image courtesy of ION CHANNEL MEDIA GROUP LTD

In an article published in PLoS ONE [1] stated that “The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.”  This statement is without a doubt  the result of the work of Gallo, et. al, at the University of San Diego that was initially published in Nature Magazine [2].

So what is cationic cathelicidin peptide LL-37?  It is an Antimicrobial peptide (AMP) which is part of our immune system that attack invading bacteria or other microbes to defend our body. There has been some evidence that rosacea may be a result of an immune system disorder. [3] Gallo, mentioned earlier, said in 2004, that rosacea may be an “abnormality in the innate immune system … caused by too much cathelicidin.”  He is also quoted as saying “if we believe that the disease is caused by too much cathelicidin, we could develop a strategy to block the effects of the cathelicidins by making molecules that mimic that protein but don’t have the same effects.” [4]

When reading these articles, one might conclude that the theory of what causes rosacea is over and that cathelicidin is the culprit. However, the article only said that the “cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.”  The jury is still out on what causes rosacea. [5]

However, it is important to note that as Dr. Gallo pointed out, “if we believe that the disease is caused by too much cathelicidin” then the treatment might be radically different.  Antibiotics are regularly used to treat rosacea and may be treating the wrong target. [6] So this new article published in PloS One by Zhang, et. al, “tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs)”  on mouse skin. The result:

“Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37.”

So we wait and see what will become of this new treatment for rosacea based on the theory that the cause is an overproduction of Cationic Cathelicidin Peptide LL-37.

End Notes

[1] Novel Sulfated Polysaccharides Disrupt Cathelicidins, Inhibit RAGE and Reduce Cutaneous Inflammation in a Mouse Model of Rosacea.
Zhang J, Xu X, Rao NV, Argyle B, McCoard L, Rusho WJ, Kennedy TP, Prestwich GD, Krueger G.
PLoS One. 2011 Feb 9;6(2):e16658.

[3] Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea
Kenshi Yamasaki¹, Anna Di Nardo¹, Antonella Bardan¹, Masamoto Murakami², Takaaki Ohtake³, Alvin Coda¹, Robert A Dorschner¹, Chrystelle Bonnart^4,5, Pascal Descargues^4,5, Alain Hovnanian^4,5,6, Vera B Morhenn¹ & Richard L Gallo¹
Nature Medicine 13, 975 – 980 (2007)
Published online: 5 August 2007 | doi:10.1038/nm1616

[3] Innate Immune Response
post by Brady Barrows, Director of the RRDi

[4] Innate immunity: Role in rosacea?
Michelle Stephenson
Dermatology Times, June 1, 2004
posted at Rosacea Support Group

[5] Cause of Rosacea Revisited

[6] Dr. Gallo is quoted as saying, “Antibiotics tend to alleviate the symptoms of rosacea in patients because some of them work to inhibit these enzymes [STCE]. Our findings may modify the therapeutic approach to treating rosacea,since bacteria aren’t the right target.”
UCSD Researchers Discover Cause of Rosacea
By Debra Kain, University of California, San Diego, August 7, 2007

Image Credit
Image of  Solution structure of the LL-37 core peptide bound to detergent micelles courtesy of ION CHANNEL MEDIA GROUP LTD.

Copyright 2010 • All Rights Reserved • July 2010 by Brady Barrows

Artist Depiction of H Pylori

H Pylori (Helicobacter Pylori) has been a controversy with rosacea for some time now.  Some experts dismiss H Pylori’s role in rosacea and yet it remains a controversy since other rosacea experts continue to discuss H Pylori as a possible factor in rosacea. A report in January 2010 states that “Helicobacter pylori infection is implicated in the pathogenesis of extradigestive diseases such as acne rosacea…” A report by Mc Leer, Lacey and Powell in 2009 listed H Pylori as a possible factor in the pathophysiology in rosacea. One report in 2003 suggests “some form of relationship between rosacea and H. pylori infection.” Two reports in 1996 suggested H Pylori’s role in rosacea with titles such as “Eradication of Helicobacter pylori as the only successful treatment in rosacea” and “Acne rosacea and Helicobacter pylori betrothed.” Rebora suggested in 1995 that the “role of H. pylori is more probable in erythrotic rosacea than in its papulopustular and granulomatous stages.” [1] These are just a few reports suggesting H Pylori as a factor in rosacea.

When you consider the fact that H Pylori was ‘officially’ discovered in 1986 by Drs Marshall and Warren in Australia who both won the Nobel Prize in 2005 for this discovery and changed the textbooks about how bacteria can survive in the human stomach and its relation to ulcers and other gastric problems and the fact that this gram negative bacteria is considered an infection that half the world’s population is carrying with most being totally asymptomatic it is a wonder that anyone can even connect H Pylori with rosacea at all.  Yet the reports on H Pylori and rosacea keep coming out despite the fact that many reports negate H Pylori’s role in rosacea.

While there are many older reports suggesting H Pylori having some role in rosacea, newer reports dismiss this role. For instance, the late Dr. Kligman noted H Pylori’s controversial role in rosacea in his 2003 report. [2]

A report released in 2002 mentions ‘promising recent reports of beneficial H. pylori eradication’ in many cutaneous skin diseases except rosacea. [3]

A study published in May 2010 concluded, “There is no association between Helicobacter pylori infection and rosacea in current study.” [4]

Nevertheless, there are reports of H Pylori associated with rosacea indicating that eradicating H Pylori clears rosacea and discuss the possible cutaneous pathology of H Pylori to an autoimmune mechanism. A report in 2009 says, a “few case reports have documented associations between Helicobacter pylori infection and rosacea.” [5]

What is H Pylori and how does it relate to rosacea?

H Pylori is a gram negative bacteria that is considered an infection and harmful to humans.

According to one report, “more than 50% of the human population have long-term Helicobacter pylori infection.” [3] Wikipedia says that the diagnosis of H Pylori is done with different tests that are not failsafe and sometimes results in false positives.  How anyone can know for sure that 50% of the human population is infected with H Pylori is quite suspect. The percentage of ‘infection’ of H Pylori, if indeed it is an infection, may be more or less than 50% .

According to Wikipedia, “Helicobacter pylori is a Gram-negative, microaerophilic bacterium that can inhabit various areas of the stomach, particularly the antrum. It causes a chronic low-level inflammation of the stomach lining and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer. Over 80% of individuals infected with the bacterium are asymptomatic.”

So, if 80% of individuals are asymptomatic and they only discovered H Pylori in 1986 how do they know that H Pylori is a human pathogen?  There is an amusing article, “So, What’s Your Problem with Gram-Negative Bacteria??,” that gets you thinking. Do you really think that medical science knows everything about H Pylori in a little over twenty years?  Obviously sometimes H Pylori is a human pathogen and runs amuck causing us problems. But in 80% of individuals H Pylori is asymptomatic and obviously is in the stomach for some reason, possibly for some nefarious purpose such as an ulcer, but it is quite possible for some beneficial purpose as well.  Could it be possible that a gram negative bacteria serves some useful purpose that as yet hasn’t been discovered? For instance, E. coli can help people and animals to digest food and help in providing vitamins but sometimes runs amuck causing some serious food poisoning. Could H Pylori have some beneficial yet undiscovered function for humans yet sometimes cause issues like E. coli does?

Could H Pylori be asymptomatic because it is helping us for some reason yet undiscovered, and sometimes for some yet undiscovered reason turns into a monster that causes problems like ulcers and rosacea?

Helicobacter pylori and rosacea.
Zandi S, Shamsadini S, Zahedi MJ, Hyatbaksh M
East Mediterr Health J. 2003 Jan-Mar;9(1-2):167-71.

Eradication of Helicobacter pylori as the only successful treatment in rosacea
Kolibásová K, Tóthová I, Baumgartner J, Filo V.
Arch Dermatol. 1996 Nov;132(11):1393.

Acne rosacea and Helicobacter pylori betrothed
Wolf R.
Int J Dermatol. 1996 Apr;35(4):302-3

May Helicobacter pylori be important for dermatologists?
Rebora A, Drago F, Parodi A.
Dermatology. 1995;191(1):6-8

[2] A Personal Critique on the State of Knowledge of Rosacea
Albert M. Kligman, M.D., Ph.D.

[3] Helicobacter pylori infection in skin diseases: a critical appraisal.
Wedi B, Kapp A.
Am J Clin Dermatol. 2002;3(4):273-82.

[4] Risk factors associated with rosacea.
Abram K, Silm H, Maaroos HI, Oona M.
J Eur Acad Dermatol Venereol. 2010 May;24(5):565-71. Epub 2009 Oct 23.

[5] Helicobacter pylori infection and dermatologic diseases.
HERNANDO-HARDER AC, BOOKEN N, GOERDT S, SINGER MV, HARDER H.
Eur J Dermatol. 2009 Sep-Oct;19(5):431-44. Epub 2009 Jun 15.

[6] Small Intestinal Bacterial Overgrowth: A Comprehensive Review
Andrew C. Dukowicz, MD, Brian E. Lacy, PhD, MD, and Gary M. Levine, MD
Gastroenterology & Hepatology Volume 3, Issue 2 February 2007

[7] ice2meetyu’s report July 4, 2010

[8] Rosacea and digestive problems

Copyright 2010 by Brady Barrows

If you were around in August 2007, there were headlines such as, Scientists unmask the cause of rosacea, [1] and UCSD Researchers Discover Cause of Rosacea [2] not to mention all the other headlines which created quite a stir in all the online rosacea groups and brought a lot of hope for rosacea sufferers. These articles seemed to conclude that rosacea’s mystery is resolved and within time a treatment would be found to eradicate rosacea. These startling headlines were the result of a paper published by researchers at UCSD associated with Richard L Gallo, et.al, in a study published by  Nature Medicine [3]. This paper concluded:

“These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.”  More info on cathelicidins.

If you will notice in the above statement that the findings suggest an explanation for the pathogenesis of rosacea. Gallo, et.al, never said they found the cause of rosacea.  The newspapers came to the conclusion that now all the mystery of rosacea is over and we now have the cause nailed down. All we have to do is wait for the treatment. This is not exactly the truth.  While the research of Gallo, et.al, at UCSD is remarkable and insightful, the jury is still out on what causes rosacea. And while the jury is still out, there is more news worth mentioning that may be related to cathelicidin, peptides or antigenic proteins.

According to The Irish Times, Irish Scientists blame bacteria as the cause of rosacea according to a different study. This study is the result of researcher Dr Kevin Kavanagh, a senior lecturer in biology at NUI Maynooth. According to The Irish Times, “Working with the Mater hospital, the researchers previously identified a Bacillus bacterium inside Demodex mites. The bacteria release two proteins that trigger an inflammation in patients with facial rosacea.” [4]

At least one type of bacteria is associated with demodex mites and rosacea. This bacteria is Bacillus oleronius according to an NRS press release [5] which quotes Dr. Kavanagh as saying, “This indicates that the Bacillus bacteria found in the Demodex mite produce an antigen that could be responsible for the tissue inflammation associated with papulopustular rosacea.”  A study released in September 2007 by Dr. Frank Powell, et.al, also concluded, “Antigenic proteins related to a bacterium (B. oleronius), isolated from a D. folliculorum mite, have the potential to stimulate an inflammatory response in patients with papulopustular rosacea.” [6] Another study released in January 2010 also said, “The strong correlation provides a better understanding of comorbidity between Demodex mites and their symbiotic B oleronius in facial rosacea and blepharitis.”  [7]

In the recent past, a couple of noted rosacea online gurus have dismissed the role of demodex in rosacea. One such rosacea guru said, “Rosacea experts all agree that this mite plays no real role in the development of progression of rosacea (except for the odd pustule).”  [8] The other rosacea guru says, “I have always pushed the line that demodex mites have thus far only been proven to be innocent bystanders in rosacea symptoms.” [9] However, the NRS continues to sponsor research into demodex and the RRDi just released a paper by Dr. Kosta Y. Mumcuoglu and Dr. Oleg E. Akilov on demodex’s role in rosacea. [10] In fact, there is probably not many other type research with as many papers on the subject of demodex except for a scarce few. [11]

Another theory on the cause of rosacea is that irritable bowel syndrome is related to rosacea. “Rosacea may be a symptom of an unhealthy gastrointestinal system and healing the entire gastrointestinal system may be the basis for eliminating rosacea. Many people with rosacea also have been diagnosed with Irritable Bowel Syndrome (IBS), Crohn’s Disease or some for of Colitis.”  [12]

This theory also is related to bacteria in the gut and that using antibiotics clears rosacea. An article in the St. Louis Dispatch [13] says that one doctor has been prescribing Xifaxan, an antibiotic for gastric problems and reports clearing of rosacea. Previously to this report a study in Italy published that eradicating the bacteria in the gut had improved rosacea. [14]

Another theory that has come up is that SIBO is related to rosacea. The previously mentioned rosacea online guru had this to say about SIBO and rosacea:

“This sort of abstract just make me shake my head. If you read quickly you will think that this abstract suggests that Small Intestinal Bacterial Overgrowth (SIBO) causes rosacea. What this abstract is saying that is that rosacea sufferers seem to have a higher incidence of SIBO than non rosacea sufferers.” [15] “The link between SIBO and the papules and pustules of rosacea is still a mystery.” [16] For more information on rosacea and SIBO click here.

There is also a continuing controversy as to whether H Pylori is a factor in rosacea and I have written an article on this subject for your interest.

So in conclusion, the jury is still out on what causes rosacea but it appears that the jury hasn’t ruled out demodex quite yet, despite what the rosacea gurus tell you. The headlines may one day come to another ’cause’ of rosacea or highlight the ones discussed above. Whatever happens, keep an open mind, since we still don’t know what causes rosacea. We may be surprised one day to actually read a headline that says truthfully what the cause of rosacea is.

For more information on the cause of rosacea and other theories on this subject click here.

[1] Scientists unmask the cause of rosacea
August 06, 2007|Alison Williams, Los Angeles Times Staff Writer

[2] UCSD Researchers Discover Cause of Rosacea
UCSD News Center

[3] Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea
Kenshi Yamasaki¹, Anna Di Nardo¹, Antonella Bardan¹, Masamoto Murakami², Takaaki Ohtake³, Alvin Coda¹, Robert A Dorschner¹, Chrystelle Bonnart^4,5, Pascal Descargues^4,5, Alain Hovnanian^4,5,6, Vera B Morhenn¹ & Richard L Gallo¹
Nature Medicine 13, 975 – 980 (2007)
Published online: 5 August 2007 | doi:10.1038/nm1616

[4] Study finds cause of rosacea
Claire O’Connell
The Irish Times – Tuesday, July 14, 2009

[5] New Study Shows Role for Bacteria in Development of Rosacea Symptoms
NRS Press Release, May 3, 2004, Suzanne Corr / Barbara Palombo

[6] Mite-related bacterial antigens stimulate inflammatory cells in rosacea.
Lacey N, Delaney S, Kavanagh K, Powell FC.
Department of Biology, National University of Ireland, Maynooth, Co. Kildare, Ireland
Br J Dermatol. 2007 Sep;157(3):474-81

[7] Correlation between Ocular Demodex Infestation and Serum Immunoreactivity to Bacillus Proteins in Patients with Facial Rosacea,
Li J, O’Reilly N, Sheha H, Katz R, Raju VK, Kavanagh K, Tseng SC.
Ophthalmology. 2010 Jan 14,

[8] page 110 quote
Beating Rosacea Vascular, Ocular & Acne Forms
Geoffrey Nase, Ph.D.
Nase Publications 2001

[9] Mar 29, 2007 R-S post by David Pascoe

[10] The Role of Demodex Mites in the Pathogenesis of Rosacea and Blepharitis and Their Control
Kosta Y. Mumcuoglu, Ph.D., Oleg E. Akilov, M.D., Ph.D.
Journal of the Rosacea Research & Development Institure, Vol.1, No.1

[11] For a partial list of Demodex in rosacea and acne click here.

[12] Dr. David Dahlman, a Chiropractic Physician with a degree in Nutrition

[13] New way to treat skin disorder
By Cynthia Billhartz Gregorian, St. Louis Post Dispatch, 04/29/2010

[14] Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication.
Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, Parodi A, Savarino V.
Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa, Italy.
Clin Gastroenterol Hepatol. 2008 Jul;6(7):759-64

[15] SIBO eradication clears rosacea: are you serious ?
May 7th, 2008, by David Pascoe

[16] Gut Bacteria and Xifaxan get some press coverage
April 30th, 2010, by David Pascoe