Crohn's disease

by Mati_Roy 10mo13th Nov 201848 comments

-12


Authors: This article was written by Martin Laurence (see Martin's comment below). I helped with structuring and reviewing the article.

Update by Martin (November 15th 2018): Following some of your input in the comment section on the impact of this research, the phrase “There are ~2 million Crohn’s disease sufferers worldwide, and many use immunomodulatory injections (such as adalimumab which costs ~50K$ USD/year) to reduce inflammation and symptoms. A back of the envelope calculation suggests this would have a direct economic impact of 50K$ x 2M = ~100B$ USD/year.” was changed to “A cheap cure for Crohn's would save a large fraction of the $33B spent on Crohn's each year, and in turn, these funds could save thousands of lives per year if spent on other causes.” This remains a rough and narrow estimate of the potential impact of this project, and additional help to improve this estimate would be greatly appreciated.

Summary: Recent studies strongly suggest Crohn’s disease is caused by a fungus, most likely a Malassezia species (Laurence et al 2018). The FDA approved antifungal drug itraconazole might cure patients by clearing this fungus from the gut, as reported in a small study (Samuel et al 2010). Since this drug’s patent has expired, there is little financial incentive to formally demonstrate its efficacy in Crohn’s disease—this would be required to change clinical practice. A cheap cure for Crohn's would save a large fraction of the $33B spent on Crohn's each year, and in turn, these funds could save thousands of lives per year if spent on other causes. More information can be found at www.malassezia.org.

Importance

Direct impact

There is currently no known cure for Crohn's disease. Onset usually occurs in young adults, who are then affected for life. Though Crohn’s disease is typically non-fatal, it greatly decreases the quality of life of patients (Norton et al 2012, Benedini 2012) and increases their risk of colon cancer. Curing this disease would improve the life of an estimated 2 million sufferers worldwide. Current interventions include surgical removal of affected regions of the intestines (this can mean defecating into a bag strapped to one’s stomach from then on) and drugs which reduce the aggressivity of the immune system such as adalimumab, infliximab and azathioprine (which increase the risk of various infections). Neither intervention is appealing.

Leverage value

Crohn's disease is part of a group of immunologically similar diseases known as spondyloarthritides. These diseases are the result of abnormal activation of alpha beta T cells, though the specific antigens targeted by these T cells remain a mystery. Spondyloarthritide symptoms include chronic inflammation of the gut, skin, joints, eyes, spine and genitals (Laurence et al 2018); affected organs can flare-up alone or in combination. Common phenotypes include Crohn's disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, psoriasis, psoriatic arthritis, acute anterior uveitis and oligoarthritis.

Recent studies suggest all these diseases are caused by alpha beta T cells attempting to clear a fungus from affected organs—and failing miserably, making us sick in the process. We strongly suspect this fungus is part of the genus Malassezia (Laurence et al 2018). This means proving beyond all doubt that Crohn's disease is caused by this fungus will very likely lead to a cure for all spondyloarthritide symptoms using antifungal drugs. These symptoms include chronic non-radiographic back pain which is a mild spondyloarthritide symptom affecting a large subset of the adult population.

Though supporting evidence is not as strong as for spondyloarthritides, it is probable that B cell-mediated diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus share the same infectious etiology (Laurence et al 2017, Benito-Leon et al 2017, Benito-Leon et al 2018). If so, antifungal treatments should be effective for these debilitating diseases as well.

Though supporting evidence is weaker than for spondyloarthritides, it is probable that prostate cancer and benign prostatic hyperplasia are caused by the same fungal infection, and antifungal treatments would prevent these two common diseases (Laurence et al 2018).

If an important disease is shown to be caused by Malassezia and is cured using antifungal drugs—Crohn’s is currently the best candidate—then government agencies like the NIH would probably invest billions of dollars to see if the same holds true for other diseases, especially those in bold above.

Tractability

My academic collaborators and I have published many articles making the case for a fungal etiology in spondyloarthritides (including Crohn's disease), multiple sclerosis, prostate cancer and benign prostatic hyperplasia (Sutcliffe et al 2014, Laurence et al 2018, Laurence et al 2017, Benito-Leon et al 2017, Benito-Leon et al 2018). We suspect a single ubiquitous fungal species or genus is causing all these diseases. The only known fungi which fit the bill are Malassezia restricta and Malassezia globosa.

The main open question which pressingly needs an answer is: “Can existing antifungal drugs eliminate this fungus, curing Crohn’s and other diseases listed above?” Antifungal compounds are very effective at treating dandruff and seborrheic dermatitis, two skin conditions known to be caused by Malassezia. The small study run by Samuel et al suggests oral itraconazole is effective in Crohn's disease. This hypothesis is readily testable by replicating Samuel et al in a double-blind placebo-controlled study. This is our primary goal. Thereafter, we'd like to run additional studies to test the efficacy of antifungal drugs in other diseases listed above.

Neglectedness

Why it’s neglected

The vast majority of microbiome studies focus on bacteria, and ignore fungi. There are technical reasons for this: assays to detect bacteria are cheaper and easier to run. There are many more bacterial species in humans than fungal species, so study results seem more interesting when bacteria are included. For historical reasons, bacteria such as Klebsiella and Mycobacteria were considered the prime suspects in spondyloarthritides (including Crohn’s disease). In short, studying fungi has not been an appealing prospect for researchers.

Malassezia restricta and Malassezia globosa were first identified in 1996 using DNA sequencing. The tardiness of this discovery is best explained by the fact that they don’t grow well in culture. This means only recent studies using DNA sequencing have any hope of detecting them. In addition, Malassezia have the thickest cell wall of medically important fungi, which means most kits used to extract DNA to detect microbes can’t crack them open (Vesty 2017). Malassezia are the Brazil nut of microbes!

Drugs currently used to treat spondyloarthritides (including Crohn’s disease) are expensive biologics which depress the patient’s immune system. Imagine if we were treating syphilis with immunosuppressants rather than penicillin! Immunosuppressants would reduce symptoms, but wouldn’t address the root cause of the disease. The correct treatment for syphilis is penicillin, which quickly kills the causative bacterium, permanently resolving symptoms. The correct treatment for spondyloarthritides might well be existing antifungal drugs. We need to test this to be certain. However, there is no financial incentive to do this because patents on most antifungal drugs have already expired.

A similar situation unfolded in the 1980s when Barry Marshall discovered that stomach ulcers were not caused by stress, smoking and acid (as previously thought), but rather by a bacterium in the stomach called Helicobacter pylori. Antibiotics to eliminate Helicobacter pylori had been on the market since the 1950s, we simply did not know how to use them. Instead, we gave patients antacids which reduced their symptoms, but did not address the root cause of their disease. This is well explained here.

Funding gap

This project has been running since 2012, full-time and self-funded. I’d rather not know how much I have invested so far, but it’s in the hundreds of thousands of dollars.

I currently have a quote of 500K$ USD to replicate Samuel et al 2010 with controls (n=20 itraconazole, n=20 placebo, for six months). I would eventually like to run additional clinical trials for each important spondyloarthritide symptom. I cannot fund these clinical trials entirely myself, though this would have been my preference.