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Posts Tagged ‘Appendix’

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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