Crohn‘s is an inflammatory disease of the digestive tract involving diarrhea, vomiting internal lesions, pain, and severe weight loss. Left untreated, Crohn’s can lead to death through direct starvation/malnutrition, infections caused by the intestinal walls breaking down and spilling feces into the rest of the body, or a whole host of other horrible symptoms, like pyoderma gangrenosum–basically your skin just rotting off.
Crohn’s disease has no known cause and no cure, though several treatments have proven effective at putting it into remission–at least temporarily.
The disease appears to be triggered by a combination of environmental, bacterial, and genetic factors–about 70 genes have been identified so far that appear to contribute to an individual’s chance of developing Crohn’s, but no gene has been found yet that definitely triggers it. (The siblings of people who have Crohn’s are more likely than non-siblings to also have it, and identical twins of Crohn’s patients have a 55% chance of developing it.) A variety of environmental factors, such as living in a first world country, (parasites may be somewhat protective against the disease), smoking, or eating lots of animal protein also correlate with Crohn’s, but since only 3.2/1000 people even in the West have it’s, these obviously don’t trigger the disease in most people.
Crohn’s appears to be a kind of over-reaction of the immune system, though not specifically an auto-immune disorder, which suggests that a pathogen of some sort is probably involved. Most people are probably able to fight off this pathogen, but people with a variety of genetic issues may have more trouble–according to Wikipedia, “There is considerable overlap between susceptibility loci for IBD and mycobacterial infections. ” Mycobacteria are a genus of of bacteria that includes species like tuberculosis and leprosy. A variety of bacteria–including specific strains of e coli, yersinia, listeria, and Mycobacterium avium subspecies paratuberculosis–are found in the intestines of Crohn’s suffers at higher rates than in the intestines of non-sufferers (intestines, of course, are full of all kinds of bacteria.)
Crohn’s treatment depends on the severity of the case and specific symptoms, but often includes a course of antibiotics, (especially if the patient has abscesses,) tube feeding (in acute cases where the sufferer is having trouble digesting food,) and long-term immune-system suppressants such as prednisone, methotrexate, or infliximab. In severe cases, damaged portions of the intestines may be cut out. Before the development of immunosuppressant treatments, sufferers often progressively lost more and more of their intestines, with predictably unpleasant results, like no longer having a functioning colon. (70% of Crohn’s sufferers eventually have surgery.)
A similar disease, Johne’s, infects cattle. Johne’s is caused by Mycobacterium avium subspecies paratuberculosis, (hereafter just MAP). MAP typically infects calves at birth, transmitted via infected feces from their mothers, incubates for two years, and then manifests as diarrhea, malnutrition, dehydration, wasting, starvation, and death. Luckily for cows, there’s a vaccine, though any infectious disease in a herd is a problem for farmers.
If you’re thinking that “paratuberculosis” sounds like “tuberculosis,” you’re correct. When scientists first isolated it, they thought the bacteria looked rather like tuberculosis, hence the name, “tuberculosis-like.” The scientists’ instincts were correct, and it turns out that MAP is in the same bacterial genus as tuberculosis and leprosy (though it may be more closely related to leprosy than TB.) (“Genus” is one step up from “species;” our species is “homo Sapiens;” our genus, homo, we share with homo Neanderthalis, homo Erectus, etc, but chimps and gorillas are not in the homo genus.)
The intestines of cattle who have died of MAP look remarkably like the intestines of people suffering from advanced Crohn’s disease.
MAP can actually infect all sorts of mammals, not just cows, it’s just more common and problematic in cattle herds. (Sorry, we’re not getting through this post without photos of infected intestines.)
So here’s how it could work:
The MAP bacteria–possibly transmitted via milk or meat products–is fairly common and infects a variety of mammals. Most people who encounter it fight it off with no difficulty (or perhaps have a short bout of diarrhea and then recover.)
A few people, though, have genetic issues that make it harder for them to fight off the infection. For example, Crohn’s sufferers produce less intestinal mucus, which normally acts as a barrier between the intestines and all of the stuff in them.
Interestingly, parasite infections can increase intestinal mucus (some parasites feed on mucus), which in turn is protective against other forms of infection; decreasing parasite load can increase the chance of other intestinal infections.
Once MAP enters the intestinal walls, the immune system attempts to fight it off, but a genetic defect in microphagy results in the immune cells themselves getting infected. The body responds to the signs of infection by sending more immune cells to fight it, which subsequently also get infected with MAP, triggering the body to send even more immune cells. These lumps of infected cells become the characteristic ulcerations and lesions that mark Crohn’s disease and eventually leave the intestines riddled with inflamed tissue and holes.
The most effective treatments for Crohn’s, like Infliximab, don’t target infection but the immune system. They work by interrupting the immune system’s feedback cycle so that it stops sending more cells to the infected area, giving the already infected cells a chance to die. It doesn’t cure the disease, but it does give the intestines time to recover.
Unfortunately, this means infliximab raises your chance of developing TB:
There were 70 reported cases of tuberculosis after treatment with infliximab for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. … Of the 70 reports, 64 were from countries with a low incidence of tuberculosis. The reported frequency of tuberculosis in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of tuberculosis among patients treated with infliximab was higher than the available background rates.
because it is actively suppressing the immune system’s ability to fight diseases in the TB family.
Luckily, if you live in the first world and aren’t in prison, you’re unlikely to catch TB–only about 5-10% of the US population tests positive for TB, compared to 80% in many African and Asian countries. (In other words, increased immigration from these countries will absolutely put Crohn’s suffers at risk of dying.)
There are a fair number of similarities between Crohn’s, TB, and leprosy is that they are all very slow diseases that can take years to finally kill you. By contrast, other deadly diseases, like smallpox, cholera, and yersinia pestis (plague), spread and kill extremely quickly. Within about two weeks, you’ll definitely know if your plague infection is going to kill you or not, whereas you can have leprosy for 20 years before you even notice it.
TB, like Crohn’s, creates granulomas:
Tuberculosis is classified as one of the granulomatous inflammatory diseases. Macrophages, T lymphocytes, B lymphocytes, and fibroblasts aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. When other macrophages attack the infected macrophage, they fuse together to form a giant multinucleated cell in the alveolar lumen. The granuloma may prevent dissemination of the mycobacteria and provide a local environment for interaction of cells of the immune system. However, more recent evidence suggests that the bacteria use the granulomas to avoid destruction by the host’s immune system. … In many people, the infection waxes and wanes.
Crohn’s also waxes and wanes. Many sufferers experience flare ups of the disease, during which they may have to be hospitalized, tube fed, and put through another round of antibiotics or sectioning (surgical removal of the intestines) before they improve–until the disease flares up again.
Leprosy is also marked by lesions, though of course so are dozens of other diseases.
Note: Since Crohn’s is a complex, multi-factorial disease, there may be more than one bacteria or pathogen that could infect people and create similar results. Alternatively, Crohn’s sufferers may simply have intestines that are really bad at fighting off all sorts of diseases, as a side effect of Crohn’s, not a cause, resulting in a variety of unpleasant infections.
The MAP hypothesis suggests several possible treatment routes:
- Improving the intestinal mucus, perhaps via parasites or medicines derived from parasites
- Improving the intestinal microbe balance
- Antibiotics that treat Map
- Anti-MAP vaccine similar to the one for Johne’s disease in cattle
- Eliminate map from the food supply
Here’s an article about the parasites and Crohn’s:
To determine how the worms could be our frenemies, Cadwell and colleagues tested mice with the same genetic defect found in many people with Crohn’s disease. Mucus-secreting cells in the intestines malfunction in the animals, reducing the amount of mucus that protects the gut lining from harmful bacteria. Researchers have also detected a change in the rodents’ microbiome, the natural microbial community in their guts. The abundance of one microbe, an inflammation-inducing bacterium in the Bacteroides group, soars in the mice with the genetic defect.
The researchers found that feeding the rodents one type of intestinal worm restored their mucus-producing cells to normal. At the same time, levels of two inflammation indicators declined in the animals’ intestines. In addition, the bacterial lineup in the rodents’ guts shifted, the team reports online today in Science. Bacteroides’s numbers plunged, whereas the prevalence of species in a different microbial group, the Clostridiales, increased. A second species of worm also triggers similar changes in the mice’s intestines, the team confirmed.
To check whether helminths cause the same effects in people, the scientists compared two populations in Malaysia: urbanites living in Kuala Lumpur, who harbor few intestinal parasites, and members of an indigenous group, the Orang Asli, who live in a rural area where the worms are rife. A type of Bacteroides, the proinflammatory microbes, predominated in the residents of Kuala Lumpur. It was rarer among the Orang Asli, where a member of the Clostridiales group was plentiful. Treating the Orang Asli with drugs to kill their intestinal worms reversed this pattern, favoring Bacteroides species over Clostridiales species, the team documented.
This sounds unethical unless they were merely tagging along with another team of doctors who were de-worming the Orangs for normal health reasons and didn’t intend on potentially inflicting Crohn’s on people. Nevertheless, it’s an interesting study.
At any rate, so far they haven’t managed to produce an effective medicine from parasites, possibly in part because people think parasites are icky.
But if parasites aren’t disgusting enough for you, there’s always the option of directly changing the gut bacteria: fecal microbiota transplants (FMT). A fecal transplant is exactly what it sounds like: you take the regular feces out of the patient and put in new, fresh feces from an uninfected donor. (When your other option is pooping into a bag for the rest of your life because your colon was removed, swallowing a few poop pills doesn’t sound so bad.) EG, Fecal microbiota transplant for refractory Crohn’s:
Approximately one-third of patients with Crohn’s disease do not respond to conventional treatments, and some experience significant adverse effects, such as serious infections and lymphoma, and many patients require surgery due to complications. .. Herein, we present a patient with Crohn’s colitis in whom biologic therapy failed previously, but clinical remission and endoscopic improvement was achieved after a single fecal microbiota transplantation infusion.
Here’s a Chinese doctor who appears to have good success with FMTs to treat Crohn’s–improvement in 87% of patients one month after treatment and remission in 77%, though the effects may wear off over time. Note: even infliximab, considered a “wonder drug” for its amazing abilities, only works for about 50-75% of patients, must be administered via regular IV infusions for life (or until it stops working,) costs about $20,000 a year per patient, and has some serious side effects, like cancer. If fecal transplants can get the same results, that’s pretty good.
Antibiotics are another potential route. The Redhill Biopharma is conducting a phase III clinical study of antibiotics designed to fight MAP in Crohn’s patients. Redhill is expected to release some of their results in April.
Mechanism of action: The vaccine is what is called a ‘T-cell’ vaccine. T-cells are a type of white blood cell -an important player in the immune system- in particular, for fighting against organisms that hide INSIDE the body’s cells –like MAP does. Many people are exposed to MAP but most don’t get Crohn’s –Why? Because their T-cells can ‘see’ and destroy MAP. In those who do get Crohn’s, the immune system has a ‘blind spot’ –their T-cells cannot see MAP. The vaccine works by UN-BLINDING the immune system to MAP, reversing the immune dysregulation and programming the body’s own T-cells to seek out and destroy cells containing MAP. For general information, there are two informative videos about T Cells and the immune system below.
Efficacy: In extensive tests in animals (in mice and in cattle), 2 shots of the vaccine spaced 8 weeks apart proved to be a powerful, long-lasting stimulant of immunity against MAP. To read the published data from the trial in mice, click here. To read the published data from the trial in cattle, click here.
Dr. Borody (who was influential in the discovery that ulcers are caused by the h. pylori bacteria and not stress,) has had amazing success treating Crohn’s patients with a combination of infliximab, anti-MAP antibiotics, and hyperbaric oxygen. Here are two of his before and after photos of the intestines of a 31 yr old Crohn’s sufferer:
Here are some more interesting articles on the subject:
Last week, Davis and colleagues in the U.S. and India published a case report in Frontiers of Medicine http://journal.frontiersin.org/article/10.3389/fmed.2016.00049/full . The report described a single patient, clearly infected with MAP, with the classic features of Johne’s disease in cattle, including the massive shedding of MAP in his feces. The patient was also ill with clinical features that were indistinguishable from the clinical features of Crohn’s. In this case though, a novel treatment approach cleared the patient’s infection.
The patient was treated with antibiotics known to be effective for tuberculosis, which then eliminated the clinical symptoms of Crohn’s disease, too.
Through luck, hard work, good fortune, perseverance, and wonderful doctors, I seem to be one of the few people in the world who can claim to be “cured” of Crohn’s Disease. … In brief, I was treated for 6 years with medications normally used for multidrug resistant TB and leprosy, under the theory that a particular germ causes Crohn’s Disease. I got well, and have been entirely well since 2004. I do not follow a particular diet, and my recent colonoscopies and blood work have shown that I have no inflammation. The rest of these 3 blogs will explain more of the story.
What about removing Johne’s disease from the food supply? Assuming Johne’s is the culprit, this may be hard to do, (it’s pretty contagious in cattle, can lie dormant for years, and survives cooking) but drinking ultrapasteurized milk may be protective, especially for people who are susceptible to the disease.
However… there are also studies that contradict the MAP theory. For example, a recent study of the rate of Crohn’s disease in people exposed to Johne’s disease found no correllation. (However, Crohn’s is a pretty rare condition, and the survey only found 7 total cases, which is small enough that random chance could be a factor, but we are talking about people who probably got very up close and personal with feces infected with MAP.)
Another study found a negative correlation between Crohn’s and milk consumption:
Logistic regression showed no significant association with measures of potential contamination of water sources with MAP, water intake, or water treatment. Multivariate analysis showed that consumption of pasteurized milk (per kg/month: odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.69, 0.97) was associated with a reduced risk of Crohn’s disease. Meat intake (per kg/month: OR = 1.40, 95% CI: 1.17, 1.67) was associated with a significantly increased risk of Crohn’s disease, whereas fruit consumption (per kg/month: OR = 0.78, 95% CI: 0.67, 0.92) was associated with reduced risk.
So even if Crohn’s is caused by MAP or something similar, it appears that people aren’t catching it from milk.
There are other theories about what causes Crohn’s–these folks, for example, think it’s related to consumption of GMO corn. Perhaps MAP has only been found in the intestines of Crohn’s patients because people with Crohn’s are really bad at fighting off infections. Perhaps the whole thing is caused by weird gut bacteria, or not enough parasites, insufficient Vitamin D, or industrial pollution.
The condition remains very much a mystery.