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Posts Tagged ‘microbiota’

Sorry there’s been a delay in getting anything new out. I’ve had some exams, a quick trip to Colorado, and am now just finding my feet on my surgery clerkship. I have a bunch of things I intend to write about soon, but this paper popped up the other day and it ties in really nicely to some of the things I’ve already written about. I just had to write about it! I promise that in my upcoming posts I will get away from bowels and microbiota (though these subjects are incredibly important!).

You may remember Clostridium difficile from one of my previous posts on the appendix. C. diff is an anaerobic bacterium that frequently resides in the large intestine. After a course of antibiotics, when other gut-inhabitants have been killed, an overgrowth of C. diff can lead to a very nasty spectrum of symptoms ranging from mild diarrhea to death. Because of the frequent use of antibiotics and because of new hyper-virulent strains of C. diff, infection with this bacterium has reached epidemic levels. Alas, this is one of the most common infections found in hospitals, nursing homes, and other medical facilities.

The incidence of C. diff is on the rise, with both the number of cases and the mortality from infection recently doubling. There are approximately 3 million cases of C. diff infection in the US each year, and it’s estimated that care for these cases is in excess of $3.2 billion. C. diff infection leads to a number of discomforts, including abdominal pain, diarrhea, fatigue, and flu-like symptoms. Alas, treatment can be difficult, and symptoms can persist for months or even years.

As I mentioned in a previous post, the usual treatment for C. diff is further antibiotic treatment. C. diff infection usually occurs after all the normal gut flora has been eliminated and further antibiotics (sometimes given with probiotics to encourage the return of commensal bacteria) are targeted at eliminating C. diff (there’s even a new antibiotic (Dificid) specifically targeted at C. diff). The problem, of course, is that IF these antibiotics are effective, you now have a relatively unpopulated gut that is barren and ready for the taking by whatever stray bacteria have survived the courses of antibiotics or whatever quick growing bacteria happens to make their way to the intestines to claim the empty territory- unfortunately C. diff is frequently the victor in this foot race!

Recurrent rates of C. diff infection range from 15-30%, and once you’ve had one recurrence, you’re more likely to have another: a 40% chance of having a second, and a 65% chance of having a third. Obviously antibiotics are of limited efficacy here, so what is an appropriate course of action?

In my previous post, I discussed a paper that showed that having an appendix (and thus having a safe house for normal commensal bacteria that can repopulate your gut after infection or antibiotic treatment), is protective against a recurrence of C. diff [1]. But what if you don’t have that safe house, or if you get a recurrence despite having an appendix? Again, as mentioned in a previous post, a Fecal Microbiota Transplant (FMT) seems to do the trick.

A paper published at the end of March [2], combined data from 5 sites and showed that FMT can provide RESOUNDING cure rates in people suffering from recurrent C. diff infections. Here’s a quick review: 77 patients, with average symptom duration of 11 months (range 1-28) underwent FMT at 1 of 5 medical centers in an attempt to cure their chronic infection. On average, these patients had already undergone 5 treatment regimes to try and cure their infection. FMT (most donors were family members, spouses, partners, or friends) was infused by colonoscopy into the terminal ileum, cecum, and (depending on the site) parts of the colon. Resolution of a number of symptoms- abdominal pain, fatigue, and diarrhea, were recorded.

In 70% of patients, pain resolved with FMT, while it improved in an additional 23%. 42% of patients saw a resolution of fatigue, with an additional 51% reporting an improvement. An astounding 82% saw a resolution of diarrhea and 17% saw an improvement within 5 days of FMT. These are patients, remember, that have been suffering from symptoms for an average of 11 months.

Alas, 7 patients (just under 10%) experienced an early recurrence (less than 90 days after FMT), and required a secondary treatment (either antibiotics targeted at C. diff or another FMT), which successfully treated the recurrence. Thus, the “primary cure rate” (resolution of diarrhea within 90 days of FMT) was 91%, and the “secondary cure rate” (resolution of infection after a further course of antibiotics or a second FMT), brought the cure rate to 98%. (It is worth noting that the one not “cured” patient died in hospice and was not re-treated after failure of a primary cure).

Some patients did have late recurrent infections of C. diff. Not surprisingly, these cases all occurred in patients that took a course (or multiple courses) of antibiotics to treat an unrelated infection. Recurrence occurred in 8 of the 30 patients that took a course of antibiotics. Interestingly, recurrence may also be associated with the use of proton-pump inhibitors (perhaps not a surprise, as PPIs inadvertently affect our microbiota [3])

This paper is excellent evidence to support FMT becoming a first-line therapy for the treatment of C. diff infection (and I will add especially for those that lack an appendix). FMT restores a natural biodiversity to the intestine of someone who has had their own microbiota disturbed by disease and/or antibiotics. For many people (those that experienced a primary cure), the restoration of the biodiversity was enough to overcome C. diff infection. For others, the restored biodiversity gave them the edge to overcome infection with a further targeted antibiotic or a second transplant. Remember- these are patients that had failed MULTIPLE treatments for C. diff and had been experiencing symptoms for an average of 11 months.

While there are definitely risks to FMT (it is important that donors be screened to rule out dangerous transmissible infections such as HIV, hepatitis, and parasitic infections), there are arguably additional benefits. One patient in this study reported a significant decrease in allergic sinusitis and another reported an improvement in arthritis. Both associated the improvement of symptoms with FMT. Indeed, FMT has been reported as a successful treatment for a number of conditions including inflammatory bowel disease (such as ulcerative colitis), irritable bowel disease, idiopathic constipation and insulin resistance [2].

It is important to recognize that some of the patients in this trial did suffer from subsequent disorders that should be further explored. While the conditions were not apparently associated with FMT, 4 patients that received this therapy later developed conditions including peripheral neuropathy, Sjogren’s disease, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. Further studies need to determine if there is an association between FMT and autoimmune or rheumatologic disorders. If associations are found, I would expect that this would call into question the appropriate selection of donors for individual patients.

It is becoming increasingly obvious that an appropriate and diverse microbiome is important for health. When this microbiome is thrown out of whack, be it by an evolutionary-novel lifestyle, infection, or antibiotic treatment, the restoration of this environment should be the focus of medical treatment. Fecal Microbiota Transplant is a rational and effective method of restoring a healthy and diverse intestinal microbiome.

(It is worth mentioning that 97% of the patients in this study stated that they would undergo another FMT if they experienced a recurrence of C. diff, and 53% would choose FMT as their first treatment option before a trial of antibiotics. Yes, the idea of FMT may seem gross, but it is effective. For those that have suffered for upwards of a year, this treatment truly is a life-changing option.).

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.            Brandt, L.J., O.C. Aroniadis, M. Mellow, A. Kanatzar, C. Kelly, T. Park, N. Stollman, F. Rohlke, and C. Surawicz, Long-Term Follow-Up of Colonoscopic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. Am J Gastroenterol, 2012.

3.            Vesper, B.J., A. Jawdi, K.W. Altman, G.K. Haines, 3rd, L. Tao, and J.A. Radosevich, The effect of proton pump inhibitors on the human microbiota. Curr Drug Metab, 2009. 10(1): p. 84-9.

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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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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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