• Welcome to Crohn's Forum, a support group for people with all forms of IBD. While this community is not a substitute for doctor's advice and we cannot treat or diagnose, we find being able to communicate with others who have IBD is invaluable as we navigate our struggles and celebrate our successes. We invite you to join us.

Remicade anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases

I suppose I'm thinking about preventative/ risk reduction measures for direct relatives due to the genetic link as well as anything that might help those of us suffering with this disease.
Nothing you can really do. Maybe tell them to get enough vitamin D, watch out for foodborne infections and don't use antibiotics when it's not needed. Other than that you can't proactively prevent this disease I think.
 
All the data on treatment supports the (well established by now) theory that inflammation in crohn's disease is directed at pathogens (with a possibly minor role for fungi) within intestinal tissue.
A few years after my Crohn's diagnosis, I had oral and oropharyngeal candidiasis due to corticosteroid use. It didn't go away with liquid nystatin so I had to use a more systemic and powerful antifungal (fluconazole) to treat that. I found it interesting to find out that fluconazole was also helping my intestines to a considerable degree.
 
Last edited:
It will be much easier to block AIEC than to treat the fungi, but I think fungi are only a minor player in crohn's disease.

Treatment against AIEC will become a reality, simply due to the fact that you have increasingly resistant E Coli bacteria.

Also simply due to the urinary tract infections where the E Coli is clearly using fimbriae to avoid being removed during urination in patients. In Crohn's disease AIEC uses fimbriae to attach to the intestinal wall.

Anti FimH are in development for both urinary tract infections and crohn's disease.

''Takeda has paid $50 million (€44 million) upfront to co-develop Enterome’s early-phase Crohn’s disease candidate EB8018. The deal gives Takeda a stake in a small molecule designed to disarm virulent bacteria and thereby treat gastrointestinal disorders.

EB8018 blocks the activity of FimH, a lectin expressed by enterobacteriaceae such as Escherichia coli. Research suggests the lectin activates TLR4 and thereby encourages the production of TNF-alpha, a cytokine that is the target of Crohn’s drugs such as Humira and Remicade. Enterome hopes EB8018 will prevent production of the cytokine by blocking the local inflammatory cascade.''
 
Also interesting that in 3rd world countries, you often have kids being infected with certain strains of E Coli early in life, and they somehow gain resistance to it. Somehow they become quite resistant to very virulent strains of E Coli that cause a lot of disease in the West.

Now you can argue that this is normal, because the infections simply resulted in acquired adaptive immunity through the activation of memory T cells.

But it's not that simple, they seem to have developed anti-adhesion immunity against E coli, which protects them from very virulent strains of E coli.
 
Last edited:
Qu Biologics press release (July 23rd, 2019):

At the time Qu initiated the first CD trial, the Crohn’s Disease Activity Index (CDAI) was the instrument of choice to evaluate how well a treatment was working in patients with CD. However, the bar for evidence is shifting, and there is now a greater emphasis on obtaining objective evidence for mucosal healing in the intestinal tract via endoscopy. Qu is currently running a follow-on trial, which is enrolling at three sites across Canada, to evaluate mucosal healing with SSI treatment. This follow-on trial is 85% enrolled, but interested patients with moderate-to-severe CD can still inquire about participation. Dr. John Marshall, Director of Gastroenterology at McMaster University, who is a co-author of the recently published study, is one of the principal investigators of the current trial. He discussed in an earlier interview how very different the SSI approach is to current CD treatments and his patients’ experience to date with SSI therapy.

Others: https://www.qubiologics.com/news-investors/news/
 
I don't know how QUbiologics, the company some people keep mentioning, got around the idea of injecting E coli into the skin to treat crohn's disease, but they of course read that study.
In this new interview, Hal Gunn mentions his recent conversation with Anthony Segal.

 
In this new interview, Hal Gunn mentions his recent conversation with Anthony Segal.
Anthony Segal is a very smart person.

Rutgeerts et al. showed that the fecal stream was driving the inflammation. But that still didn't explain why the disease featured patchy granuloma in the form of skip lesions, not much different from the skip lesions that are a feature in intestinal TB.

Anthony Segal showed innate immunodeficiencies in crohn's disease and pointed out to me that foodborne infections also lead to patchy inflammatory lesions. I have read countless stories about crohn's diseae patients on this forum, and what patients (including myself) first experienced are all the symptoms of an acute foodborne infection. The patient has acute abdominal disstress, fevers, night sweats, throwing up, etc,.

These acute fevers and night sweats don't generally present themselves later in the disease, the acute infection seems to have been overcome, but it would leave a permeable bowel behind. They also wouldn't find them during diagnosis, by the time they check biopsies or test for foodborne infections in stool, it is too late to find the offending pathogen. The studies that show a link between salmonella infection and crohn's disease are not based on early intervention in crohn's disease. But the lesions that might lead to chronic disease are still there.

Bodeau in 1999 showed that E coli, especially invased E Coli named AIEC, exploits this inflammatory environment and chronically invades those inflammatory lesions.

(there was a team before Rutgeerts that showed the fecal stream was driving inflammation also, but I can not find it, but Rutgeerts references it, maybe I'll find it if one of these days)
 
Last edited:
The studies by Van Kruiningen that show crohn's disease happens within specific geographic regions, in clustering patterns, is also easy to explain with Anthony Segal's theory. They simply ate the same food infected with the same foodborne pathogens.

That crohn's disease is primarily diagnosed in patients 15-24 of age, is also fairly straightforward to explain with this theory. 15-24 is simply when peyer's patches are most active and the offending pathogen that causes the initial infection invades peyer's patches through M cells.
 
The explanation for the dysbiosis is also straightforward now. The dysbiosis happens due to the inflammatory environment. It's not the cause of the disease itself, dysbiosis is simply a result. Under inflammatory stress, some bacteria will thrive (like AIEC), and others will not. Dysbiosis is much less during remissions and only manifests itself during active disease.

Targeting the opportunistic bacteria like AIEC with anti-FimH or bacteriophages, might not technically cure the patients, but it should make flares and inflammation much less common.
 
M cells simply don't seem to have any mucus covering them. Salmonella and AIEC are specifically targeting ileum entry through the few hundred peyer's patches.

It explains why even after complete mucosal healing in patients, the patient isn't necessarily cured. When AIEC regains entry through M cells and reactivates tissue macrophages, patients relapse.

Restoring innate immune function would need to be combined with anti-FimH, bacteriophage or antibiotic therapy, to have higher success rates.
 
Last edited:
I don't know who this woman is, but it is of course insane to suggest flares are just fine and a normal thing if you go off medication, and you should just let it happen and treat Crohn's naturally. Half the video is quackery.

No one should be playing their own doctor, it's a very bad idea to simply drop your medication. Immunosuppressants serve a purpose, they limit tissue damage from cytokine expression.

Even if one could restore innate immune function, you would still expect inflximab to be used to treat acute phases of inflammation to limit tissue damage.

Regarding the lady from QuBiologics saying that medication has a poor record for mucosal healing. I don't know what she means by that, Infliximab has a very good record of mucosal healing.
 
Last edited:
Just because researchers point out the double edged sword of immune suppression in a disease that is hallmarked by immunodeficiences, doesn't mean they suggest you should change your medication.

The lady from QuBiologics said that medication for crohn's disease has a bad track record for mucosal healing. This isn't true, Infliximab has an excellent track record for mucosal healing.

Before biologics, there was nothing doctors could give crohn's disease patients to treat acute forms of cascading inflammation.

Back when Dalziel treated patients, they had nothing at all. People with crohn's disease had no treatment and it was surgery or death for them.

Just because people question the chronic use of immunosuppression, doesn't mean that infliximab isn't helping people. There is nothing as effective as infliximab to get people in remissions. If one agrees with the chronic use of it, is a different question.
 
Last edited:
So Kiny you are basically saying that initially inflix is very effective in causing mucosal healing but in the long term it actually makes things worse - I understand that from reading this thread but how does long term infliximab use effect mucosal healing then?
 
@kiny, could you put the oral aphthous ulcers seen at the onset of Crohn's into a perspective? I had them right before my diagnosis. After I got hospitalised, diagnosed and received treatment, they were immediately gone and they never recurred; even though I have never been in remission for years

I think I am not the only one who experienced the same.


Studies have shown that around 60% of patients with Crohn’s disease present with oral manifestations including cheilitis, oral ulceration, fissuring and glossitis and this may be the first sign of the disease in 5-10% of cases.

Are those an epiphenomenon, or a manifestation of Crohn's aetiology (maybe in line with your thesis that CD is first triggered by an acute infection)?

What I find interesting is the fact that they never recurred.
 
Last edited:
So Kiny you are basically saying that initially inflix is very effective in causing mucosal healing but in the long term it actually makes things worse - I understand that from reading this thread but how does long term infliximab use effect mucosal healing then?
As long as infliximab can suppress the adaptive response by blocking TNF-α patients won't relapse. But when patients build resistance in the form of antibodies, or when the body starts to upregulate other inflammatory cytokine in response, treatment stops working.

When patients relapse on immunosuppressants, one assumes the relapse will be far more pronounced in some patients because it will very hard to deal with bacterial content when the immune system has been chronically downregulated for so long.
 
As long as infliximab can suppress the adaptive response by blocking TNF-α patients won't relapse. But when patients build resistance in the form of antibodies, or when the body starts to upregulate other inflammatory cytokine in response, treatment stops working.

When patients relapse on immunosuppressants, one assumes the relapse will be far more pronounced in some patients because it will very hard to deal with bacterial content when the immune system has been chronically downregulated for so long.
Ok that makes sense - thanks.

Ok so what about Qu finding that patient who were previously treated with anti TNF taking longer to respond to their treatment? In other words does long term anti TNF use do permanent damage to the immune system?
 
Ok so what about Qu finding that patient who were previously treated with anti TNF taking longer to respond to their treatment? In other words does long term anti TNF use do permanent damage to the immune system?
No, the immune system recovers eventually.

It's just that people on anti-TNF have a diminished response to infections. Patients won't recruit as many neutrophils, blood monocytes and the adaptive response will also be weaker.

A response to subcutaneous injection of heat killed E Coli, or whatever they use, would be much slower with patients recovering from anti-TNF treatment.

If the immune cell recruitment is slowed down, the QuBiologics treatment won't result in the same blood monocyte and neutrophil response, until the patient recovers.
 
@kiny, could you put the oral aphthous ulcers seen at the onset of Crohn's into a perspective? I had them right before my diagnosis. After I got hospitalised, diagnosed and received treatment, they were immediately gone and they never recurred; even though I have never been in remission for years
Aphthous ulcers in the mouth seen in crohn's disease are the same type seen in chronic granulomatous disease. People with UC don't get them.

The early inflammation you see in early CD intestine, are little inflamed lymphoid follicles, small red dots that look like the aphthous ulcers in people's mouths.

The M cells of peyer's patches are being compromised and it results in small inflamed spots of inflammation. It's either the peyer's patches sampling bacterial content or, what is more likely, M cells being invaded by bacteria.

Why people with crohn's disease have these small inflammatory spots in their mouths too, probably due to immunodeficiencies. We don,t really know what causes aphthous ulcers in people's mouths, but we do know there is a rich bacterial population in people's mouth.


3784
 
Just because medication blocks the immune response, doesn't mean the body won't recover to a normal state before treatment was initiated if they go off the treatment.

Some people develop lymphopenia on infliximab treatment, but when the treatment is stopped, they tend to recover, it just takes a long time. Some people have neutropenia or lymphopenia due to malnutiriton too, once the malnutrition is dealt with, the immune system recovers, it can just take a very long time.

Exeptions are disease like AIDS, where the lymphopenia is permanent and CD4 keeps dropping and the immune system doesn't recover. But that's different from treatment induced immune changes.
 
In crohn's disease it's groups macrophages literally trying to wall off bacteria like AIEC from invading intestinal tissue. They're full of E Coli DNA.
 
How do researches who think CD is an autoimmune disorder explain the granulomas' existence in CD, do you know?
They can't.
They can't explain why the inflammation is patchy instead of everywhere on the organ.
They can't explain why it's the ileum or colon, but not higher up in the intestinal tract.
They can't explain why the age onset of disease is 15-24.
They can't explain geographic disease clustering.
They can't explain why antibiotics results in decreased inflammation.
They can't explain why fecal stream diversion results in remission.

They can't explain anything, they can't even prove the basis of their argument, they can't show a self-antigen.
 
I've noticed clustering in my own neighborhood (and family), enough to be concerned, eg, meeting a group of 20 people containing 4 people with Crohn's disease. Thinking back to your earlier comment on "organic" food and a very bad experience I had once after eating inadequately washed veggies from the farmer's market, I'm wondering if the common factor is a local, hippie-ish tendency to eat more "organic" and farmers' market veggies.

I know many people with Crohn's don't tolerate salads well, possibly because they are physically rough, possibly because of the bacteria on them; my husband used to eat lots of salads and has been feeling quite a bit better since he stopped. Personally, I've been much more careful about my raw veggie consumption since the incident, including things like raw tomatoes at restaurants. I can definitely see the possibility for a slightly more mild version of an incident like mine to trigger long-term disease.

When I've brought up this seemingly very high rate of local Crohn's disease with my son's gastro, though, I've just gotten answers that amount to "whites get more Crohn's disease and our city has more white people."
Could just be the whole concept of westernization, germ theory of disease/antibiotic usage, low fiber/high sugar/high fat diets, and a clothed indoor life low in vitamin d, all of this promoting the extinction of microbes and the weakening of immune system. White people are also kind of the epitome of modern western culture, which we impose on the rest of the world through our historical power sometimes for better, sometimes for worse. https://www.cdc.gov/ibd/IBD-epidemiology.htm
 
The clustering is family and geographic clustering confined to small areas. They can not be explained with ''westernisation''' or ''diets''. The likely explanation is what Tony Segal proposed, the fact people with salmonella and campylobacter infection are far more likely to develop CD.

Clustering cases.

''Two French families were investigated. In the first a husband, wife, and 4 children had Crohn's disease; in the second 7 of 11 children had the disease. There was no history of Crohn's disease in antecedent generations and no linkage to HLA haplotypes. ''

''A large family of Moroccan immigrants was investigated. In this family the father developed Crohn's disease (CD) after moving from Morocco to Belgium and successively 4 of his 8 children subsequently developed CD. There was no previous history of familial CD. ''

''Ten pairs of husband-wife couples are reported with inflammatory bowel disease who were seen in the same geographical area in Nord Pas de Calais region of France and in Liège county (Belgium). In one couple, one spouse had Crohn's disease before marriage and the other partner experienced symptoms afterwards. Eighteen children were born to eight of 10 couples. Five of them developed Crohn's disease but four belong to the same family. In all cases the affected children were born to parents who both developed Crohn's disease after they had married and were conceived at a time when parents did not yet have symptoms. It is proposed that this pattern of emergence of inflammatory bowel disease suggests a role for an infectious agent yet to be identified. ''

'' Five affected fathers preceded 9 affected children; 7 affected mothers preceded 10 affected children. First borns were affected more frequently. Within sibships there were 21 instances (36%) when an affected sibling was consecutive in birth order with an affected sibling. ''
 
Last edited:
All the data on treatment supports the (well established by now) theory that inflammation in crohn's disease is directed at pathogens (with a possibly minor role for fungi) within intestinal tissue.
A few years after my Crohn's diagnosis, I had oral and oropharyngeal candidiasis due to corticosteroid use. It didn't go away with liquid nystatin so I had to use a more systemic and powerful antifungal (fluconazole) to treat that. I found it interesting to find out that fluconazole was also helping my intestines to a considerable degree.

Some research and links:


The effects of itraconazole on inflammatory bowel disease activity in patients treated for histoplasmosis
S. Samuel E. V. Loftus W. J. Sandborn
First published: 06 October 2010

Sirs, We read with interest the article by Schneeweiss and colleagues studying the risk of bacterial infections in patients treated with infliximab for the treatment of inflammatory bowel disease (IBD).1 We would like to share with the readers some interesting observations following a retrospective database review of histoplasmosis in IBD patients on immunosuppressive treatment.

Between 2000 and 2009, six patients with moderate‐to‐severe IBD (five Crohn’s disease and one ulcerative colitis) developed histoplasmosis as a consequence of their immunosuppressive regime and received treatment with itraconazole (an azole antifungal agent) and withdrawal of immunosuppression. Four of the six patients (67%) were in clinical and endoscopic remission at the end of itraconazole therapy (6 months median treatment duration) despite being off their immunosuppression (Table 1). The two patients whose IBD was active at the time of initiation of treatment had complete clinical and endoscopic response after 6 and 9 months of itraconazole treatment respectively (Table 1). Majority of our Crohn’s patients had previously experienced intestinal complications (fistulas and/or strictures), and had required multiple prior surgical resections suggesting an aggressive natural history. Despite this, and in the absence of continued biological and/or immunosuppressive therapy, they were able to withdraw immunosuppression and anti‐TNF‐α therapy during the entire itraconazole treatment course and the time to relapse in two of the Crohn’s patients was at least 10 months post‐itraconazole therapy (Table 1).

Table 1. Demographic and clinical characteristics of six patients with inflammatory bowel disease and histoplasmosis treated with both itraconazole and withdrawal of immunosuppressives and/or biologics

���
Age§ (years)Type of IBDMontreal classification of IBDImmuno‐suppressive therapyNo. of infliximab infusionsNumber of previous surgical resectionsDisease activity at initiation of itraconazoleDisease activity at stoppage of itraconazoleTime to relapse (after itraconazole therapy)Itraconazole dosage (mg/day); Rx duration (months)
Age at diagnosisLocationBehaviour
Patient 172CDA2L1B2IFX+AZA163Inactive (clinical and endoscopic)14400; 6
Patient 237CDA1L3B3IFX+AZA143Active (clinical)Inactive (clinical and endoscopic)10400; 9
Patient 344CDA1L2B1IFX400Active (clinical and endoscopic)Inactive (clinical and endoscopic)3 (off immuno‐suppres‐sives still)200; 6
Patient 434CDA1L3B3IFX140Active (clinical and endoscopic)0400; 12
Patient 521UCE2 (Left sided UC)IFX+6‐MP0*0400; 6
Patient 651
CDA2L3B3IFX+AZA31Inactive (clinical and endoscopic)3400; 5

  • IFX, Infliximab; AZA, azathioprine; MP, mercaptopurine; CD, Crohn’s disease; UC, ulcerative colitis.
  • * This patient’s disease flared 4 months into treatment with itraconazole.
  • † The number of doses of infliximab received was unknown.
  • ‡ Information not available.
  • § Age at the time of histoplasmosis diagnosis.

Although the above findings were unexpected, azole group of drugs inhibit the expression of both various TNF‐α‐induced cell adhesion molecules and angiogenesis and thereby ameliorate colitis in rat models.2-4 This interesting observation should be explored further in controlled studies to assess the effect of itraconazole in patients with IBD. Clinical trials are already underway on the topical use of clotrimazole (another azole antifungal) in pouchitis (http://clinicaltrials.gov/ct2/show/NCT00061282).
The effects of itraconazole on inflammatory bowel disease activity in patients treated for histoplasmosis



Malassezia yeasts found in oily skin and scalp follicles are linked to skin conditions, including dandruff. These microscopic fungi also end up in the gut, but it's not known how or what they do there.
"We were surprised to find that Malassezia restrica was more common on intestinal tissue surfaces in Crohn's disease patients than in healthy people," says co-author David Underhill, Janis and William Wetsman Family Chair in Inflammatory Bowel Disease at Cedars-Sinai in Los Angeles. "Further, the presence of Malassezia was linked to a common variation in a gene known to be important for immunity to fungi -- a genetic signature more common in patients with Crohn's disease than the healthy population."

...

Changes in intestinal fungi such as M. restricta -- and host responses to these fungi -- may be a factor in exacerbating symptoms that contribute to disease in a subset of patients with Crohn's disease, says co-author Jose Limon, a Cedars-Sinai research team member.

The researchers had originally found that fungi are present in the gut microbiome of mice and that immunity against these fungi helps control gut-based inflammation. In mice, the presence of M. restricta worsened colitis, a type of intestinal inflammatory disease.

Looking at the mucosa-based intestinal fungi of healthy people and patients with Crohn's disease, a form of IBD, the researchers found several mucosa-associated fungi that were significantly more abundant in Crohn's patients. In particular, M. restricta was elevated in Crohn's patients carrying a genetic variation known as the IBD CARD9 risk allele.


The study was published in the journal Cell Host & Microbe, which featured it on the cover of its March issue along with an alcohol-ink painting of fungi created by Andrea Wolf, PhD, a research scientist in the Department of Biomedical Sciences at Cedars-Sinai. Wolf was a co-author of the study, and David Underhill, PhD, the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease at Cedars-Sinai, was the corresponding author.

Under the headline, "Dandruff Could Be Key to Crohn's disease," the Daily Mail reported: "A fungus linked to dandruff may be a crucial factor driving the chronic stomach condition Crohn's disease, according to a new study. Malassezia yeasts found in oily skin and scalp follicles are linked to skin conditions, including dandruff.

"Researchers discovered that the fungus commonly found in human hair follicles also resides in the gut. In most of us, it is harmless, but in some people with a certain genetic make-up it appears to worsen their intestinal disorders such as inflammatory bowel disease (IBD)."

The article by Mia de Graaf, DailyMail.com health editor, quoted Underhill as saying, "We were surprised to find that Malassezia restrica was more common on intestinal tissue surfaces in Crohn's disease patients than in healthy people." De Graaf stated the next steps involve exploring whether eradicating the yeast from the intestinal microbiome clears the patients' symptoms.


Dandruff could be a crucial factor in Crohn's disease: Scientists discover the hair fungus also resides in the GUT and causes inflammatory reactions in people with digestive diseases
Researchers discovered dandruff-linked fungus resides in many people's guts, but doesn't cause a reaction in most (left). Some people, however, suffer inflammation from it (right)


Researchers discovered dandruff-linked fungus resides in many people's guts, but doesn't cause a reaction in most (left). Some people, however, suffer inflammation from it (right)

In mice, the presence of M. restricta worsened colitis, a type of intestinal inflammatory disease.

Looking at the intestinal fungi of healthy people and patients with Crohn's disease, a form of IBD, the researchers found several mucosa-associated fungi that were 'significantly more abundant' in Crohn's patients.

The findings, published in the journal Cell Host and Microbe, showed that M. restricta in particular was elevated in Crohn's patients carrying a genetic variation known as the IBD CARD9 risk allele.

The researchers said that the genetic variant enhances the ability of human immune cells to pump out inflammatory cytokines in response to M. restricta.

'We found it in some healthy people, and in mice it does not seem to cause disease in the gut by itself.

'However, if there is some intestinal inflammation, Malassezia seems to make it worse.'



Malassezia
Is Associated with Crohn’s Disease and Exacerbates Colitis in Mouse Models
Jose J. Limon Jie Tang Dalin Li Stephan R. Targan Dermot P.B. McGovern David M. Underhill
Published:March 05, 2019

Highlights


    • M. restricta is associated with the colonic mucosa in Crohn’s disease (CD) patients

    • M. restricta exacerbates colitis in wild-type and gnotobiotic mice

    • M. restricta is found in CD patients with a disease-linked polymorphism in CARD9

    • Malassezia-exacerbated colitis in mice requires signaling via CARD9


      Summary
Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn’s disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.




Malassezia
Despite being the most prevalent fungal genera in the human microbiome, Malassezia are little known outside the field of dermatology. Malassezia were first described in 1889, yet it took nearly a century to firmly establish their role in dandruff and seborrheic dermatitis (47). This delay can be attributed to Malassezia's difficulty growing in culture (they require just the right concentration of certain lipids) (48), their extremely high prevalence on the skin (~100% throughout life) (49), and their resistance to fungicides (commonly used antifungal drugs do not completely eradicate Malassezia and their populations rebound once such treatments are discontinued) (50). About 50% of adults have first-hand experience with Malassezia-associated symptoms: they use antifungal shampoo to keep their dandruff under control, and whenever they switch back to normal shampoo, Malassezia and dandruff return (47).


Until very recently, it was believed that Malassezia were restricted to the skin, except in rare immunocompromised or lipid-rich parenteral nutrition cases (34, 51). Due to improved microbe detection techniques, many groups now report finding Malassezia within the body of both healthy adults and immunocompetent patients with various ailments (1416, 2325, 33, 5261). Malassezia's potential role in diseases of internal organs is just coming to light (19, 54, 6264). It is important to note that Malassezia's presence is not synonymous with disease: in the vast majority of individuals, Malassezia colonize the body without causing symptoms. This means detecting Malassezia in a given organ is far from sufficient to prove their involvement in diseases of that organ. Additional lines of evidence are necessary to implicate them, for example the efficacy of antifungal drugs in treating the disease, immunological evidence (such as antibodies against Malassezia) and genetic evidence (such as genes affecting Malassezia's lipid supply or the immune response against fungi).


Since Malassezia are not well-known in the field of neurodegenerative disorders, this section is included as a primer on Malassezia's suspected role in SD, acquired immune deficiency syndrome (AIDS), Crohn's disease (CD), spondyloarthritides (SpA), and MS. Each of these conditions is informative for PD.


Malassezia Are a Necessary Factor in Seborrheic Dermatitis

Malassezia's role in SD is now generally accepted (29, 42, 43, 50). Given the right conditions, Malassezia over proliferate on the skin (65), resulting in SD—though specific mechanisms are still open to debate (29, 42, 43, 50). Most SD cases respond well to topical fungicides which reduce Malassezia populations on affected patches of skin to levels tolerated by patients (29, 42, 43).


SD occurs mainly in lipid-rich skin regions, especially the face, trunk and scalp (29, 42, 43). Malassezia are lipid-dependent fungi: they lack key lipid metabolism genes (including fatty acid synthase, stearoyl-CoA desaturase, and enoyl-CoA isomerase), and thus depend on host lipids for survival (48). Skin lipid production varies during our lifetime, with a peak in the first year of life, followed by a second peak in adolescence (6668): production is depressed during the rest of childhood, which corresponds to the period of lowest SD risk (69). In adults, the risk of SD increases substantially with age (69). This is unexpected because skin lipid levels slowly decline with age (67), so Malassezia should have increasing difficulty securing lipids in the elderly.


Azathioprine and cyclosporin, two immunosuppresive drugs which target T cells, substantially increase SD risk (39). Similarly, CD4+ T cell counts are inversely associated with SD risk and severity in AIDS patients (29). Peripheral blood mononuclear cells (PBMC) from SD patients produce less IL-2 and interferon gamma (IFNγ) when exposed to Malassezia antigens as compared to age-matched controls (70), suggesting a weak type 1 helper T cell (Th1) response against Malassezia is a characteristic of SD. In healthy individuals, thymic involution reduces naive T cell production, which results in a slow decline in T cell efficacy over our lifespan (71). This can be observed in part by measuring T cell receptor (TCR) diversity (71, 72). T cell immunosenescence can explain why SD risk increases with age, despite declining skin lipids. SD seems to be mainly due to the combination of ample lipids (29, 42, 43) and weak T cell-mediated control (70, 73, 74) of Malassezia, which together allow this fungus to over proliferate on the skin.


Seborrheic dermatitis (SD) is a well-known symptom associated with PD: PD patients have ~50% SD prevalence, while controls only have ~3% prevalence (44, 45). Though these are the most frequently cited figures, they are based on old studies whose accuracy has drawn criticism (75). We only found one recent study which measured the association between PD and SD (46). It reported that SD increases the risk of a subsequent PD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; p < 0.001). This association remained significant when the SD diagnosis was made at least 5 years before the PD diagnosis, suggesting PD-associated treatments or behavior cannot explain it (46). This study reported an SD diagnosis rate of 4% prior to a PD diagnosis, as compared to 2.5% for age matched controls (46). This low rate of association indicates factors predisposing to SD and PD are mostly different. Of note, this report (46) is only available as an abstract and has not been published as a peer-reviewed article. Specific mechanisms underlying the association between SD and PD are not known (75). Nonetheless, this association suggests that mechanisms allowing Malassezia to over proliferate and cause SD (ample lipids and T cell immunosenescence) should be thoroughly investigated as possible mechanisms underlying PD as well.


Malassezia Are a Necessary Factor in Crohn's Disease and Spondyloarthritides

Spondyloarthritides (SpA) are a group chronic immune-mediated diseases mainly driven by alpha beta T cells recognizing intracellular peptides through HLA-B*27 presentation (62, 83). Affected organs include the spine, joints, skin, eyes, gut, and prostate (62). Historically, isolated inflammation of the eyes, gut, and skin—respectively acute anterior uveitis, inflammatory bowel disease (Crohn's disease [CD] and ulcerative colitis) and psoriasis—were considered separate diseases unrelated to SpA. However, SpA, acute anterior uveitis, inflammatory bowel disease and psoriasis run together in families (84), and share many polymorphisms in genes controlling T cell activation (85), strongly suggesting that they are the same immunological pathology (84). In particular, the fact that HLA-B*27 increases the risk of each disease strongly suggests the same antigens are being targeted (62). Varied lines of evidence support the presence of an elusive necessary intracellular fungal infection in each affected organ, which is efficiently detected by HLA-B*27 and CARD9 (62). CARD9 is an essential signaling protein for fungal immunity: homozygous loss-of-function CARD9 mutations cause severe mycoses (37). CARD9 polymorphisms are associated with inflammatory bowel disease and SpA (62, 64). Oral antifungal drugs are effective in psoriasis (8689), psoriatic arthritis (89, 90), and likely in Crohn's disease as well (91).


In inflammatory bowel disease and psoriasis, strong evidence points to Malassezia as being the causative genus (62). Enteric Malassezia is strongly associated with CD (54, 64) and ulcerative colitis (63). Immune recognition of Malassezia occurs specifically through CARD9 in the gut, and knocking out CARD9 in mice abrogates colitis symptoms following exposure to Malassezia (64). In CD, CARD9 risk alleles increase PBMC secretion of tumor necrosis factor alpha (TNF-α) following Malassezia antigen challenges (64). Antibodies against Malassezia are associated with CD (64) and psoriasis (92, 93). Applying lysed Malassezia to the skin provokes psoriasis lesions in susceptible individuals (94). The only known fungus which is commonly present in the gut (61) and on the skin (49), and thus can explain why Crohn's patients develop psoriasis during vedolizumab treatment (95), is Malassezia. Finally, PBMCs in psoriasis react strongly to Malassezia antigens (96). These data suggest that a dysregulated immune response against Malassezia in the gut is causative in CD (64).


CD and SpA provide three key insights for PD. First, they demonstrate that Malassezia can cause diseases of internal organs in genetically predisposed individuals. Second, the increased risk of psoriasis in overweight individuals (97100), and the increased risk of CD in carriers of certain LRRK2 alleles (101, 102) are most simply explained by enhanced lipid availability (103) which promotes Malassezia's growth by supplying it with lipids [the same LRRK2 alleles increase PD risk (101, 102)]. Third, intracellular melanin reminiscent of neuromelanin (104) is associated with inflammation of the prostate (104106). Though indigenous production of melanin by human cells has been proposed as an explanation (104), a second possible origin would be from Malassezia which have colonized the prostate and CNS. Malassezia produce DOPA-melanin from L-DOPA (107). Both prostate epithelial cells and dopamine neurons contain intracellular lipid droplets which can fulfill Malassezia's requirement for lipids.


Our goal is to send Crohn’s, prostate cancer, and hopefully many other diseases the way of dandruff: cured by antifungals. Please watch the videos, share your insights and subscribe.

 
Last edited:
It sounds a bit confusing to me, reading their comment as:

"What’s more, the CARD9 protein comes in different variants (alleles) which are passed down from parents to their children. One of these variants (CARD9 rs4077515:A) greatly increases the risk of Crohn’s disease and ulcerative colitis by increasing TNF-α production when Malassezia is detected by the Mincle hook, resulting in immune hypersensitivity to Malassezia. "

For me the conclusion is that Anti TNF-α should be the main treatment, and should work for all patients, since the inflammation is in fact because of a hypersensitivity. Just if i follow their logic.
And if one genetic allele rs4077515:A (according to promethease its like 36% of the general population have that) is responsible for this disease then GWAS studies would have already pointed this out long time ago.

So this concept looks a bit blurry to me, nevertheless i look forward to the results of their trials.
 
Location
San Diego
And if one genetic allele rs4077515:A (according to promethease its like 36% of the general population have that) is responsible for this disease then GWAS studies would have already pointed this out long time ago.
Studies have not pointed this out because the notion that one CARD9 allele is alone responsible for Crohn's disease is incorrect. The majority of Crohn's patients do not have the rs4077515:A allele, including me. (I have 23&Me and my Promethease report.)

So there is clearly something more going on to trigger Crohn's than one nasty gene. What that allele does more than cause Crohn's is to make the disease more aggressive. That gene is much more prognostic than it is diagnostic. CD patients with that allele are more likely to suffer severe Crohn's, and those without it are more likely to have milder disease.

One thing that reading the Crohn's research has taught me is that Crohn's is a multi-factorial disease. It's a mistake to focus trying to find the one big cause for Crohn's. The cause of Crohn's is not genes, although that may play an important role in some or many cases. The cause of Crohn's is not MAP, although that may play an important role in some or many cases. The cause of Crohn's is not a primary defect in the immune system, although that may play an important role in some or many cases. The cause of Crohn's is not the western diet, although that may play an important role in some or many cases. The cause of Crohn's is not emulsifiers or other food additives, although they may play an important role in some or many cases. And so on....

And what this multiplicity of causes and triggers implies is that a multiplicity of treatments may be needed to cure or even to successfully manage Crohn's disease. And indeed that is just what we see. Just skimming the posts by members on this site shows some degree of success (and a lot of failure) for many different approaches to therapy and diet. But none of them works for everybody.

Whether all this confusion will ever get sorted out into a single unified theory Crohn's disease with a resultant cure that works for everybody looks pretty doubtful at this point. Those focused on finding the one big answer to Crohn's may well be chasing something that doesn't exist.
 
kiny, what do you think about this? Could you share your thoughts?

The primary pathology in most case of CD appears to affect macrophages recruited from the blood as monocytes301. Advances in gene editing with the CRISPR-Cas390,391 technology make the corrective treatment of CD a real possibility in the relatively near future. Once a primary causal mutation has been identified, and validated in animal models, bone marrow could be extracted, edited and reinfused into a conditioned patient in much the same way as is being applied to gene therapy for primary immunodeficiencies392.
Segal AW. Making sense of the cause of Crohn’s – a new look at an old disease [version 2; peer review: 2 approved]. F1000Research 2016, 5:2510
(https://doi.org/10.12688/f1000research.9699.2)

These are the last three articles Segal cited in that quote:
Edit: I think what’s important in Segal’s statement is the emphasis on the “identification” of a “primary causal mutation” in the future. Based on the current evidence, the possibility of that do not seem high to me.
 
Last edited:
The fungal aspect is interesting, I've had recurring fungal issues for most of my crohn's-having life, especially my scalp, but I've had it in the groin area, and in my nose. They tried to treat my nose with topicals + fluconizale but it didn't work. I actually caved and tried tea tree oil diluted in coconut oil and it cleared it in like a week, and I am generally the, "Essential oils are a load of crap" type.

The scalp is especially stubborn and I basically have to avoid any kind of ingredients that could potentially trigger it or I have a flare for a month unless until I use Nizorale daily.

Kind of like my crohn's.

I disagree with the notion that Crohn's being linked to multiple causes means that it is multiple causes requiring multiple treatments. I know Occam's razor is just a philosophic principle but it often holds true. It's more likely that Crohn's is a more specific cause perpetuated by a perfect storm of circumstances that allow it to become worse and propagate. That doesn't mean a singular treatment can't work.
 
Anti-TNF agents linked to increased risk of IBD. https://www.medscape.com/viewarticle/915613

“The question then arises as to how anti-TNF drugs can be effective against a condition in which the secretion of TNF and other pro-inflammatory cytokines is impaired? The answer is in the timing of the different components of the immune system. The call to arms of the innate immune system is a very early and explosive secretion of pro-inflammatory mediators, including TNF. If the clearance of faecal material from the tissues is incomplete, it becomes walled off by macrophages, endotoxin diffuses into the circulation, and cells of the adaptive immune system are recruited257. They secrete a wide array of mediators over the next weeks including TNF which acts as an amplifier of the response258. It is of interest that in a recent study of high-resolution gene expression profiling using RNA sequencing of inflamed biopsies from patients with CD, UC and controls, levels of pro-inflammatory cytokines like TNF, IL-1β, IL-6 and IL-23 were all elevated to a lesser extent in CD than in UC259. The very early secretion of TNF and other mediators is required to prevent the development of the Crohn’s lesions whereas at a later stage it is the TNF and associated mediators that produce the symptoms, which in some cases respond to anti-TNF treatment. This explains why anti-TNF therapeutics can both cause260 and alleviate symptoms of the disease261.”

Segal AW. Making sense of the cause of Crohn’s – a new look at an old disease [version 2; peer review: 2 approved]. F1000Research 2016, 5:2510 (https://doi.org/10.12688/f1000research.9699.2)
 
Last edited:
E coli have become incredibly resistant bacteria. Those won't be the last deaths from fecal transplants.
 
This research doesn’t surprise me at all. Biologics/immunosuppressants all made me 1000x worse, and my GI doctor basically blamed it on me saying I was probably smoking cigarettes, weed, or drinking alcohol and that was what caused them not to work. I was in fact doing none of those things and had gone on an almost exclusively liquid diet. Dropped all the bullshit they were giving me kept up with the liquid diet, then started ingesting very large quantities of thc/cbd oil (1000-1500mg a day of each) and was symptom free with a nice clean colonoscopy 30 days later. Started testosterone injections after finding my levels were incredibly low as well. Those things in combination with cannabis oil and a very clean low fiber diet have not only held me in remission, but have allowed me to get my weight/strength back and I feel great most of the time and have more energy than ever before. Prednisone, sulfasalizine, 6-mp, humira, etc all failed miserably for me and made the disease worse. My colonoscopies as of late have shown little to no inflammation just a lil scar tissue from my 2 big flares that has lessened significantly.
 
Top