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Archive for the ‘Evolution’ Category

As the popularity of an evolutionary approach to wellness grows, the belief that everything can be fixed with an appropriate diet and exercise plan seems to diminish. While eliminating Neolithic components of the diet that humans don’t thrive on and participating in physical activities that challenge and benefit our bodies are vital elements of wellness, it’s becoming increasingly obvious that food and movement alone do not a healthy body make.

One of the big topics du jour in the paleosphere and in scientific research is the role of an appropriate gut microbiome in health and wellness. I’ve written about it a bit in some of my past posts on the appendix and breast-feeding, and it seems like you can’t surf too far on the paleo interwebz without seeing something about how to feed, nurture, or modify your microbiome. Having the right little guys inhabit your gut is important as commensal bacteria are capable of utilizing molecules that we can’t otherwise metabolize (turning them into compounds we can use), are capable of making vitamin K which we need to thrive, and they outcompete nasty bacteria that cause disease. Also, as mentioned in one of my posts on the appendix, a healthy and appropriate gut microbiome is probably essential in keeping the immune system appropriately occupied so that it doesn’t get bored and start attacking our own body.

But there’s more to a healthy human biome than bacteria. If we imagine out large intestines as something akin to the Great Plains, I imagine our bacteria as the diverse species of rodents that run around and occupy their little niches. Mice, voles, prairie dogs and beavers- they all play their part in keeping that ecosystem healthy. There is another creature, however, one much larger that once roamed those grassy prairies. The Bison were a keystone species of the Great Plains: their grazing and migration helped maintain the native prairie and shape the environment. Much as the buffalo were almost eradicated by modern civilization, the keystone species of our intestine- parasites such as helminths- have all but disappeared in the modern world.

In my first year of medical school I attended a seminar by one of the faculty in our immunology department where he discussed the role of intestinal parasites in appropriately priming the immune system. The human body did not evolve in a sterile bubble; it coevolved with bacteria and intestinal parasites. This means that our immune system has been selected to function in (and indeed is optimized for) an environment where we interact with parasites. Similarly, while there are definitely situations where parasites are problematic (when in the wrong host, or when infections occurs on top of other disease or malnutrition, and when the parasite burden is too high), parasites have not evolved to be overly harmful to their host. A parasite that kills its host is an evolutionary dead end.

It turns out that internal parasites significantly modulate our immune system. The gut is especially rich in immune tissue, specifically GALT (gut-associated lymphoid tissue) as mentioned in previous posts. Helminths secrete a multitude of molecules, including protease inhibitors, cytokine homologues, and a number of other compounds that alter T-cell function. These molecules down-regulate the host’s immune system. While the idea of down-regulating our immune system may make some wary, remember that this is a relationship that our immune system (indeed, probably the immune system of all mammals) evolved to handle. In fact, our rather unique modern environment, in which our immune system is no longer occupied with intestinal parasites, might be considered as something of an evolutionary arms race that has suddenly gone unopposed.

This theory is supported by a number of interesting findings, both in people living in pre-industrial cultures who are chronically exposed to parasites, and in those of us living in the hygienic modern world where our immune systems have become a bit out of whack. In Africa, children living in rural communities carrying chronic parasite infection have a shorter course of asthma (a condition caused by inflammation of the respiratory tract) [1]. Similarly, a study in children in Gabon demonstrated that chronic parasite infection decreased the immune response to common allergens such as dust mites [2, 3]. In these situations, carrying parasites appears to mitigate or prevent an abnormal immune response.

In the developed world, where hygiene and pharmaceuticals have all but eliminated human parasites, we are starting to recognize conditions that may occur as a result of an immune system with a well-developed arsenal and no enemy to use it on. One interesting and promising example of this was an experimental trial where individuals with Crohn’s disease were infected with porcine whip worms (used because they are self-limiting and do not leave the intestine) in an attempt to otherwise occupy an immune system that had turned on its host. While the trial was limited in size, the results were resounding. Almost 80% of participants saw a decrease in disease severity, with 72% seeing a remission of disease [4]. In another study, patient with multiple sclerosis who were also infected with intestinal parasites had significantly fewer adverse events and diminished disease progression in comparison to those free of parasites [5]. Furthermore, experiments utilizing animal models of immune-regulated diseases such as colitis, type 1 diabetes, arthritis, and allergies also show promising results that appropriate parasitic infection may prevent these conditions.

Principle into Practice

Reconstituting the human biome in order to control the epidemics of allergic and autoimmune diseases has been suggested. Much like some other things I’ve written about, there’s a certain ‘gross factor’ that some people find uncomfortable when you start to suggest that everyone should have a domestic helminth residing within them. Perhaps the idea of reconstituting the cocktail of secreted compounds that helminths produce to modulate our immune system is a little more appealing, but the problem here, as with so many other aspects of biology, is that we are only just starting to understand the complex interaction between our immune system and the parasites they were ‘designed’ to control. With only a limited understanding, how can we hope to fully and correctly mimic biology? Furthermore, the understanding that normal parasites, which we evolved with over hundreds of thousands of years, actively alter the functioning of our immune system makes us realize that almost all our research on the immune system has thus far focused on the very evolutionary-novel depopulated gut.

There is a fantastic paper that was published last year in ‘Medical Hypotheses’ (it’s probably time for me to admit that “Publish in ‘Medical Hypotheses’” is one of the few items on my bucket list) entitled Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases [6]. If you’re interested in this subject, I highly recommend you give this paper a look. I particularly like their statement that:

“Just as we have the option of safely utilizing proper diet and exercise regimens to give our cardiovascular system what it has evolved to require, it is expected that, far more effortlessly, we can safely utilize selected organisms to give our immune system what it is evolved to require”.

Parasites are definitely not something to be ignored or downplayed. While I’ve focused here on the role these interesting creatures can play in health and wellness, parasites can also be the source of illness and disease. For the most part, a low or moderate burden of normal human parasites in an otherwise healthy individual seems to be benign, if not helpful. Problems arise, however, with some non-human parasites and in unwell individuals. Porcine whipworms are a useful model for studying the effects of parasites in humans because they elicit an immune response, are limited to the intestines, and are self-limiting (you have to keep dosing yourself every 2-weeks if you want to sustain an infection). On the other hand, some parasites that did not evolve with humans as their host are not always so well behaved. Perhaps the best-known pathogenic parasite infections are those that occur with non-human parasites that exit the intestines. Parasites evolved with their host, and as such have a bit of a built in road map as to where they should migrate within their normal host. Unfortunately, in the wrong host, this road map can take parasites very seriously off course. Cysticercosis is a condition that occurs when humans are infected with pork tapeworm that encyst in different parts of the body, including the brain in a condition known as neuro cysticercosis. Similarly, if humans pick up the raccoon roundworm Baylisascaris procyonis, the course is frequently fatal because of damage caused during the parasites’ migration throughout the body. A good parasite does not want to kill its host- doing so would be self-destructive- but in the wrong host parasites can go awry. Nonetheless, ‘domestication’ of appropriate human parasites and their prophylactic or therapeutic use may one day be an important and normal part of modern wellness.

1.            Medeiros, M., Jr., J.P. Figueiredo, M.C. Almeida, M.A. Matos, M.I. Araujo, A.A. Cruz, A.M. Atta, M.A. Rego, A.R. de Jesus, E.A. Taketomi, and E.M. Carvalho, Schistosoma mansoni infection is associated with a reduced course of asthma. J Allergy Clin Immunol, 2003. 111(5): p. 947-51.

2.            van den Biggelaar, A.H., C. Lopuhaa, R. van Ree, J.S. van der Zee, J. Jans, A. Hoek, B. Migombet, S. Borrmann, D. Luckner, P.G. Kremsner, and M. Yazdanbakhsh, The prevalence of parasite infestation and house dust mite sensitization in Gabonese schoolchildren. Int Arch Allergy Immunol, 2001. 126(3): p. 231-8.

3.            van den Biggelaar, A.H., R. van Ree, L.C. Rodrigues, B. Lell, A.M. Deelder, P.G. Kremsner, and M. Yazdanbakhsh, Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet, 2000. 356(9243): p. 1723-7.

4.            Summers, R.W., D.E. Elliott, J.F. Urban, Jr., R. Thompson, and J.V. Weinstock, Trichuris suis therapy in Crohn’s disease. Gut, 2005. 54(1): p. 87-90.

5.            Correale, J. and M. Farez, Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol, 2007. 61(2): p. 97-108.

6.            Bilbo, S.D., G.A. Wray, S.E. Perkins, and W. Parker, Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases. Med Hypotheses, 2011. 77(4): p. 494-504.

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As my last post may have suggested, I’ve recently been taking a deeper look at the large intestine – specifically the appendix. The appendix is a small, intestinal, diverticulum (basically a little pouch) that protrudes off the cecum (the first part of the large intestine, itself a little pouch- though much bigger than the appendix). You may have heard (and indeed, at the time of writing, Wikipedia has it written) that the appendix is a vestigial structure- a now useless remnant of something that was useful to our ancestors. Darwin actually helped propagate this belief, theorizing that the appendix was a shrunken remnant of a larger cecum. Furthermore, the relatively common and apparently benign surgical removal of the appendix, the procedure known as appendectomy, seems to support the idea that the appendix is of no particular use to humans today.

But is it?

There is an increasing body of information supporting the idea that the appendix is not a vestigial structure and that it has a specific role in human health. This might get a bit lengthy, so I will approach this topic in stages- probably culminating in a few posts.

First things first- is the appendix really vestigial? As I mentioned above, Darwin believed that the appendix was vestigial. He came to this idea because of the (erroneous) belief that hominids were the only primates to possess an appendix. Other primates that eat vast quantities of leaves and fibrous material that needs to be fermented by gut microflora, have large cecums where fermentation can occur. Humans, who don’t rely on copious vegetation for nutrition, only have a small cecum. It was thus hypothesized that the appendix was the shrunken remains of our forbearers’ large cecum. What Darwin was missing, however, was the fact that a number of species, including many primates, have large cecums and ALSO have an appendix. Hmm…

Another clue that the appendix is not simply the excess baggage of our herbivorous forbearers is that according to phylogenetic analysis, the appendix has actually arisen at least twice, independently, in evolutionary history. Such research also suggests that the appendix has been maintained in mammalian evolution for 80 million years [1]. To have evolved twice, independently, and to have been maintained for 80+ million years, suggests the appendix is not a useless remnant.

If the appendix is not vestigial, what is its function?

The dual evolution of the appendix, and the occurrence of an appendix in species with large cecums suggests that the organ plays an important role in normal physiology. Anatomically, the appendix is found at the end of the cecum, in a rather secluded corner of the intestines (if you can imagine such a thing). While the length of the appendix varies greatly from human to human, the diameter remains relatively constant. Another constant is the appendix’s association with a large amount of immune tissue known as GALT (gut-associated lymphoid tissue). While most people tend to think of immune tissue as ‘bacteria-fighting’ stuff, it turns out that some immune tissue produces substances (such as secretory IgA and mucin) that actually support bacterial growth, specifically the growth of biofilms.

Biofilms have been the focus of quite a bit of research recently, and usually not in a good way. Because people tend to think of biofilms (literally aggregates of bacteria embedded in self-produced slime) as pathogenic and problematic conglomerates, the focus of most research has been how best to disrupt and destroy them. It’s not entirely unwarranted either, Biofilms tend to be associated with unpleasant conditions, such as infections of medical implants and dental plaque. However, biofilms of commenselate bacteria (the ones we evolved with, on our skin and in our gut) are a way of safeguarding good bacteria.

When this is all put together, it appears that the appendix, with its relatively constant diameter and with the secreted products of GALT, is well adapted to facilitate and maintain communities of mutualistic intestinal flora [2]. It has thus been theorized that the appendix can act as a source of normal microbiota that can inoculate the gut when needed.

Why would your gut need to be inoculated with normal microbiota? Isn’t that what’s already in your gut?

It has been suggested [2, 3] that the appendix acts as a ‘safe house’ for resident microbiota when a GI infection occurs. When disease-causing bacteria are flushed from the intestines by diarrhea, the normal bacteria are eliminated as well. The appendix safe-guards a population of the normal bacteria that can then repopulate the large intestine after the diarrhea has passed. This function may not seem too important today in the developed world, where we enjoy relatively good hygiene and relatively low levels of epidemic diarrhea, but in the not too distant past and in populations that still suffer from diseases such as cholera, the appendix likely plays an important role in recovering from diarrheal diseases.

While the appendix offers benefits if you live in a developing country, it is less important (though not entirely so- I’ll get to that later) in developed countries with modern hygiene practices such as water treatment and sewage systems. In fact, in the developed world, the appendix has become a bit of a liability, with a surprisingly large portion of the population developing appendicitis at some point during their life. In my next post I’ll discuss the appendix in disease and health, and probably wax poetic about how we should consider this interesting little organ in our modern environment.

1.            Smith, H.F., R.E. Fisher, M.L. Everett, A.D. Thomas, R.R. Bollinger, and W. Parker, Comparative anatomy and phylogenetic distribution of the mammalian cecal appendix. J Evol Biol, 2009. 22(10): p. 1984-99.

2.            Bollinger, R.R., A.S. Barbas, E.L. Bush, S.S. Lin, and W. Parker, Biofilms in the normal human large bowel: fact rather than fiction. Gut, 2007. 56(10): p. 1481-2.

3.            Laurin, M., M.L. Everett, and W. Parker, The cecal appendix: one more immune component with a function disturbed by post-industrial culture. Anat Rec (Hoboken), 2011. 294(4): p. 567-79.

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