Recent surge in studies on human-associatedtriggered a major transition in our understanding of human biology. Some outright inaccurate concepts such as the terms bacteria and pathogen/germs being used interchangeably are deservedly poised for erasure. Though unfortunately enshrined as a standard in biology textbooks and even more so in popular culture, increasing knowledge of human-associated microbiota renders such utterly false equivalence moot. OTOH, compared to human-associated microbiota, our knowledge of human-associated eukaryotes is even more in its infancy. Human-associated eukaryotes include fungi, , and (platyhelminths/flatworms and nematodes/roundworms). Reflexively dismissed as undesirable even when routinely found in normal people, modern medicine considers human-associated protists and helminths a priori harmful/pathogenic and uses drugs to remove them ( , , 3, 4). Thus, protists and helminths stand practically eliminated within humans in industrialized countries even as their rates of allergies, autoimmunity and inflammatory diseases have spiraled out of control over the past half century.
Just as these skyrocketing rates of dysregulated immune function forced a conversation about the need to distinguish bacteria from pathogen so too our understanding of what constitutes a beneficial/neutral eukaryotic partner versus a parasite may need similar revision. What started with microbiota is now slowly but inevitably expanding to eukaryotes. As with bacteria, far from being only harmful, research is uncovering that the diverse set of protists and helminths found in our bodies, guts in particular, may be essential for
- Training and maintaining balanced immune function, a corollary of their effort to resist expulsion from the body.
- Helping maintain diverse, beneficial microbiota, for e.g., by influencing the amount and composition of gut-associated mucus, the substrate that’s the soil for gut microbes.
After all, the gut is a major niche for not just commensal bacteria but also eukaryotes. Mammals evolved with bacteria and eukaryotes as coadapted partners. Modern sanitation, lack of close contact with farm animals, and antibiotics are some of the recent major changes that profoundly disturbed these ancient relationships. Of course, it’s crystal clear in hindsight that the fallout has been self-inflicted damage to human health.
Some Human-Associated Protists And Helminths
is a common protist found in 10 to 100% of surveyed individuals, frequently in those who are healthy (5, , , , ), and with a lower prevalence in inflammatory bowel diseases. For e.g., an European study found a lower prevalence of Blastocystis in active ulcerative colitis (UC) patients ( ). Protists such as Blastocystis and Dientamoeba may also be beneficial for immune function ( , ).
Helminths are worms associated with humans over evolutionary time. Many of them can’t replicate within their host but rather co-exist through their extensive manipulation of the host’s immune function. High helminth colonization and low prevalence of allergy, autoimmunity and inflammatory diseases appear to go hand in hand among rural residents in less industrialized countries (, ), a cornerstone of the . Epidemiological studies have in fact consistently observed that IgE-mediated hypersensitivity is rare in tropical areas endemic to worms ( ). Helminths such as can transiently colonize the human colon. OTOH, , a geohelminth colonizes pig colon ( ). Geohelminth means fertilized eggs require several weeks of incubation in moist soil. This renders such worms incapable of direct human to human transmission, i.e. safer for therapeutic use. Staying confined to the GI tract producing a self-limited colonization, T. suis eggs (TSO) have been used in a number of clinical trials ( , ).
Some intestinal eukaryotes are indeed pathogenic. Examples are protists such as Cryptosporidium and Entamoeba histolytica, and helminths such as Ascaris lumbrocoides and Strongyloides stercoralis (). However, cheek by jowl with the far more voluminous literature on how to get rid of such pathogens is a tiny but growing one on the Eukaryotome ( ) or Eukaryome ( ), i.e., the more commensal/benign/neutral ‘normal’ eukaryotic inhabitants of the human GI tract.
Human Clinical Trials With Helminth Eggs: Some Successes With Autoimmune And Inflammatory Diseases
Since at least 2000, a few pioneering clinical trials have assessed whether seeding guts with live helminth eggs can reverse allergies, autoimmunities and inflammatory diseases. While such studies showed poor outcome for allergies (, , ), they’ve had remarkable success in autoimmunity and IBD (inflammatory bowel disease), achieving remission ( , 24) in MS (multiple sclerosis) for example, and reversal of symptoms in Crohn’s ( , ), UC ( , ) and coeliac disease. Why then aren’t such Rx becoming more mainstream? A range of factors.
- Convincing patients to swallow live ‘parasite’ eggs as Rx is understandably difficult and therefore fraught with failure.
- Regulatory barriers are higher for such live Rx. For e.g., the US FDA currently defines helminths as ‘drugs’, i.e., requiring as high and rigorous validation standard including a thorough pharmacokinetic study as for chemical agents. Contrast with leeches and maggots which the FDA considers ‘medical devices’, i.e., relatively low standard for approval (29).
- More difficult to ‘manufacture’ such live Rx to scale using standardized procedures and maintaining high quality control.
These are some of the reasons big pharma has evinced little interest in investing effort to translate such promising preliminary trial data into large scale therapies, and only small biotechs such as Coronado Biosciences, now renamed Fortress Biotech, even invested some effort into this research. Meanwhile academic researchers have begun identifying helminth molecular entities that could recapitulate some biological outcomes of worms and their eggs (29). One of the best studied such entities is ES-62, a 62 kilo dalton excretory/secretory (ES) protein purified from the rodent filarial nematode Acanthocheilonema viteae (). However, traveling down such a road brings another set of potential problems.
- Through evolutionary time, we coadapted to a wide variety of protists and helminths. We have scarcely scratched the surface of this association. How well could a purified moiety from one such organism recapitulate the whole, which is often more than the sum of its parts?
- Typically allergies, autoimmunities and inflammatory diseases we seek to redress through such therapies are each themselves multitudes, grouped together under one name simply for convenience when they’re in fact separate diseases. A particular working in particular subsets rather than in entire groups of patients may simply reflect that unaddressed reality.
- Certain helminths paired with certain groups of people over evolutionary time. However, currently we are far from understanding this eukarytome/eukaryome landscape across the global human population, let alone which helminth optimally pairs as Rx for which allergy/autoimmunity/inflammatory disease. If a certain pairing fails, it may be just as likely from poor pairing choice rather than failure of the approach itself.
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