Showing posts with label Crohn's Disease. Show all posts
Showing posts with label Crohn's Disease. Show all posts

Wednesday, April 3, 2013

Blastocystis and IBD

We recently published what could be seen as a pilot study on inflammatory bowel disease (IBD) and the two most common intestinal parasites, Blastocystis and Dientamoeba fragilis.

The aim of the study was to identify possible differences in the prevalence of infection with Blastocystis and D. fragilis in patients with active and inactive IBD compared to controls.

We included 100 Danish patients with IBD (42 with Crohn's Disease, 41 with ulcerative colitis and 17 with ileal pouch-anal anastomosis) and 96 controls, used state-of-the-art diagnostics for Blastocystis and D. fragilis (PCR) and we saw striking differences in prevalence. While 19% of all healthy individuals had Blastocystis, only 5% of those with IBD had Blastocystis, and of the 42 patients with Crohn's Disease, only 1 had Blastocystis. In contrast, D. fragilis was not more common in healthy individuals than in IBD patients. Also, in patients with ulcerative colitis, Blastocystis was significantly more common in patients with inactive disease compared to patients with active disease.

Absence of Blastocystis in patients with Crohn's Disease and active ulcerative colitis may be due to unfavourable conditions for colonisation and should be explored further in order to investigate whether these potentially unfavourable conditions reflect differences in the composition of the microbiota in these patients, and/or whether this has something to do with host immunity. We are currently confirming the virtual absence of Blastocystis in Crohn's patients in another study based on metagenomic analysis of faecal DNA, and it will be very interesting to analyse the differences in Blastocystis prevalence in view of potential differences in bacterial communities.

The literature on Blastocystis and IBD is relatively limited, and I plan to return, maybe later this year, with a more elaborate post on the topic.


Petersen AM, Stensvold CR, Mirsepasi H, Engberg J, Friis-Møller A, Porsbo LJ, Hammerum AM, Nordgaard-Lassen I, Nielsen HV, & Krogfelt KA (2013). Active ulcerative colitis associated with low prevalence of Blastocystis and Dientamoeba fragilis infection. Scandinavian journal of gastroenterology PMID: 23528075

Saturday, November 17, 2012

Amelioration of Colitis by Parasites - or "An Elliott & Weinstock Special"

Common parasites such as Blastocystis and Dientamoeba fragilis are often incriminated of causing chronic or intermittent diarrhoea or other intestinal symptoms despite the absence of compelling evidence. What most of us probably fail to realise is that parasites may actually prevent and ameliorate intestinal illness, including inflammatory bowel disease, other types of colitis, and other types of autoimmune diseases.

Inflammatory bowel disease (IBD) includes the two most common manifestations ulcerative colitis and Crohn’s Disease and affects more than 2 million people in North America and Europe. They are chronic inflammatory conditions of the gut that usually begin when people are in the second to third decade of life. Although the causes of these inflammatory diseases remain unknown, they are assumed to result from inappropriately aggressive mucosal (i.e. related to our intestinal lining) immune responses to elements or substances in our intestine. IBD is treated with immuno-suppresive drugs.

IBD has emerged primarily in the Western world along with a significant reduction in cases of intestinal helminthiasis due to clean food and water, improved hygiene and sanitation, and the development and use of antibiotics. In Denmark, helminthic infections due to previously common parasitic worms such as Ascaris (roundworm) are now at the point of being almost extinct in the indigenous population.

The hygiene hypothesis proposes that a causal link exists between the adoption of modern hygiene and the increase in the prevalence of immune dysfunctions. The extent of perinatal maturation of the immune system may play a crucial role in terms of our likelihood of developing allergic and autoimmune diseases later in life. The maturation process includes establishment of tolerance to food and harmless microorganisms, but also defence mechanisms against pathogens. If our environment is "too clean", we may fail to give our immune system the best possible opportunity to mature and differentiate appropriately. A robust immune response will protect us from recurrent infections, but if misdirected, it can cause disease.

Part of our immune system is the "adaptive immune system" -  or our "immunologic memory" - made up by cells such as lymphocytes (T- and B-cells), macrophages, dendritic cells, etc. plus antibodies and hormone-like substances (eg. cytokines) that are secreted to activate/inactivate or up- and down-regulate these cells. Our immune systems has to be able to recognise a plethora of foreign material such as bacteria, viruses and parasites, and to distinguish "self" from "non-self". IBD may be caused by mal-functions in our own immune system, and so may a lot of other diseases, diseases that we call "autoimmune diseases", and which include coeliac disease, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis.

10,000 years ago, humans were infected by a variety of species of worms that are common in some parts of the world even today and hence humans and parasites have co-evolved over thousands of years. Importantly, most wild animals in their natural habitat are carriers of many types of parasites. A "clever" parasite does little harm to its host. Parasites have developed mechanisms that enable them to survive in their hosts, and also, the human immune system has developed a way to adapt to these common intruders.

Egg of Trichuris trichiura. Courtesy of Dr Marianne Lebbad.
How can one explain the amelioration of symptoms due to colitis by the presence of intestinal nematodes? Helminths appear to induce immune host regulatory cells that suppress inflammation, and helminth infections are strong inducers of immune regulatory circuits. The immune system changes in response to helminth colonisation and factors secreted by helminths that can influence immune cell function. It is likely that several immune-regulatory mechanisms are exploited by individual helminths. Otherwise, a helminth could not reliably evade our immune system to reproduce.

A new study has produced data that suggest that treatment of macaques suffering from chronic diarrhoea with eggs of the whipworm Trichuris suis can alleviate symptoms and modulate both the intestinal microbiota and immunoregulatory pathways. Trichuris suis is the whipworm of the pig, and contrary to Trichuris trichiura (image), T. suis appears not to be able to produce disease in primate hosts (including humans). When T. suis ova (TSO) are administered to humans, transient shedding of ova in faeces may be seen after a few weeks, but the individual remains asymptomatic.
Gene expression profiling of colonic biopsies from the macaques treated with TSO revealed up-regulation of genes typically involved in the so-called Th1-type immuno-response prior to TSO challenge, while induction of the Th2-type response followed after the TSO challenge; the Th2-type response resulted in mucosal repair, probably by increasing mucus production and turnover of epithelial cells, which again led to a reduction of bacterial attachment to the gut lining and a restoration of microbial diversity.

Briefly, a Th1-type response is generally a pro-inflammatory response that, among many other things, is responsible for microbicidal actions and perpetuating autoimmune responses. Excessive pro-inflammatory responses can lead to uncontrolled tissue damage, so there needs to be a mechanism to counteract this. The Th2­-type response includes the secretion of the anti-inflammatory cytokines, co-responsible for a general anti­-inflammatory response. In excess, Th2-type responses will counteract the Th1-mediated microbicidal action. The optimal scenario would therefore seem to be that humans should produce a well balanced Th1- and Th2-type response, suited to the immune challenge.
On top of the immunoregulatory impact, there is emerging evidence that helminths promote the growth and expansion of groups of bacteria that are beneficial or "probiotic" to the host. In the study of the macaques, the TSO induced a change in the intestinal microbiota.

While variation in160 genes in the human genome or more have been associated with increased risk of developing IBD, no specific gene variant that is sufficient or required for dysregulated mucosal inflammation as occurs in Crohn's disease or ulcerative colitis has been identified so far. There is a field of thought now saying that - over thousands of years - the human gut flora, including helminths, drove the development of variations in genes orchestrating various immune response pathways, and such genetic variations selected to operate under the influence of helminth infection could cause disease when operating without that influence.

So, the take home message here is that infestation by intestinal parasites may be a double-edged sword: While on one hand they may cause symptoms, they may on the other hand prevent us from developing inflammatory bowel disease and other autoimmune or allergic manifestations. Hence, helminths, although parasites, may contribute something in return to their hosts, and the loss of helminths removes a natural governor that helped to prevent disease due to immune regulation. Of course, more trials are needed before "helminth therapy" can actually be standardised, commercialised and used in the prophylaxis and treatment of IBD and gut allergic conditions. Once a good mechanistic understanding of how helminths alter immunity is available, it may even be possible to apply identified factors individually or in combination to treat disease.

As always, things are much more complex than presented here, but this post gives an impression of some of the fields of thought. Not all autoimmune diseases are driven by excessive Th1-type responses; some types of asthma may be driven by Th2-type response, but even here, helminths may favourably modulate immunoregulatory pathways.

Obviously, it would be interesting to explore how other parasitic infections impact on our immune system and gut flora. Interestingly, one helminth species appears to have "survived" in our "sterile" environment, - the pinworm (Enterobius)... and as pointed out in one of my recent blog posts (go here), many of us are definitely exposed to parasites that persist in our intestines for months, maybe years. What's their role in all of this?

Further reading:

Dirtying Up Our Diets - go here

Parasitic Worm Eggs Ease Intestinal Ills By Changing Gut Microbiota - go here.

Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491 (7422), 119-24 PMID: 23128233

Berger, A. (2000). Science commentary: Th1 and Th2 responses: what are they? BMJ, 321 (7258), 424-424 DOI: 10.1136/bmj.321.7258.424
Elliott, D., & Weinstock, J. (2012). Where are we on worms? Current Opinion in Gastroenterology, 28 (6), 551-556 DOI: 10.1097/MOG.0b013e3283572f73
Elliott, D., & Weinstock, J. (2012). Helminth-host immunological interactions: prevention and control of immune-mediated diseases Annals of the New York Academy of Sciences, 1247 (1), 83-96 DOI: 10.1111/j.1749-6632.2011.06292.x
Weinstock, J. (2012). Autoimmunity: The worm returns Nature, 491 (7423), 183-185 DOI: 10.1038/491183a

Elliott DE, Summers RW, & Weinstock JV (2007). Helminths as governors of immune-mediated inflammation. International journal for parasitology, 37 (5), 457-64 PMID: 17313951

Broadhurst, MJ., et al.Therapeutic helminth infection of macaques with idiopathic chronic diarrhoea alters the inflammatory signature and mucosal microbiota of the colon PLoS Pathogens (PLoS Pathog 8(11): e1003000. doi:10.1371/journal.ppat.1003000).