acids, e.g. proprionic acid that supports Treg development; modern superfine flour supports autoimmune diseases and allergies.

Cultural Practices Make Gluten Safe

Wheat has been bred to produce bread as fast as possible from superfine flour.  This rapid bread production eliminates the exposure of gluten to enzymes from both germinating wheat seed and fermenting bacteria, which are part of traditional bread making.  Coarsely milled, traditional flour responds to soaking in water by activating enzymes that partially digest gluten, since gluten is a storage form of amino acids destined for the seedling.  Sour dough starter, a mixture of bacteria that can ferment the starch and gluten into short chain fatty acids and bubbles of carbon dioxide, has been used traditionally to provide leavening and flavor to bread.  Both flour and bacterial enzymes modify the structure of gluten to render it less toxic to the intestines.  Cultural traditions insured that gluten would be systematically detoxified by enzymes during hydration and fermentation of dough prior to baking.  Modern processing leaves wheat gluten in bread unmodified and toxic.

Prevention and Cure:  Eliminate or Detoxify Wheat and Add Bacteria

Preventing and curing diseases associated with gluten and transglutaminase is simple.  Eliminating wheat would do the trick.  Unfortunately, wheat is the mainstay in many parts of the world.  Fortunately, gluten intolerance is not uniformly observed where wheat is eaten.  This indicates that there are potentially safe ways to eat wheat and bread.  I gained insight into how to eat wheat safely from two books that were recently published:  Cooked by Michael Pollan and Artisan Bread in Five Minutes a Day by Jeff Hertzberg, MD and Zoë François.

Michael Pollan has recently become interested in gut flora and his book revealed how he built up a healthy gut flora eating homemade fermented food and compromised his work with antibiotics.  The major breakthrough that I made by reading Cooked was based on his experiments in baking whole wheat bread.  He hydrated the flour first and then used sour dough starter for lengthy fermentation.  This was the same process that I had used to make great loaves of bread (photo above) using Jeff Hertzberg’s directions in Artizan Bread in Five Minutes a Day.

The answer to gluten intolerance and most autoimmune diseases amounts to eliminating wheat or treating wheat in a safe, traditional process that inactivates the toxic properties of gluten; and maintaining a healthy gut flora (probiotics are not enough) with hundreds of different species of bacteria that promote the development of the suppressive immune system mediated by regulatory T cells:

Safe Traditional Bread 

• Remove bran and discard as toxic insoluble fiber.
• Grind wheat to retain starch grain structure.
• Soak flour to hydrate and activate wheat enzymes to start digestion/detox of gluten.
• Ferment dough with bacteria (sour dough starter) to continue digestion/detox of gluten.
• Bake.

Develop Healthy Gut Flora and Suppressive Immune System

• Avoid antibiotics that kill bacteria.
• Avoid hygiene practices, e.g. antibacterial soaps, bleaching surfaces, closing toilet covers, etc. that eliminate sources of healthy bacteria.
• Kiss your loved ones and pets, and encourage everyone to garden/play in the soil (an excellent source of thousands of different species of bacteria.)
• Recruit healthy gut bacteria by eating a variety of homemade fermented vegetables. My most highly recommended source is my friends at: http://www.fermentista.us
• Remember that cooked or pasteurized foods do not contain useful bacteria.
• Remember that dairy probiotic bacteria cannot live in the human gut and can only provide a temporary help to the immune system.
• Limit the variety of foods that are consumed and gradually change with the seasons to avoid rapid changes in nutrients to which gut flora cannot adapt.  Food intolerances indicate maladapted gut flora.
• Constipation indicates dysfunctional gut flora and a compromised immune system.

Vagus Nerve Controls Gut Inflammation II

Inflammatory Mast Cells Silenced

In a previous article, I outlined the role of the vagus nerve in responding to infection/damage signals by producing signals that inhibit inflammation. In a recent article (ref. below), the role of the vagus nerve in gut inflammation was examined using real-time biophotonic labeling. Basically that means that a video camera sensitive to infrared can be used to detect infrared dyes produced when NFkB is activated -- the camera is able to visualize regions of inflammation in living mice. Using this technique, researchers were able to demonstrate that cutting the vagus nerve produced heightened inflammation in gut treated with an irritant. The vagus nerve appears to stimulate regulatory T cells that lower the activity of inflammatory cells.

Inflammation/NFkB Activation Visualized in Live Mice

The studies were performed in a mouse line constructed to express an infrared fluorescent protein in cells in which the inflammation transcription factor, NFkB, is activated. Mice of this strain were prepared with and without the vagus nerve intact leading to the intestines. The mice were then exposed to sodium dextran sulfate (DSS) to simulate inflammatory bowel disease symptoms.

Cutting the Vagus Nerve Permits Inflammation

Mice with intact vagus nerves exhibited much less inflammation in their gut than those without vagus innervation. The cut vagus experiments demonstrated that the vagus nerve was responsible for suppressing inflammation. Further experiments were performed to determine if the inflammatory and anti-inflammatory reactions could be transferred to other mice by transferring cells from the treated mice.

Regulatory T Cells (CD4+, CD25+) Block Inflammation

Transfer experiments showed that inflammatory T cells (CD4+, CD25-) from cut vagus, DSS mice would cause bowel inflammation in other mice, but that did not happen with the same type of cells from mice with intact vagus nerves. Further tests showed that either cutting the vagus or adding inflammatory T cells from a mouse with a cut vagus, reduced the population of regulatory T cells (CD4+, CD25+) in control mice treated with DSS. So, without the vagus stimulation, the regulatory T cell population declined in the presence of inflammatory signals.

Absence of Regulatory T Cells Can Explain Many Inflammatory Diseases

In many inflammatory diseases, e.g. celiac, Crohn’s disease, rosacea, there appears to be a deficiency of regulatory T cells. In the absence regulatory T cells, signals from vagus nerves will no longer produce anti-inflammatory suppression. In fact the same nerve signals may become inflammatory. This would explain why rosaceans will become inflamed by hot or cold stimulation that would normally lead to anti-inflammatory stimulation of regulatory T cells. Similarly, capsaicin, castor oil and menthol, which normally produce an anti-inflammatory response, produce inflammation in rosaceans.

[Vagal stimulation exercise links:  here and here.]

reference:
O'Mahony C, van der Kleij HP, Bienenstock J, Shanahan F, O'Mahony L. 2009. Loss of vagal anti-inflammatory effect - in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. Aug 12. [Epub ahead of print]

Constipation, Gut Flora and Health

“If you notice your bowel movements, they are unhealthy.”

Scatological jokes are common. The guide on my Swedish language tour of Moscow in 1976, told a joke about Russians.  She described Russian toilets that are dry, with a shelf for stools to drop upon and a lower hole in the back into which the stool is swept with water.  This was contrasted to Western toilets that partially concealed the stools as they dropped into water.  The joke was that Russians had no art, because they could easily observe their creations each morning.

You Are What You Eat and the Proof Is in the Toilet

Refer to Mr. Monastyrsky for a broad discussion of constipation and stool characteristics.  This web site has lots of information about stool types, how to get them and how to change them.  His recommendations to avoid constipation center on a healthy diet, like my Anti-Inflammation Diet, plus glutamine to help the gut heal.

Another useful perspective on gut flora is provided by a Nature web site on gut flora genomics. This site describes genomic research to show that changing diet changes relative proportions, but not the types of bacteria in gut flora.  Each person has a recognizable, individual composition of gut bacteria.

Feces Is Primarily Bacteria

What you eat and your eating/health history determines your gut flora, and feces is made up of gut flora and some undigested food.  Healthy bowel movement stools are made up of more than 50% bacteria and the consistency of the stools is determined by the bacterial content.  Less bacteria means drier, harder stools.  Bacteria hydrate stools and prevent constipation.

Pathogenic Gut Flora

Why does a total bowel irrigation with PEG, polyethylene glycol, make people with chronic diseases feel as good as if they had an antibiotic treatment (barring die off)?  I think that the answer is that both disrupt and change the gut flora and in many cases disease symptoms are supported by an unhealthy gut flora/biofilms.  In many cases, the antibiotic cannot have a lasting impact, because it is hard to kill bacteria in biofilms.  PEG may actually clean out more of the biofilms, because it should also disrupt the polysaccharide matrix of the biofilms.

Disruption of Gut Flora Leads to Disease

Babies fed breastmilk vs. formula display very large difference in inflammation and susceptibility to disease.  Formula causes gut inflammation and susceptibility to intestinal and respiratory diesease.  Formula also causes a dramatic shift in gut flora from a simple flora dominated by Bifidobacter to a complex adult gut flora. 

Gut Controls Immune System

The impact of the two different gut flora on development of the GI tract and on the newborn immune system is dramatic also.  Remember that most of the immune system of the body is located in the lining of the gut and immune organs, such as the tonsils, are outgrowths of the GI tract.  The thymus, which is responsible for producing T lymphocytes, is twice as large in breastfed babies.  Thus, feedback from the gut of formula fed babies inhibits thymus and immune system development.

Change Your Gut Flora and Change Your Health

Experiments in mice, and I think in humans, have shown that changing the bacteria in the gut changes interactions with food.  Exchanging gut bacteria between fat and lean individuals, causes fat people to lose weight and lean people to gain weight.  I think that this indicates that gut flora participate in the so called metabolic set point, that determines if it is going to be easier to gain or lose weight.  These experiments suggest that a powerful approach may be to eliminate the gut flora of individuals with chronic disease and replace it with healthy gut flora.  This healthy gut flora, along with a healthy diet may make a powerful contribution to elimination of chronic diseases.  Rosacea, which involves both the face and gut, might best be treated by topical antibiotics and anti-inflammatory agents, after the gut contribution has been eliminated by a fecal transplant with healthy gut flora/diet.

Anti-Inflammatory Diet Should Support Healthy Gut Flora

The efficacy of an anti-inflammatory diet (AID) should be displayed in reversal of inflammatory symptoms and unmemorable bowel movements.  A gut and gut flora that resist inflammation as a result an AID, should also produce a healthier immune system and contribute to a reduction in chronic inflammation and disease.  The gut may also have an impact on gut flora and a diet that does not contribute to inflammation in the body, e.g. lacks fructose and vegetable oils, may also support an anti-inflammatory gut flora.

Cure for Inflammatory Diseases

Destabilizing Gut Biofilms by Simple Remedies

The intercommunication between the gut flora biofilms, the cells of the immune system juxtaposed with the intestinal endothelium and cryptic bacteria/tissue biofilms produces stable chronic inflammatory disease. Disrupting the gut biofilms may permit a resumption of effective immunity and remission.

Disrupting Biofilms to Treat ASDs

Cristian Stremiz brought to my attention the work of Dr. Anju Usman on the treatment of autism spectrum diseases by attacking inflammatory gut biofilms.

A Panacea

This approach, based on the use of common food components, to attack the gut biofilm matrix of acid polysaccharides, cations and proteins, should be generalizable to most inflammatory diseases. The interventions also provide facile explanations for the utility of numerous traditional cures such as vinegar, fiber, glucosamine, pectin, whey, proteases and probiotics.

Cures Act via Gut Flora Biofilms

There are numerous anecdotal reports of traditional, simple remedies working for essentially all diseases. Tantalizingly, many of these diseases are also occasionally successfully treated with antibiotics. The common thread seems to be the involvement of inflammatory gut flora and perhaps cryptic bacteria residing in the tissues displaying symptoms. Glucosamine works sometimes for arthritis, but little of the glucosamine that is eaten reaches the blood stream and the aching joints that seem to become less inflamed. Vinegar, pectin, and fiber have also been attributed with curative powers, yet none is likely to impact inflamed joints directly. Impacting gut biofilms is much easier to explain.

Biofilms of Bacteria Attached to Acidic Polysaccharides and Divalent Cations

Acidic polysaccharides are produced by bacteria and divalent cations cross-link the polysaccharides into a matrix. The bacteria have agglutinins to attach to the matrix. Gut pathogens produce agglutinins that they use to attach to the heparan sulfate (HS), the predominant acid polysaccharide of the intestinal epithelium. Mast cells of the intestines normally release heparin, which is a mixture of HS fragments, to stick to the agglutinins and block attachment to the HS of the epithelium. Numerous bacterial species form complex communities on the polysaccharide matrix and prevent access by antibiotics. Biofilms require 100X the antibiotic concentrations and a cocktail of different antibiotics to eradicate the bacteria.

Biofilms Disrupted by Competing Acid Polysaccharide Fragments and Cation Chelators

The Achille’s heal of biofilms is the ionic interaction between the acidic polysaccharide and divalent cations. This interaction can be attacked by both small fragments of similar acid oligosaccharides, by organic acids that can solubilize the cations, e.g. acidic acid in vinegar, or by chelators, such as EDTA. All of these treatments can remove the calcium, magnesium and iron that is essential to the matrix. Small molecules, such as glucosamine, chondroitin sulfate fragments, heparin, and pectin, can disrupt biofilms. Molecules that bind to heparin or nucleic acids, e.g. berberine, quinine (tonic), methylene blue, should also be effective in disrupting biofilms. [Note that the similarity between amyloid production and biofilms, means that treatments should overlap.] Lactoferrin is effective, since it both binds iron and binds to acidic polysaccharides via its heparin-binding domains.

Proteases Cleave Agglutinins

Stomach proteases, e.g. pepsin, specifically cleave proteins to release heparin-binding, acidic polysaccharide-binding domains that inhibit biofilm production in the stomach. Subsequently, the basic, antimicrobial peptides and agglutinins are cleaved by proteases, e.g. trypsin, that hydrolyze the binding domains. Eating proteases, such as nattokinase present in fermented soybeans, dissolves intestinal biofilms by attacking the agglutinins. The pathogenic E. coli and avian H5N1 also have these agglutinins. It is, therefore, wise to avoid establishing gut biofilms that can immobilize pathogens.

Probiotics Protect Against Biofilms

Resident gut bacteria that produce organic acids, e.g. lactic acid or acetic acid, provide protection against biofilm formation. Examples are the bacteria present in common forms of fermentation and food preservation, e.g. Lactobacillus sp., and the bacterium present in exclusively breastfed babies, Bifidobacter sp. Formula fed babies rapidly develop inflammatory biofilms, which explains their high rates of intestinal and respiratory diseases, as well as increased rates of inflammatory diseases.

Biofilm Inflammation Results in Inflammatory Bowel Disease, etc.

Gut biofilms support system-wide chronic inflammation that leads to allergies, autoimmune diseases, degenerative diseases and probably cancers. This attach on the gut also produces a leaky gut that supplies the bacteria that a moved by macrophages of the gut to all parts of the body. This may be how Chlamydia pneumoniae colonizes sites of inflammation throughout the body.

Attacking Gut Biofilms Is the First Step in the Treatment of All Inflammatory Diseases

Many inflammtory diseases, e.g. chronic lyme disease, rosacea, may be refractory to treatment with antibiotics, because of the reservoir of bacteria in gut biofilms. Attacks on gut biofilms with relatively non-intrusive treatments, such as vinegar, EDTA, lactoferrin and proteases, may lower the total resident pathogen load and make subsequent antibiotic treatment more effective.

Baldness/Prostatitis Treatment, Impotence, Inflammation

Male pattern baldness appears to result from the interaction between enzyme-modified male sex hormones (DHT) and receptors in some hair follicles of the scalp.  Inhibition of the enzyme by topical (Rogaine) or oral administration (Propecia) of an inhibitor, e.g Finasteride, can stop hair loss.  One of the significant side effects of oral use of Finasteride is loss of all sexual functions, which can be temporary and reversible after the drug is stopped, or permanent.  I think that inflammation may play a critical role in both hair loss (and prostatitis) and loss of sexual functions in response to Finasteride and an anti-inflammatory approach my be helpful.

Testosterone is Converted to  Dihydrotestosterone (DHT) by 5-Alpha Reductase

The male hormone, testosterone, is produced in the testes and travels to hair follicle or to other parts of the body via the blood in either a free state, or bound to a carrier protein.  Only the free form interacts with the 5-alpha reductase enzyme in the scalp to produce the DHT that diminishes hair follicles.  Application of the Reductase inhibitor, Finasteride, directly to the scalp stops the production of DHT in the scalp.  Taking oral Finasteride blocks DHT production throughout the body, and unlike topical application, can also result in apparent changes in the brain, which can explain loss of sexual behavior.

DHT Role in Hair Loss and Brain-Based Sexual Behavior is Poorly Understood

Surprisingly, the molecular biology of male pattern baldness (MPB) is not known, even though this is one of the classic examples of a dominant, sex-associated phenotype, i.e. a single copy of the baldness allele in males produces baldness.  Of course, this is not a sex linked gene, since baldness is not inherited from mothers with their X chromosome, and in some cases as many as 80% of the males in a single family exhibit male pattern baldness.  It appears to me that baldness is also likely to have an environmental, e.g. gut flora, heritability similar to obesity.  In fact, metabolic syndrome and type 2 diabetes are substantial risk factors for male pattern baldness.

There is also an association between MPB and polycystic ovary syndrome (PCOS) in females of the same family.  I would also expect that MPB is related to prostatitis, since the prostate is a major processor of testosterone to DHT via 5-alpha reductase and prostatitis can be treated with Finasteride.  PCOS is also treated with Finasteride.  PCOS is also associated with obesity and metabolic syndrome.  Prostatitis, PCOS, obesity and metabolic syndrome can all be treated as inflammatory diseases with significant contribution of dysfunction of gut flora.

  

PMB, Testosterone, 5-Alpha Reductase and Aromatase

In PMB, testosterone levels are lower and 5-alpha reductase is higher.  This suggests that testosterone has been converted into DHT in scalp hair follicles.  In order for DHT levels to make a difference, the hair follicles have to have specific receptors for DHT.  Testosterone/DHT receptors, like all steroid hormone receptors, are proteins in the cytoplasm of cells, which bind the hormone and become activated as transcription factors that migrate to the nucleus and control the expression of particular genes.

Testosterone can also be converted by another enzyme, aromatase, into estrogen.  DHT cannot be converted enzymatically into estrogen.  Estrogen has a separate receptor and controls a different set of genes.  Thus, enhanced conversion of testosterone into DHT in MPB follicles, may shift the balance away from estrogenic in favor of androgenic effects.  Women exposed to aromatase inhibitors, stop converting their limited testosterone into estrogen and more is converted into DHT, resulting in rapid signs of baldness.   All brain estrogen is produced from testosterone via aromatase in the brain and aromatase inhibitors can reduce libido in women.

DHT Activates Inflammatory NFkB (and Block Nerve Apoptosis?)

Prolonged exposure of cerebral blood vessels to DHT has been shown to activate the inflammatory transcription factor NFkB.  Conversion of testosterone to DHT by 5-alpha reductase may amplify the inflammatory impact of testosterone by virtue of the stronger activation of the androgen receptor by DHT.  Activation of NFkB also suppresses apoptosis and may be necessary to maintain some neural cells.  Reducing DHT production by 5-alpha reductase inhibitors, may reduce NFkB activation in the brain and expose androgen-sensitive parts of the brain to apoptosis.  This loss of brain cells may result in loss of sexual behavior.

Vitamin D is also Steroid Hormone/Co-Transcription Factor

It should be remembered that vitamin D also has a cytoplasmic receptor that acts as a transcription factor and that vitamin D deficiency can result in hair loss.  If fact, vitamin D is required for the normal hair growth cycle, as well as intestinal villi development (defensin production).   The vitamin D receptor can also inhibit the inflammatory transcription factor NFkB.

Thus, multiple steroid hormone receptors are involved in hair development, prostate function and brain sexual behavior.  Modification of the conversion of testosterone into DHT or estrogen can have diverse consequences directly or indirectly by modification of inflammation/development signaling.  This is also true of fertility/menstrual cycles, mammary tissue and perhaps intestinal epithelial villi or skin/follicle development in the case of rosacea.  All of these processes are affected by enzymatic interconversion of steroid hormones and interaction of hormone/receptor and NFkB transcription factors.

Questions

The questions that I have about hair loss (or prostatitis), treatment with 5-alpha reductase inhibitors, and subsequent loss of sexual function are:

1. Why are the genetics of MPB so unusual/non-Mendelian?  There are too many males with MPB in the same family.  This points to some hereditary predisposition, but with a major environmental component, e.g. “inherited gut flora.”
2. Why are only a few of the people treated with 5-alpha reductase inhibitors rendered permanently impotent?
3. There is anecdotal evidence that dexamethasone (or prostate message and antibiotics) can reverse some impotence.  Does this indicate that inflammation is involved in hair loss and/or impotence?  Where do the antibiotics act and is their action to kill bacteria?

Treatment for Finasteride-Induced Impotence

Impotence is a severe side effect of a few men using Finasteride to treat baldness or prostatitis.  I doubt that those with induced impotence are genetically predisposed, but rather these individuals probably had an altered immune system.  I suspect two types of alterations:  a compromised blood/brain barrier and a compromised suppressive immune system.  Diet-based chronic inflammation is a typical path to a leaky blood/brain barrier that facilitates the penetration of Finasteride into the brain to alter 5-alpha reductase in the DHT-responsive regions responsible for sexual function.  I presume that the subsequent reduction of DHT also results in inflammation that contributes to loss of function.  Dexamethasone and some antibiotics could attenuate the inflammation and return normal function.

Suppression of attack of normal tissues by the immune system is mediated by development of the suppressive immune system in the gut in response to specific bacteria of the gut flora.  A history of antibiotic treatment can yield a dysfunctional gut flora and a compromised immune system that results in allergies and autoimmunity.  Prostatitis may have an autoimmune component and may result from compromised gut flora.

All of the symptoms discussed from hair loss to prostatitis to impotence should be improved by normal function of the gut and immune system by my anti-inflammatory diet and normal gut flora.  Use of antibiotics will always lead to further side effects by perturbing and limiting the function of gut flora and the immune system that is dependent on the gut flora.

I particularly suspect that vitamin D deficiency is a significant contributor.  Most “anti-inflammatory diets” will lead to chronic inflammation, because they are just high carb diets with a few vegetables.  All of the complex phytochemicals produced by plants will be “antioxidants”.  Adding these antioxidants to an inflammatory diet has no impact.  Look at my anti-inflammatory diet and note that it requires attention to serum vitamin D levels, gets most calories from saturated fat and not carbs (low carb/high saturated fat), no vegetable oils and high omega-3 (EPA, DHA) to 6 ratio.  That means meat/fish/eggs/dairy and lots of fresh vegetables for new gut bacteria.