The Macrobiome and Mycobiome in IBD: A Look at the Role of “Dirty Old Friends”

A very recent paper, published just this past May, caught my eye because of its title:  “Inflammatory bowel diseases, the hygiene hypothesis and the other side of the microbiota: Parasites and fungi.”[i]  How often on this blog have I talked about the incredible complexity of the human biome?  This paper was a very interesting read on this topic, so I definitely want to share some highlights.

It starts with one of the best explanations of “evolutionary mismatch” I have ever read:  “According to this concept, an organism that evolved in a given environment might be maladapted to a novel, different environment.  In other  words, a mismatch in the conditions in which we live today, compared to the conditions in which our genes and bodies had been shaped by natural selection, might imply that several hereditary traits are maladapted; this, in turn could lead to overall perturbances in homeostatic equilibrium.”  It goes on to point out that, until the industrial revolution – microseconds away in evolutionary terms – we lived in conditions essentially similar to those of wild animals.

To sum up:  “Co-existence with parasites, and with a variety of other ‘almost-pathogenic’ microorganisms, is thus to be regarded as the normal condition for our ancestors…we humans evolved in a type of environment that no longer exits, and are now living in a radically different condition: we are experiencing an evolutionary mismatch.”

Dr. William Parker of Duke University, a foremost authority on the immunology of helminth colonization, talks about this concept over and over in his papers.  Read a couple of examples here and here.

Here are a few super interesting facts from today’s paper:

A.  Inflammatory bowel diseases were among the first pathologies to be associated with alterations in the microbiome.  One of the papers referenced in this section dates back to 1991 in fact, even before more modern lab techniques were developed to look at the microbiota.  Noted 30 years ago were the fact that bacteria like Desulfovibrio species (I have written about this too)  were at increased levels in those with IBD.

B.  There is now very strong evidence that the bacterial microbiota is heavily influenced by the presence (or lack of the presence) of other components of the biome, including protozoa, fungi and helminths. In turn, the bacterial components influence them right back.  And of course, ALL these critters are influenced by diet and other lifestyle factors.

C.  Some interesting facts about fungi in IBD:

1. 1. Studies seem to indicate that Candida albicans might “represent the true gut symbiotic fungi.” The two species Sacchromyces cervesisiae and restricta may or may not be as well – research is ongoing.
   2. Recent research shows that dysbiosis of the mycobiome, including overgrowth of Candida species, is correlated to IBD, as well as other diseases including ulcers, antibiotic-associated diarrhea, hepatitis, etc. An increase in albicans are known to be associated with inflammatory flareups in IBD.  The relationship of alterations to the mycobiome is pretty well established in IBD.  In fact, in those with Crohn’s disease, an increase in antibodies to fungal targets has been seen BEFORE the disease diagnosis!
   3. Other research has shown a positive correlation of S.cervesisiae to bacteria, including Bifidobacterium, Roseburia, etc. These kinds of bacteria are highly anti-inflammatory and are at low levels in those with IBD, especially during flare ups.
   4. Likewise, there is a positive correlation, between the abundance of the fungi, tropicalis, which is significantly increased in IBDs, and potentially pathogenic species like E.coli, and these worked together to create a protective (to themselves) biofilm. I’ve written about this before, here.
   5. Metabolites of bacteria, including short-chain fatty acids, keep C.albicans in check. (Reminiscent of  my last post on proteobiotics, right?!.)

D.  Most of the info in the paper about the macrobiome (helminths) is stuff I have covered in past posts, but a quick refresher:

1. 1. Helminths stimulate the Th2 family of cytokine which “…promote rapid intestinal epithelial cell turnover, mucus production and increased gut motility…” along with increased production of regulatory cytokines, which modulate the inflammatory response, promote wound healing and intestinal repair.
   2. “Numerous studies support the hypothesis that helminths are able to induce beneficial effects to modulate IBDs, both directly and/or indirectly.” The former is by suppressing the production of damaging inflammatory cells, responsible for maintaining inflammation in IBD.  The latter is by modulating the gut bacteria, thereby reducing the inflammatory response.  They reference several papers in which demonstrated this beneficial effect on the gut bacteria.  (As just one example of many on The Biome Buzz, you can read more about this here.)
   3. Different helminths appear to have somewhat different effects, likely because they excrete different metabolites; they appear to affect the levels of different probiotic bacteria. A couple of examples:  Necator americanus (hookworm), for example, seems to promote the growth of Lactobacillus and of SCFA-producing species.  An antigen produced by the helminth, Hymenolepis diminuta, seems to ameliorate colitis in a rodent model.  (You can read way more about this here.)

The authors point out, by the way, that other organisms, like protozoa, also undoubtedly play a critical role in the whole picture but were beyond the scope of this paper.  (And don’t forget archaea too!  And wait…how about the virome?! Seriously…the complexity is enough to boggle the mind.)

So, the conclusion?  “There is now convincing evidence that a correct shaping of the immune balance requires some type of contact with parasites, and with a varied microcosm of gut-dwelling microorganisms, or perhaps even with just transient, but frequent, “gut-passengers.  The so called dirty old friends.”  They authors go on to state that obviously we are not going to go backwards and live in non-hygienic circumstances. They believe it would be difficult to “…imagine an extensive use of worm therapies,” and think the way to go is pharmaceutical products made from the excretions of helminths.  I find that ironic in that, the whole paper talks about the incredible complexity of the interactions between all these native members of the human biome.  Isolating one or two chemicals is hardly a replacement for the living interactions going on between all these organisms.  It would be like saying that the droppings of birds in the woods is a replacement for their actual presence in the ecosystem of a forest, no?   They suggest the same, by the way, for fungi:  “We are still far from applications, but the prospects are encouraging, for a future in which molecules derived from parasites and fungi will vicariate the disappearance of our dirty old friends, helping us in the maintenance of a healthy gut.”

Maybe I’m wrong and “sterile” pharmaceuticals will work but…you can’t fool Mother Nature, can you?

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[i] Panelli,  S, et. al.  Inflammatory bowel diseases, the hygiene hypothesis and the other side of the microbiota: Parasites and fungi. Pharmacological Research. 2020;159. https://doi.org/10.1016/j.phrs.2020.104962