This Month in Blastocystis Research - AUG 2016

Last month, I asked about your thoughts on Blastocystis and age... is age a limiting factor with regard to the susceptibility to infection/colonisation? One of the reasons why I asked is that we and others have noted that Blastocystis becomes more and more common with age... at least until a certain stage in life (adulthood) and at least in certain countries.

Among the answers I got, I'd like to highlight one from Dr Graham Clark, London School of Hygiene and Tropical Medicine, with whom I've had the tremendous privilege of working for more than 10 years. Dr Clark writes:

In my opinion, prevalence is a mixture of three things: exposure, immunity and ‘loss’.

To illustrate the latter, infection with Entamoeba histolytica (and probably other Entamoeba species) can be lost spontaneously with a half-life of 13 months (in one study at least, Blessmann et al. 2003 J Clin Micro). There is no evidence that immunity is involved, just chance. Extrapolating to Blastocystis, I suspect the same is true – loss can occur spontaneously but what the half-life of colonisation is we have no idea and it would be difficult to evaluate without high resolution genotyping (which is what we used in E. histolytica). If you had a population of infected individuals that were followed over time and a high res[olution] typing method you could calculate rates of loss and of new infections, as we did for E. histolytica.

I do not think there is any evidence for immunity to Blastocystis infection, which leaves exposure. If the rate of exposure is greater than the rate of spontaneous loss then you would get an increase in prevalence with age. I suspect (hope!) exposure is higher in children for behavioural reasons than in adults so you will get a levelling out of prevalence with age to a point where the rate of new infection balances the rate of spontaneous loss. If exposure stays high then this plateau may not be reached.

So why are other parasites different? Probably there is immunity leading to clearance of the infection in children.

Certainly, we have quite good data from Ireland indicating that once established, Blastocystis will keep colonising the GI tract for ages (i.e., many years). Regarding loss, I hope that I'll soon be able to refer to some data that we have obtained in a study on experimental animals.

Exposure is obvisouly something to think about - Blastocystis is transmitted by ingesting food/drink contaminated with Blastocystis and/or improper hygiene. The fact remains that studies using molecular methods for detection have identified most children in Sub-Saharan African study populations as being colonised, while in more developed countries, parasites such as Dientamoeba fragilis are more common in toddlers and smaller children; Blastocystis emerges and gains in prevalence only in teenagers and older individuals... roughly speaking.

One aspect of colonisation that I've been very interested in myself, is whether it's each individual's gut microbiota that "decides" whether Blastocystis colonisation/infection establishes upon exposure. We are seeing some data emerging from a couple of labs on this, and maybe next month I'll be able to bring you up to speed in this matter. To my knowledge, there is not a lot of precedence–if any–for such a situation, but the fact that we have seen quite clear differences in gut microbiota patterns between those who have Blastocystis and those who have not, has left me thinking...

If you want to contribute to the discussion, please drop a line. 

References:

Blessmann, J., Ali, I., Ton Nu, P., Dinh, B., Ngo Viet, T., Le Van, A., Clark, C., & Tannich, E. (2003). Longitudinal Study of Intestinal Entamoeba histolytica Infections in Asymptomatic Adult Carriers Journal of Clinical Microbiology, 41 (10), 4745-4750 DOI: 10.1128/JCM.41.10.4745-4750.2003

Scanlan PD, Stensvold CR, Rajilić-Stojanović M, Heilig HG, De Vos WM, O'Toole PW, & Cotter PD (2014). The microbial eukaryote Blastocystis is a prevalent and diverse member of the healthy human gut microbiota. FEMS microbiology ecology, 90 (1), 326-30 PMID: 25077936

Parasite-Microbiota-Host Interactions

One of the current mantras in microbiology is that 'bacterial cells in the human body outnumber human cells 10 to one'. This has been known for a long time, but I guess that the main reason why this is being hyped nowadays is due to the fact that current technologies now enable us to look at entire microbial communities in a given ecological niche at any time point and how for instance they relate to health and disease.

Casadevall and Pirofski already made this point clear back in 2000 in their great minireview in the journal Infection and Immunity on 'Host-Pathogen Interactions: Basic Concepts of Microbial Commensalism, Colonization, Infection, and Disease'. This is a great paper that helps us understand and distinguish between the many ways microbes impact on our body. First and foremost, it allows us to understand that microbes can be commensals in some hosts but cause disease in other hosts, and that very few microbes are obligate pathogens.

Anatomical drawing of abdomen, ca. 1900 (Elisa Schorn). Source.

Commensalism is defined by these authors as 'a state of infection that results in either no damage or clinically inapparent damage to the host, though it can elicit an immune response'. And a commensal is a 'microbe that induces either no damage or clinically inapparent damage after primary infection; a state that is thought to be established early in life'. In terms of the antibody response, 'it is not known whether these immune responses reflect the occurrence of an unidentified form of damage to the host'. Importantly, 'commensals also synthesise metabolites that are essential nutrients for the host'.

According to Casadevall and Pirofski, colonisation is 'a state of infection that results in a continuum of damage from none to great, with the latter leading to the induction of host responses that could eliminate or retain the microbe, or progress to chronicity or disease; for organisms that induce no damage during infection this state is indistinguishable from commensalism'.

I guess that to this end comes the concept of tolerance...Some single-celled parasites are common in young mammals such as calves and lambs (for instance Cryptosporidium and - it appears - microsporidia (unpublished data)), but appear to be cleared by host immune response mechanisms, while other parasites are establishing chronic colonisation, - parasites such as Entamoeba and Blastocystis. The latter parasites may also colonise humans for years on end... So why do we not eliminate these parasites? Blaser writes back in 1997: 'Failure to eliminate the parasite implies that the cost to the host is greater than the benefit. This may be due to high costs (e.g., loss of vital (...) functions), or significant benefits (e.g., protection against lethal diseases), or that both cost and benefit are relatively low'.

In Blastocystis research most scientists appear to be preoccupied by identifying a role for Blastocystis in disease, driven by the black and white concept that either it's pathogenic or not... or at least that if it can cause disease, it's by definition a pathogen! I think the paper by Casadevall and Pirofski shows with great clarity why we should try and take a much more differentiated view on Blastocystis and it's role in health and disease.

As mentioned in a previous blog post, Blastocystis is practically an obligate finding in some societies, while more rare in others. In some communities it may be common to contract it in very early childhood (infants/toddlers), while in other communities you may not be infected or infected only in adulthood. In Denmark, the prevalence in the healthy adult population is about 30%, and there may be countries where the prevalence is even lower - typically in regions, where the general population has been 'intestinally defaunated' (presumably due to excessive hygiene combined with a Westernised diet). And so, in some places this parasite is getting so uncommon that it may at some point become a cause of disease, a so-called 'emerging pathogen'... Conjectural maybe, but still not far fetched.

Simultaneously, evidence is emerging that intestinal microbial eukaryotes (Blastocystis and Dientamoeba fragilis) are significantly more common in healthy individuals than in patients with gastrointestinal disease such as IBS and - especially - IBD, suggesting that these parasites are protective of functional and organic bowel disease. Do they prime our immune system in a beneficial way? Do they select for beneficial bacteria? Do they keep potential harmful microbial intruders at bay? Could they be synthesising metabolites beneficial to the host just like ciliates involved in fermentation processes in the large intestine of various herbivorous mammals?

This is why the exploration of the structure and function of intestinal pro- and eukaryotic communities is so important. For instance, can we link Blastocystis to any intestinal microbial patterns? At our lab, we think we can, and it's something that we will try and explore further (if funding can be obtained). Our null hypotheses include the following:

1) The distribution of pro- and eukaryotes is random (for instance: Blastocystis is not statistically associated with the presence of particular bacteria or other eukaryotes (fungi, parasites)).

2) The introduction of a Blastocystis strain into an intestinal microbial niche does not cause alteration of the composition of the pro- and eukaryotic flora. This can be studied using an animal model, and it is tempting to try and study host immunological parameters during and after challenge with Blastocystis. Also gene expression in both host and microbial communities could be studied.

Take home message is that we should be cautious with regard to deeming a parasite as being either 'pathogenic' or 'non-pathogenic'... parasites may have a multitude of functions and may impact their hosts in a variety of ways that together with all other types of impact from and interactions with other microorganisms (microbiota) results in a health/disease matrix in every single individual.

Finally: Here's to pageview # 200,000! See you in Boston on Sunday morning at the #ASM2014 conference: Passion for Parasites !

Literature:

Blaser, M. (1997). Ecology of Helicobacter pylori in the human stomach. Journal of Clinical Investigation, 100 (4), 759-762 DOI: 10.1172/JCI119588  

Casadevall, A., & Pirofski, L. (2000). Host-Pathogen Interactions: Basic Concepts of Microbial Commensalism, Colonization, Infection, and Disease. Infection and Immunity, 68 (12), 6511-6518 DOI: 10.1128/IAI.68.12.6511-6518.2000