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Archive for March, 2012

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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Medicine of the mind

While I am a medical student, the purpose of this blog is not (or at least it wasn’t when I envisioned it) to blog about my journey through med school. One of the first blogs I remember reading was called ‘Over my med body’ and it was a brilliant blog written by a (then) medical student. I’m sure there are blogs out there of med students telling their tales on the floors, but that’s not what I want to write about. I realize, however, that over the next couple years I will go through things that most people will never experience. I’m seeing things that people only hear about third hand or see dramatized on TV. Occasionally it might be fit that I share my experiences. Now is one of those times.

 

I’m currently on my Psychiatry rotation. I don’t wish to openly discuss the medical school I attend, but I’m currently doing a clerkship at a public hospital in one of the poorest cities in the country. In general, the people that we attend to are uninsured or underinsured. There are high rates of chronic disease such as diabetes and hypertension, infectious disease such as HIV and TB, and extensive drug use. Learning medicine in this kind of environment is learning medicine in the trenches- it is one hell of an education.

 

I’ll admit that I’ve always been a bit intimidated by psychiatry. I’m in awe of the brain, specifically its ability to control such complex tasks with the use of limited resources. When it comes to neurotransmitters, there really aren’t that many. The brain effectively controls all our thoughts and actions with an incredibly limited vocabulary (5 neurotransmitter “words”: GABA, glutamate, dopamine, serotonin, and acetylcholine). I’m amazed it works in the first place, and I’ll admit that I’ve long been apt to think “Glad you work- let’s leave well enough alone” when it comes to contemplating the brain. Of course, just because something is hard to study, doesn’t mean it shouldn’t be studied. Indeed, that’s the point a fellow MD/PhD student made to me when he tried to wipe the look of surprise off my face when he said he was going into psychiatry. We need more great minds in psychiatry- the specialty is lucky to have him!

 

If you’re interested in an evolutionary approach to psychiatry, you MUST check out Dr. Emily Dean’s fantastic blog (please do- it would be the least I could do to send a couple clicks to her blog when she refers so many to me!). There’s a lot to think about and talk about when it comes to an evolution-based approach to psychiatry, and while I think that good nutrition, good sleep, good exercise, and good stress-management are all important for good mental health, I’m going to leave the tricky stuff to Emily.

 

Now, after a lengthy preamble, I get to the crux of the matter- my insight from the floors.

 

As one might imagine, the inpatient psychiatric ward at a public hospital in a poverty and drug-stricken community is… intense. I’ll admit to being thrown a bit off kilter by the bustle and (apparent) mayhem on my first day on the floor. You know you’re in a bad way when a fully psychotic patient gives you a look and asks ‘Are you ok?’. Aren’t I meant to be asking that question? Just how pale and wide-eyed am I? Inpatient psyche in this setting is not your aunt’s depression, or your roommate’s mania (not to belittle these conditions). The people we see on the floor are there voluntarily or involuntarily for a variety of reasons, but most frequently for schizophrenia, suicidal ideations or attempts, debilitating anxiety and depression, and/or delusions (frequently a combination). These patients are fascinating, and heart breaking. Some have insight into their condition (they understand that they have a mental illness), but many do not. On this floor you see how obsession can drive you to depression, and then to attempts to take your own life. You can see how delusions lead people to circumstances where they are at risk of hurting themselves and others. You see paranoia that cripples a person. These descriptions do not do the patients justice, but I don’t think any description would. It is something that has to be seen to even start to understand, and I am very grateful I have that opportunity.

 

Seeing these situations first hand is eye-opening. As I said, the first day I found myself overwhelmed. The psyche ward is a very different experience than medical wards. On medical wards, most patients are confined to their bed. You might see the odd patient out wheeling their IV around, or being taken for a walk around the floor by a therapist, but the halls are generally restricted to nurses, students, doctors, and visitors. The psyche ward is very different. These patients are almost all able bodied, and being out and about is good for them- many reap benefits from the group activities and sessions. We don’t want these patients in bed, but having them all up and about makes for a very interesting dynamic. It can get loud, it can get rowdy, and if you don’t know the patients, it can get scary (it can get scary when you know them too).

 

As I said, the first day I was overwhelmed. I saw patients only with my resident and attending (though I did have a very long chat (a real education for me) with one of our patients about the different street drugs she had taken and the various routes of administration (I learned more in that 10 minute chat then I did in all the years of drug education)). The second day I was cautiously curious, occasionally going out on my own to talk to a patient or do a mini-mental status exam, then seeking refuge behind the Plexiglas and locked half-doors of the nurses’ station. By the third day I was visiting patients on my own, and checking in on them for updates before we rounded… I think that was the turning point.

 

Psychiatry, especially in this setting, is all about observation. A patient may tell you one thing, but what you observe can give you much more information. Also, getting ‘collateral’ from family members, admitting physician’s notes, and lab results is very useful. A patient may tell you that he was brought in by the police after he called to complain about his upstairs neighbors (who frequently steal his stuff) getting in an argument, but a family member may later tell you he lives in an attic apartment and has no possessions. Equally, someone may report visiting an outpatient clinic regularly, only to name a hospital that closed years ago. These patients aren’t lying- or at least they’re not trying to. This is their reality. An accurate history is important in understanding the full picture of a patient, but obtaining one from a psychotic patient is often impossible.

 

Mental illness is not cool. It isn’t popular or sexy. I’ve received countless requests to participate in or donate to all manner of ‘walk for the cure’ events for juvenile diabetes, cancer, heart disease… chances are you’ve donated to these things if you haven’t participated in them directly. It’s an easy sell- everyone knows someone with diabetes, heart disease, or cancer. This IS your aunt, your roommate, your neighbor, and your friend.

 

Maybe it’s just me, but I’ve never seen an event aimed at raising schizophrenia awareness. Chances are, you DON’T know someone with schizophrenia, though the prevalence is actually not that low (perhaps around 1 in 100). While we’ve made great progress at eliminating gender, racial, and sexual inequalities, there remains a great stigma around mental-health. The heart is a pump, the liver a processing plant… the brain is ‘us’ and a disorder that affects who we are, without other signs of disease, can be hard to comprehend and accept.

 

Sometimes in the world of evolutionary health and wellness we like to get lost in the utopian ideal that an evolutionary appropriate lifestyle will fix everything. Overweight? Type II diabetes? Acne? Infertility? We’ve got lifestyle-modifications for that. But there are very real and very devastating conditions out there that will not and cannot be fixed with a change of diet and exercise. I’ve found the last week of my education amazing on so many levels- the patients, the staff, the doctors, and the drugs… I am in awe. I’ll miss the ward (and I will be back), but I don’t think it’s where I want to practice in the long run. I am very happy, however, that bright minds are tackling these issues and that there are people dedicated to helping a population that is often unable to ask for help.

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‘Breast is best’ is the rallying cry of many who want to encourage mums to breastfeed their children, though some think the slogan should be banished. To those who wish to do away with the slogan, it’s not a matter of what is ‘best’ but a matter of ‘biologically normal’. I’ll admit to being rather nonplussed about slogans, but I am rather adamant that one should put trust in basic biology when possible.

 

Over the years, studies have shown correlations suggesting many benefits of breastfeeding, including increased IQ, decreased obesity, and a decrease in several pediatric ailments such as gastritis and ear infections in the offspring (I think those last two are particularly interesting). While these studies are interesting, they are just correlations, and I hate to put too much weight on correlative studies (though they can be fun to look at).

 

Biology is marvelously complex. As a result, studying it and then mimicking it is time consuming and tricky. I think breastfeeding is a wonderful example of a fascinating bit of biology that shows us how tricky it is to properly and fully study complex biology, and also shows us how humans have evolved to thrive on the ‘evolutionary norm’ (breastfeeding).

 

Breast milk is interesting stuff- though to be honest, some species have much more interesting milk than humans, with some species producing milk that changes in composition from day to day (and even different compositions from different nipples to feed different offspring!). While breast milk provides sustenance for an infant, it also helps develop the immune and metabolic systems of the offspring. The composition of breast milk can pass along information from mother to child, relaying information about the relative abundance or paucity of the environment in which the offspring will develop. This transfer of information, and the relative role of this communication in growth and development, is a fascinating area of research.

 

If people think about breast milk in the context of immunity, they generally think of the active transfer of antibodies from mother to child. The earliest milk produced by a mother, colostrum, is particularly rich in antibodies, and imparts great benefits to an infant. Even mothers that don’t wish to breastfeed extensively are encouraged to at least nurse in the early days of a neonate’s life so as to transfer these important antibodies. But is that it on the breast milk/immune system link?

 

In my last few posts I’ve touched on the importance of the gut in a number of immune mediated responses. The gut is actually rather rich with immune tissue, and fosters a number of bacteria (hopefully helpful and health-promoting ones) that help keep out nasty pathogenic invaders (and also helps keep the gut healthy in other ways, such as producing short chain fatty acids to nourish cells and producing Vitamin K). In my last few posts, I’ve talked about the appendix, and how it appears to have evolved as a safe house for our native microbiota in times of duress. But where do these bacteria come from?

 

Before birth, the intestinal tract of the fetus is thin and immature- lacking any significant lymphoid tissue. The intestine of a newborn develops substantial lymphoid tissue, which indicates the active bacterial colonization of the gut, altering its structure and function. There appear to be three phases of normal gut colonization in an infant starting with whatever flora are picked up during a normal vaginal delivery. The process of breast-feeding ushers in a second phase of colonization, with the third and final stage occurring at weaning. During colonization, it appears that infants generally inherit their mother’s microflora [1], and if all goes well- this is what will populate your appendix!

 

Any one with an eye to evolution might suspect that breast milk is exquisitely effective at producing healthy offspring- we’ve been making this stuff for hundreds of thousands of years… it is nuanced in ways we’ve yet to even think about. One thing we are starting to understand is that the composition of breast milk fosters a healthy microbiome in infants. In addition to the protein, fats, and carbohydrates that make up breast milk and nourish the child, there are a number of products present in breast milk that can’t be actively digested by the infant, but that are excellent fodder for a blossoming gut microbiome. These compounds are known as human milk oligosaccharides (HMOs- not the annoying health insurance type), and we’re nowhere close to identifying all the different types, though we know there are more than 100 different molecular structures. These molecules are resistant to gastric acid and aren’t absorbed or metabolized by the baby, and instead make it to the large intestine where they can be fermented by intestinal microflora. 

 

The gut microbiome of infants that are breast fed is quite a bit different from that of formula-fed babies. A number of studies have looked into this, and I don’t want to go into details of different studies, but there appear to be significant differences in the type and number of bacteria in the gut of these populations. Depending on the study, findings showed babies that had been breast-fed tended to have the same amount or more ‘good’ bacteria (Lactobacillus sp. and Bifidobacterium sp.) and less ‘bad’ bacteria (E. coli and C. diff (remember that guy from my last post?)). Breastfeeding probably helps set the microbiome up for success in a number of ways, including the direct transfer of bacteria from mother to child and also the transfer of maternally produced prebiotics that encourage appropriate bacterial growth. There’s also evidence that there is a significant difference in the pH of the large intestines of breast-fed vs formula-fed infants (an acidic pH in breast-fed infants vs a fairly neutral pH in those fed formula). I’m not sure how much of this is a result of appropriate bacterial growth, and how much that acidic pH then encourages more appropriate bacterial growth, but it’s fun to think about (it’s probably a nice little positive feedback loop).

 

Setting the neonatal microbiome up for success is just one of the many roles that breast milk has evolved to excel at. As mentioned above, breast milk is incredibly complex, and we are only starting to understand the many ways in which is sets an infant up to thrive (and not just survive). In the ideal world, all mothers would breast feed exclusively for 6 months, and then continue to breast feed while foods are introduced, but unfortunately, reality is not this easy. For some, formula is a necessity.  So how can we take what we know about breast milk and the infant microbiome and put this into practice?

 

In addition to the digestible micronutrients that are important for the proper growth of an infant, breast milk contains a vast array of non-digestible (but fermentable!) oligosaccharides that promote the development of a robust commensal microbiome. Knowing this, it seems appropriate to supplement formula with prebiotics that might equally foster the growth of appropriate microflora. There are a number of well-known prebiotics (perhaps the best known being inulin), but as we have yet to identify all the complex molecules in breast milk, we are unlikely to recreate the full spectrum of prebiotics offered by the ‘evolutionarily appropriate’ diet of an infant. Nonetheless, it appears that formula fortified (gosh I hate that word- if something needs to be fortified, I tend to think there’s a better, naturally more nutritious, option you should be consuming instead) with prebiotics might improve the gut microbiome in comparison to that of a regular formula-fed baby. A number of researcher groups have studied the effects of supplementation, with mixed results. Some have found positive effects of supplementation [2] (I’ll admit I’ve just read the abstract as I can’t read Chinese!) and some showing no difference [3]. This is not surprising, considering the complex nature of maternally produced prebiotics, but it does suggest that this is an avenue of investigation that should be further explored.

 

We are a long way off from making a formula that adequately and completely replaces breast milk. Like the gut microbiome (and growing infant!) that it nourishes, breast milk is extraordinarily complex, and we are only just exploring the tip of the iceberg of this massive subject. Nonetheless, realizing that breast milk helps promote a healthy microbiome (that you will hopefully keep for life!), which in turn helps develop a robust and appropriately directed immune system, should encourage researchers to further pursue this avenue of exploration. The more we learn about modern diseases, the more it appears that the integrity of the gut, and the functionality of the associated immune tissue, should be a central point of exploration for understanding disease.

 

1.            Kulagina, E.V., A.N. Shkoporov, L.I. Kafarskaia, E.V. Khokhlova, N.N. Volodin, E.E. Donskikh, O.V. Korshunova, and B.A. Efimov, Molecular genetic study of species and strain variability in bifidobacteria population in intestinal microflora of breast-fed infants and their mothers. Bull Exp Biol Med, 2010. 150(1): p. 61-4.

2.            Cai, J.W., Y.D. Lu, and X.M. Ben, [Effects of infant formula containing galacto-oligosaccharides on the intestinal microflora in infants]. Zhongguo Dang Dai Er Ke Za Zhi, 2008. 10(5): p. 629-32.

3.            Xia, Q., T. Williams, D. Hustead, P. Price, M. Morrison, and Z. Yu, Quantitative Analysis of Intestinal Bacterial Populations From Term Infants Fed Formula Supplemented With Fructo-Oligosaccharides. J Pediatr Gastroenterol Nutr, 2012.

 

 

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If you’re just reading my blog for the first time, I’d recommend you go back and read the last two posts where I talk about the fallacy of the appendix as a vestigial organ and how and why this organ sometimes goes off the tracks in our modern environment.

 

In this final installment on the appendix, I’d like to explore how we can take what we know about the appendix, consider it in an evolutionary light, and think about the practical implication of this knowledge. As discussed in my first post, it has been proposed that the appendix evolved as a safe house for the commensal microbiota that live in our gut. This safe house is useful in undeveloped communities where enteric pathogens are common, but is probably not so important (or may actually be problematic) in today’s hygienic world. A recent paper, however, challenges the idea that the appendix is no longer useful in our modern world.

 

Clostridium difficile (or as it’s referred to on the floor ‘C. diff.’) is an unpleasant little bacterium that causes a condition known as pseudomembranous colitis. Many people carry around some C. diff, but an overgrowth can occur after a course of antibiotics kills off other bacteria or after infection with a particularly nasty strain of C. diff. In these situations, serious colitis can occur. Infection with this bacterium can cause anything from mild diarrhea to fulminant colitis with shock and death. C. diff is the most common form of hospital-acquired diarrhea in acute care settings, and the prevalence is increasing due to the emergence of particularly virulent strains. Unfortunately, once you’ve acquired C. diff, you’re significantly more likely to contract it again- with 20% of people getting a recurrence. Do you see where this is going? As my previous post suggested, the appendix is probably helpful in developing countries with widespread food and water-borne GI infections, but not so useful in the developed world where these things are less common. But what about in the hospital, where rates of infection are unfortunately rather high?

 

In those that have been infected with C. diff, it appears that having an appendix is significantly protective against having a recurrence [1]. This protection could be conferred by two potential mechanisms (or a combination). The GALT tissue may provoke the appropriate immune response, and/or, the normal microbiota that were kept safe in the appendix can repopulate the gut, protecting it from a recurrence. I’m not quite sure how to apply option (a) to a practical approach right now, but I think option (b) offers some interesting ideas. Full warning- this is about to get a little gross…

 

The standard treatment for C. diff is a course of serious antibiotics (the fact that C. diff overgrowth is frequently caused by antibiotics sometimes seems to be lost in the mix). One of my fellow med students informed me recently that there’s a brand spanking new antibiotic on the market that is specifically geared towards preventing the recurrence of C. diff, (Fidamoxicin, trade name Dificid) but I’m not familiar with that treatment. What I am familiar with, however, are fecal transplants.

 

Fecal transplants (bacteriotherapy sounds so much less… gross), are exactly what they sound like. You take the feces from a healthy donor, test them for all types of nasty pathogens, and then implant them in your sick recipient. I had been informed by an infectious disease doc that the preferred route of entry was a nasogastric tube, but recent studies seem to imply that transplantations via colonoscopy are very effective [2] (and I don’t know about you, but for this particular procedure, going ‘up the out-hole’ seems a whole lot more appealing that going ‘down the in-hole’). In either case, the large intestines are first flushed with an isotonic solution and then the donor material is transplanted. This procedure seems to be very effective in treating and preventing a recurrence of C. diff, though it has yet to become a common or generally accepted practice (they don’t do it at my medical school for example). The obvious advantage of this procedure is that it inoculates the gut with a population of healthy/normal bacteria after an infection (and probably some antibiotics) that has knocked down (or out) the native flora. Additionally, in a world with progressively fewer and fewer effective antibiotics, it offers a therapeutic option that does not rely on pharmaceuticals. The obvious disadvantages are the gross factor and the pressing question of ‘who is the donor’ (for the record- they usually look to your spouse if you have one). Also, the procedure remains rather expensive because of the expense of testing samples and the nature of the procedure, however efforts to streamline the process appear effective [3]. Also- if you happen to be going in for a procedure that will see your native flora eradicated, you can actually save your own sample for an autologous transplantation at a later date.

 

Fecal transplants seems to be an interesting and appropriate treatment after C. diff overgrowth, and could also be beneficial in other GI conditions that are caused by dysbiosis. There’s definitely reason to think it might also be useful for treating a number of gut conditions such as Crohn’s disease, ulcerative colitis, irritable bowel, and maybe even systemic problems such as allergies and auto-immune conditions [4]. These are all things that warrant more research.

 

But how does this all tie back to the appendix?

 

Principle into practice. If we believe that the appendix acts as a safe house for commensal micro biota that are capable of repopulating the gut when needed, we should take special consideration for those that have had their appendix removed. While I tend to think that fecal transplants could be an appropriate therapy for most people as therapy for a C. diff overgrowth, it might be an exceptionally good choice for those without an appendix who do not have a reservoir of healthy bacteria to repopulate the gut after C. diff is eliminated. Furthermore, while I’m uncertain how effective supplemental and dietary probiotics are, it would seem reasonable to encourage those without an appendix (I think it is reasonable to encourage everyone to eat these things, but I think special recommendations should be given to those without an appendix) to eat fermented foods rich in microbiota after episodes of diarrhea. Additionally- the incorporation of dietary prebiotics to encourage the growth of commensal bacteria is probably also a reasonable recommendation. If nothing else, I would suggest that these considerations warrant further thought and potentially some research.

 

It’s also interesting to consider the potential role of the appendix in inflammatory conditions that appear to have an immune component such as ulcerative colitis. It seems that a misfunctioning appendix may play a role in the etiology of these disorders. While removal of the appendix might not be ideal, if it offers a mechanism by which to control these otherwise rather devastating conditions, it should not be overlooked. In these conditions, I would approach appendectomy as a procedure of last resort, but if normal gut function cannot be achieved by normalization of gut flora through other methods, it might appear to be a reasonable approach.

 

Finally- while the appendix appears to be a highly specialized organ, with important and interesting functions, acute appendicitis is a very serious and life-threatening condition. Appendectomy has been the gold-standard treatment for appendicitis for years, however recent research suggests that medical-management (antibiotics) may be effective for some patients [5]. Medical management of this condition represents a serious shift in the approach to treating appendicitis. It also offers an opportunity to save an organ whose importance and function we are only just starting to understand. Again- appendicitis is a life-threatening condition, and not treating it is not an option (if you suspect a problem- get to an emergency room ASAP), but the understanding that this organ plays a real and important role in human physiology suggests that if we can save the organ, perhaps we should (this is in contrast to current trend of ‘if in doubt, take it out’).

 

Understanding that the appendix is a specialized organ that has evolved to play a role in maintaining the gut micro flora is an important development in the study of normal and disturbed gut function. The realization that the appendix acts as a safe house for normal gut flora that can repopulate the gut after disease offers insight into how we might preferentially treat those who lack an appendix after episodes of gut dysbiosis. Furthermore, studying the role of the appendix in maintaining and regulating the actions of the immune system in the gut may offer important insights into understanding and then hopefully treating, immune-based gut conditions. How we might study this, however, is a story for another day. Until then- I hope you’ve enjoyed these musings on the appendix- thinking about the little organ in principle and in practice

 

 

1.         Im, G.Y., R.J. Modayil, C.T. Lin, S.J. Geier, D.S. Katz, M. Feuerman, and J.H. Grendell, The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol Hepatol, 2011. 9(12): p. 1072-7.

2.         Mattila, E., R. Uusitalo-Seppala, M. Wuorela, L. Lehtola, H. Nurmi, M. Ristikankare, V. Moilanen, K. Salminen, M. Seppala, P.S. Mattila, V.J. Anttila, and P. Arkkila, Fecal Transplantation, Through Colonoscopy, Is Effective Therapy for Recurrent Clostridium difficile Infection. Gastroenterology, 2012. 142(3): p. 490-6.

3.         Hamilton, M.J., A.R. Weingarden, M.J. Sadowsky, and A. Khoruts, Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium difficile Infection. Am J Gastroenterol, 2012

4.         Borody, T.J. and A. Khoruts, Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol, 2011. 9(2): p. 88-96.

5.         Liu, K. and L. Fogg, Use of antibiotics alone for treatment of uncomplicated acute appendicitis: a systematic review and meta-analysis. Surgery, 2011. 150(4): p. 673-83.

 

 

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I hope that my last post persuaded you that the appendix is not the pathetic remains of our forbearers’ large cecum, but is in fact a nifty piece of anatomy that maintains a safe house for the normal micro flora of our gut (If you’re interested in gut micro flora, Melissa wrote a great post here). While this little organ seems to work well in developing countries where there are frequent outbreaks of enteric pathogens and minimal hygiene, something seems to have gone awry in the developing world. While appendicitis is exceedingly rare in developing countries, it has been reported that up to 6% of the population in industrialized countries develop appendicitis necessitating appendectomy [1]. Why has our bacterial safe house turned into a ticking time bomb?

As early as 1505, Leonardo da Vinci identified the appendix and recognized that it sometimes became inflamed and burst. Much of his medical knowledge was lost, and it wasn’t recognized again until 1705 when the (then very young) father of clinical case reports, Giovanni Battista Morgagni, dissected a man who had died of appendicitis and subsequent peritonitis. That case actually revolutionized the understanding of medicine, with Morgagni and his mentor Valsalva recognizing that a specific disease was caused by a specific condition in a specific part of the body. This showed that illness was not caused by an imbalance of humors or a generalized malaise, but rather a specific cause. This one case led Morgagni and Valsalva to perform autopsies on all their deceased patients, and their detailed notes of over 700 cases were analyzed and published in the book On the Seats and Causes of Disease as Indicated by Anatomy. This book, and the idea that disease is caused by specific disorders, revolutionized medicine.

While appendicitis was one of the first diseases for which the anatomical source was recognized, we still don’t clearly understand why the condition occurs. It is generally believed that appendicitis occurs when the appendix is obstructed (by obstruction of the opening into the cecum by feces or swelling of the appendix due to proliferation of the tissue of the appendix itself), and the mucinous products of the appendix build up, leading to increased pressure and eventually tissue death. This dead tissue encourages bacterial proliferation (and we’re no longer talking about the friendly house-keeping type). Acute appendicitis is a medical emergency, and one that must be diagnosed and handled quickly. The removal of an inflamed, but intact, appendix is a much easier and neater procedure than trying to manage the aftermath of a ruptured appendix and subsequent peritonitis. If you think you might have appendicitis- get thee to the emergency department!

But why has appendicitis become so common? Appendectomy is sometimes referred to as ‘bread and butter’ for a general surgeon, but in developing countries this condition is almost unheard of. The rate of appendicitis is reported to be about 35-fold higher in the United States than in areas of African unaffected by modern health care and sanitation. Additionally, as communities adopt Western sanitation and hygiene practices, the rate of appendicitis increases [2]. Could appendicitis be another result of the “hygiene hypothesis”- the idea that modern medicine and sanitation can lead to an under-stimulated and over-active immune system?

As discussed in my first post, the appendix is associated with a large amount of gut-associated lymphoid tissue (GALT). While I pointed out that the appendix does secrete some substances that actively encourage the formation of biofilms for friendly bacteria, GALT also plays a role in the more typically recognized ‘keep the bad guys out’ aspect of the immune system. It’s that part of the system that tends to go awry with our modern hygienic world. Our immune system evolved to handle and control a number of different pathogens, including unfriendly bacteria and parasites. In the absence of pathogens, however, the system can go amiss The immune system is primed and looking for a fight, and if nothing appropriate comes along to take a beating, the immune system can start getting self-destructive, going after the body in which it is housed. It’s a classic case of ‘idle hands’ (or an active teenager with no good way to get the energy out!). This may well play a role in the prevalence of appendicitis in the developed world: overactive GALT tissue causes the appendix to swell, plugging the appendix, stopping the secretions from exiting into the cecum, and leading to increased pressure and subsequent necrosis and disease. (This is the condition that tends to occur in young people. In older people, appendicitis tends to be caused by the physical blockage of the appendix by a coprolith).

So is that it? In the past, and in the developing world, the appendix operated as a safe house for commensal bacteria. In the modern/hygienic world the appendix isn’t really needed, and can in fact get a bit out of whack because it doesn’t have anything to direct it’s immune-related functions towards. It definitely seems as though this might be the case, and unfortunately the problem appears to extend beyond the appendix. It turns out that an overactive appendix may also play a role in ulcerative colitis- an inflammatory condition of the large intestine. In some people with ulcerative colitis, an appendectomy improves the symptoms of ulcerative colitis, and in others it can completely cure the condition. The intended purpose of the appendix may shed light on why this pathology occurs. First- in a hyper-immune state, the appendix may house bacteria that the immune system aberrantly attacks. Alternatively (or additionally), the GALT tissue may drive the gut into a hyper-immune state. In either case- understanding the evolutionary purpose of the appendix can help understand and treat the conditions that occur in our modern hygienic world. Furthermore, it offers evidence that we should think about the impact of our uber-hygienic world, and consider how we might best handle the mismatch between our immune system that evolved to keep us safe in a dirty world and our modern clean environment.

(If you’re looking for a scholarly discussion of this topic, I highly recommend The cecal appendix: one more immune component with a function disturbed by post-industrial culture [2].)

1.            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.

2.            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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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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I’m in the process of writing a post, but came across this paper that is too good not to share. In 1912, the Scottish anthropologist and anatomist Arthur Keith published the paper The Functional Nature of the Caecum and Appendix in the British Medical Journal (full text available to all- nerds and medical historians rejoice!).  This article discusses some intricacies of the cecum and appendix, but his conclusions will sound familiar to anyone familiar with the paleo approach.

The author points out that there was a growing opinion (in the early 1900s) that the large intestine had become (at least in humans) useless and dangerous! Indeed, in the popular 1903 book The Nature of Man, the author claims “It is no longer rash to say that not only the rudimentary appendix and the caecum, but the whole of the large intestine are superfluous, and that their removal would be attended with happy results”. Part of the argument of this time was that the modern diet no longer needed bacterial action for full digestion, making the large bowel superfluous.  Not only was the large intestine useless, but it was also possibly dangerous (being termed by one surgeon a “cesspool”).

Arthur Keith, however, offered another approach: “in place of appealing to surgery to adapt our digestive tract to our present dietary, it seems possible that we may discover a diet which is suited to our present digestive tract”.

The concluding paragraphs ring true 100 years after they were written:

When we think of how the diet of highly civilized races has changed-in quality, quantity, and character-in comparatively recent times, one must marvel that our organization, which was evolved to deal with a more primitive and more precarious supply of food, has accommodated itself to modern conditions so well as it has. We know that beyond the neolithic period, when cereals began to be cultivated, some six thousand years ago, there lies a vast hinterland of rude human existence, when man must have lived on the natural products of the country. With the discovery of fire and of the artificial preparation of food (we know that man had discovered the use of fire before the end of the Pleistocene period) the task of the alimentary system must have been greatly altered. The greatest changes, however, are those of more recent centuries- the concentrated nature of food, its plentiful supply, its highly artificial character. When we come to realize how slowly evolutionary processes have affected man’s body in past times, we can hardly expect our internal digestive system to adapt itself to the rapid pace demanded by the ever-accumulating resources of civilization.

Thus an impartial survey of the evidence at present at the disposal of the anatomists indicates very plainly that we cannot hope to prevent or cure the ailments to which the great bowel is liable so long as we regard it as a hopelessly injurious or useless structure. On the other hand, if we regard it as having all the anatomical appearances of a useful structure, our outlook becomes hopeful if we can only discover what its uses are. If we only knew how to keep it suitably and profitably employed by altering our diet to meet its requirements, it will, we have every reason to think, serve us and future generations just as well as it answered the digestive needs of primitive and successful races in the past.

Yeah- what he said!

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