Probiotics to tackle allergy in children?

I recently read an article in the Chicago Tribune “Probiotics for babies may not fight allergies later”¹.  With so many articles on parenting floating around the internet my assumption was this article would be debunking some new-fangled parenting technique like attachment parenting or elimination communication (google it).  Interestingly, it was more of a follow up of an article I read a couple years ago on birth by caesarian section  (C-section)  resulting in a greater occurrence of allergic rhinitis and allergy sensitization than in children of vaginal birth.  The gut of a fetus is sterile containing no bacteria; the bacterial colonization of the infant’s gut begins to occur immediately with childbirth.  It is thought that children born via C-section are not exposed to maternal vaginal/fecal flora and, therefore, have different bacterial profiles resulting in greater occurrence of allergy.  

This is where probiotics step in, as a healthy gut flora aids the immune system, probiotics would aid in developing the healthy gut.  Adults can’t get enough of their probiotics, as evidenced at the yogurt aisle, so investigating the effect of probiotics in children seemed a natural step.  The main problem with probiotics, for both adults and children, appears to be probiotics come as a mix of a bunch of different strains of bacteria.  While it’s known there are beneficial bacteria that aid in digestion and synthesizing vitamins, and protect against pathogens, which probiotics may be helpful is still to be determined.   Studies, like the one in the Chicago Tribune, investigating the impact of probiotics in children have resulted in a jumble of results.  These studies show small benefits in probiotic protection against allergy, with one study showing only positive results in children born via c-section³.  Are these small effects a result of the lack of data on probiotics and which strains researchers should be looking at?  I’m sure, like all things in biology, we have something that is multifactorial and not merely a result of a C-section or not, probiotic or not. As evidence for the amount of layers involved in investigating this issue research is coming out on maternal probiotic supplementation's impact on placental and fetal immune physiology⁴, as well as breast milk composition.   

For now preventing allergy is just another thing for parents to worry about.  I like to think I will still have my children build up their immunity much like I did, with the calling of poison control every other day because of the odd plant, flower, or pile of dirt I put in my mouth (who knows what bacteria were on that!), but maybe I’ll try to toss in vaginal child-birth as well. 

 

1. http://articles.chicagotribune.com/2012-09-28/lifestyle/sns-rt-us-probiotic-for-babiesbre88r13q-20120928_1_probiotics-fight-allergies-bacteria
2. Jensen, M. et al Early probiotic supplementation for allergy prevention: Long term outcomes.  The Journal of Allergy and Clinical Immunology.  (2012).
3. Kuitunen, M. et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean deblivered children but not total cohort.  The Journal of Allergy and Clinical Immunology.  (2009). 
4.  Rautava, S. et al. Probioticsmodulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial. Neonatology (2012)

The first identified neurological autoimmune disease: myasthenia gravis

Myasthenia gravis (MG) is a rare autoimmune mediated neurological disease.  The name stems from Greek mya, “muscle” and sthenia “weakness, ” and the Latin gravis “serious” which describe the hallmark symptoms of severe muscle fatigue.  This fatigue can be life threatening if the muscles affected include respiratory and/or bulbar, those of the mouth and throat. 

Thomas Willis, a physician in London, first documented the disease in 1667.  In 1960, Simpson was the first to propose that the pathogenesis of MG was an autoimmune reaction that involved an antibody specific for a neuromuscular junction protein.  Which turned out to be correct, the most common form of MG is characterized by the presence of autoantibodies for the nicotinic acetylcholine receptor (nAChR).  This receptor is found in the neuromuscular junction and when bound to the neurotransmitter acetylcholine (Ach) muscle contractions are stimulated.  There are a few ways that the autoantibody for nAChR can interfere with proper muscle contractions.  First by binding to the receptor it is competitively inhibiting muscle stimulation via ACh.  Also the valence of the antibody can play a role in AChR degradation.  In class we discussed that IgG is divalent, and the autoantibody is classified as IgG.  When the divalent IgG is bound to the AChR it can cross-link two AChR thus prompting the degradation of both receptors.  Yet interestingly, if FAb is bound (only one) then degradation of the receptor is not promoted (Fig 1).  If there is less AChR then muscle contraction would be reduced.  Another interesting way autoantibody binding can interfere with normal muscle contraction is by inducing the complement system and subsequent lysis of the muscle tissue.   

The rate of acetylcholine receptor (AChR) degradation was measured in terms of loss of AChRs by Drachman and colleagues. Accelerated degradation was observed when divalent anti-AChR antibodies were used (a), but not when monovalent anti-AChR Fab' was applied (b). To prove that it was crosslinking per se, rather than antibody binding to the AChR, that caused the degradation, they showed that increased degradation could also be seen when AChR-specific Fab's were crosslinked by anti-Fab' antibody. (Figure adapted from Vincent 2002)

While much is understood about the mechanism of MG, the cause is unknown.  We discussed that some autoimmunity can stem from cross reactivity of antibody for an antigen, i.e. streptococci, that has a low affinity for a protein found in the body, i.e. the heart valve, but this does not appear to be the case for MG as the high-affinity for AChR implies that AChR is the primary antigen not something else (Tzartos 1998).  Even though a clear target for MG treatment remains elusive, common treatment include thymectomy, removal of the thymus.  The thymus contains germinal centers, where B cell and T cells mature, and when removed a reduction in the autoimmune reaction is seen.  Another treatment option involves acetlycholinesterase inhibitors, which reduce the degradation of ACh in the neuromuscular junction in combination with immunosuppressive drugs.  Yet, neither of these options are long-term treatment plans as they make the patient susceptible to infections, among other complications.

One intriguing fact about MG patients is that they often have some other associated condition that is typically autoimmune.  Some of these conditions include Graves disease, Multiple Sclerosis and other demyelinating CNS disorders, and Rheumatoid Arthritis.  This occurrence is not understood, and considering there is no current evidence for a genetic source of MG, what types of mechanisms might be driving the presentation of both MG and another condition?  Or do you think that the presentation of one autoimmune disease causes the other (e.g. is MG caused by another autoimmune disease or vice versa)?

Drachman, D. B., Angus, C. W., Adams, R. N., Michelson, J. D. & Hoffman, G. J.Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation.N. Engl. J. Med. 298, 1116–1122 (1978).

Tzartos, S. J. et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol. Rev. 163, 89–120 (1998).

Vincent, A. Unravelling the pathogenesis of myasthenia gravis. Nature Reviews Immunology 2, 797-804 (October 2002)

 

Dendritic Cell Vaccinations

A family friend flew to Germany recently to enroll in a clinical study using an experimental treatment for her glioblastoma.  Turns out that this treatment involves dendritic cell vaccinations.  I don't know the specifics of her clinical study, but I found a similar study in the United States at Cedars Sinai which provided the details for this posting (Phuphanich et al., 2012). 

Researchers extracted white blood cells from the 17 subjects, then pulsed them in the lab with six tumor-associated antigens (TAA) that are found on glioblastoma multiforme cells.  After each subject completed surgery and radiation, these cells were re-introduced through three different vaccinations given two weeks apart.  Preliminary results of the study showed an increase in the median progression-free survival to 16.9 months (standard is 6.9 months), and an overall survival median of 38.4 months. 

Patients who had four of the six TAAs expressed in large numbers responded especially well to the vaccine, and a positive correlation was found between the size of the immune response and length of progression-free survival.  In addition, a protein (CD133) that is associated with the stem cells of a glioblastoma was decreased after the vaccinations.  This study suggests using dendritic cells to create a vaccine that targets antigens found on glioblastoma cells could be an effective treatment against this form of cancer.

Cedars-Sinai Medical Center (2012, August 15). Vaccine targets malignant brain cancer antigens, significantly lengthens survival. ScienceDaily. Retrieved September 30, 2012, from http://www.sciencedaily.com­ /releases/2012/08/120815093108.htm

Phuphanich, S., Wheeler, C. J., Rudnick, J. D., Mazer, M., Wang, H., Nuño, M. A.,  Richardson, J. E., Fan, X., Ji, J., Chu, R. M., Bender, J. G., Hawkins, E. S., Patil, C. G., Black, K. L., Yu, J. S.  (2012).  Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunology, Immunotherapy.  DOI: 10.1007/s00262-012-1319-0

The hygiene hypothesis and the increase in the incidence of autoimmunity over the last century.

As a preface to this blog post, I have have been involved in autoimmunity research for the past 2 years.  The incidence of autoimmune diseases such as type 1 diabetes and rheumatoid arthritis have been gradually increasing over time and we are unsure as to why this might be.  One simple explanation is that due to technology and advances in medicine, we're better at detecting autoimmune disease, which is true, but is this the only reason for the increase in the incidence/prevalence of autoimmune disease?  An additional explanation that attempts to explain part of the increasing incidence in autoimmune diseases that I've found fascinating is what is known as the hygiene hypothesis.  First, for the purpose of this post, autoimmunity is essential an immunoregulatory problem where our own antibodies attack self.

I've come across an article by Graham Rook titled Hygiene Hypothesis and Autoimmune Diseases that I think summarizes the hypothesis quite well.  The premise of the article is that increased incidence of autoimmune diseases can be attributed to our (humans) changing environment over the past century, i.e. modern and sanitary environments.  Think of how much cleaner we live, we have sewer systems to take our excrement far away from us, we no longer live in close proximity to our livestock, etc.  In addition to some of the more obvious alterations of our environment, we've also changed our microbial ecology (or microbiome) of our gut with our modern diet.  All these factors contribute to our immune system having to deal with less 'germs'.

Now to explain, briefly, the hygiene hypothesis.  The argument goes like this; human beings and our extraordinary immune system evolved over the course of millions of years in the presence of stuff we as a modern society deem icky, such as bacteria, parasitic worms, and various viruses, our immune systems might very well need these 'germs' in order to maintain proper immune functions.  Because our immune system evolved in tandem with 'germs', parasites and bacteria, our immune system learned to tolerate these 'germs' and in fact they play an essential role in proper immune function.  And in the absence of our 'old friends', to use a term from the article, our immune systems are more likely to be dysfunctional and in turn, sometimes attacks our own tissues/cells in our body.  This hypothesis has also been used to explain some observations in epidemiology relating to autoimmunity as well as allergies.  I find this hypothesis extremely fascinating and would suggest reading the entire article cited below.

Rook, G. A. W. (2011). Hygiene Hypothesis and Autoimmune Diseases. Clinical Reviews in Allergy & Immunology, 42(1), 5–15. doi:10.1007/s12016-011-8285-8

An additional reference:

Okada, H., Kuhn, C., Feillet, H., & Bach, J.-F. (2010). The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clinical & Experimental Immunology, 160(1), 1–9. doi:10.1111/j.1365-2249.2010.04139.x

Is Autism an inflammatory disease?

The prevalence of Autism is increasing. The CDC estimates that 1 in 88 children has Autism, and the prevalence has been increasing. Some people fear that immunizations might be to blame, although research has not supported this idea. New York Times had an opinion article last month that implicates a different aspect of the immune system in the development of a subset of cases of Autism: inflammation.

The article discusses results from a large Denmark cohort study of 700,000 women followed over 2 decades that showed an association between maternal autoimmune diseases, which are characterized by chronic inflammation, and Autism (not cited, but presumably work by Atladottir et al.). Maternal rheumatoid arthritis increased Autism risk by 80%, while celiac disease increased it by 350%! Women who had bacterial or viral infections during early pregnancy also had increased risk for Autistic offspring – perhaps due to the natural inflammatory response to fight off the infection. Other laboratory-based studies have also supported a link between maternal inflammation and autism.

The author of the article, Moises Velasquez-Manoff, recently wrote a book entitled An Epidemic of Absence. The book supports what is commonly called the hygiene hypothesis (although the author would prefer a more descriptive name, such as the “the microbial deprivation hypothesis”), which is the idea that the increase in developed countries of autoimmune disease is associated with a lack of exposure in childhood to infectious agents, parasites, and symbiotic microorganisms (eg probiotics). The hypothesis was put forth in the late 1980s, and the connection between the hygiene hypothesis and autism has been gaining traction in the scientific community in recent years.

As I mentioned, this was a newspaper opinion article. And it did get generate some mixed reactions. An obvious question is – does is accurately reflect the research? One of the scientists mentioned in the article as a key player in the research about prenatal inflammation and autism is Paul Patterson. You can check out his blog here: http://infectiousbehavior.wordpress.com/ He has a post where he comments on the New York Times article and offers more specific references. Here are some of his thoughts on the article:

But how accurate are his claims [in the article]? Moises says in his third sentence (!) that “At least a subset of autism – perhaps one-third, and very likely more – looks like a type of inflammatory disease. and it begins in the womb.” The work of Tony Persico, which I highlighted in a July 18 post here, estimates that an immune-related cluster of symptoms is present in about 18% of his autism patient population. Carlos Pardo found evidence of an immune activated state (activated microglia and astrocytes, and strikingly elevated cytokines) in the brains of most of his postmortem autism cases. Several of the Pardo findings have been reproduced by others at UCSD, UCDavis and here at Caltech. In addition, many studies have demonstrated immune abnormalities in the blood in autism…. there are several reliable studies showing that a high proportion of ASD kids have gastrointestinal problems, many of which could be related to inflammation, such as “leaky gut”, wherein the intestinal barrier allows large molecules to leak out into the circulation. So, I fully agree with Moises that there is a very significant proportion of ASD patients with immune-related problems. Whether it is a third or more than that, is open for debate and further research.

Interesting stuff.


References:

Atladottir, H. O. et al. Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders. PEDIATRICS 124, 687–694 (2009).

Atladottir, H. O. et al. Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders. PEDIATRICS 124, 687–694 (2009).

CDC. “New Data on Autism Spectrum Disorders.” (2012). Retrieved from: http://www.cdc.gov/Features/CountingAutism/

Patterson, Paul. “Huge interest in NYT article: An immune disorder at the root of autism.” (2012). Retrieved from: http://infectiousbehavior.wordpress.com/2012/08/28/huge-interest-in-nyt-article-an-immune-disorder-at-the-root-of-autism/

Velasquez-Manoff, Moises. “An Immune Disorder at the Root of Autism.” New York Times. (2012). Retrieved from: http://www.nytimes.com/2012/08/26/opinion/sunday/immune-disorders-and-autism.html?pagewanted=all&_r=0

Blood on the First Day

It was my first day shadowing the clinical director of a local clinic.  Since this was my first experience my main focus was just not to say anything too obviously ignorant.  So when the doctor turns to me to give me the patient’s information before we see them and says, “looks like we’ve got one with chronic onychomycosis and will be needing surgical removal,” my mind began to spin as this is a general internal medicine clinic.  What kind of surgery could we be doing and what was that word he just said?  Was that even English?

We enter the patient’s room and let me tell you, onychomycosis is the euphemism for toenail fungus.  The patient had been trying oral antifungals for several months and the fungus was still invading the nail bed.  In otherwise healthy individuals this type of fungal infection is more unsightly and a nuisance than anything but for those with diabetes or serious immune deficiencies it can lead to other complications.  After explaining the treatment options to the patient I was able to watch my first surgical procedure.  The physician actually removed the nail completely then used an acidic chemical on the cuticle to prevent nail regrowth as well as applied a topical antifungal to the nail bed. 

After leaving the patient’s room I had many questions.  The primary question being, why is it that hard to treat a toenail infection, and suddenly the newly formed immunology student kicked in. Obviously we have learned that the immune system has specific cells that can identify fungal antigens, however the toenail is not easily flooded by blood flow making it difficult for an immune response to occur or for antifungal medications to access.  This is usually why oral medications can take months to be effective and why treatment is usually needed in general. 

Recently there has been four laser systems approved by the FDA to treat onychomycosis and may prove to be a substantial advantage over pharmacotherapy (Gupta & Simpson 429).  None the less, for my first shadowing experience it was great to have  a patient that allowed me to have something to blog about!

Gupta, A., & Simpson, F.  “Newly Approved Laser Systems for Onychomycosis.” 

Journal of the American Podiatric Medical Association.  2012: 102: 428-429.

Herranz, P., Garcia, J., De Lucas, R., Gonzalex, J., Pena, J., Diaz, R., & Casado, M. 

“Toenail onychomycosis in patients with acquired immune deficiency syndrome: treatment with terbinafine.”  British founuil of Denmitolo.  1997: 137: 577-580.

Helpful Links:

http://www.mayoclinic.com/health/nail-fungus/DS00084/DSECTION=treatments%2Dand%2Ddrugs

Re-thinking multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease and the most common cause of non-traumatic neurologic disability in young adults. Traditionally, MS has been considered an inflammatory autoimmune disease in which circulating lymphocytes (T-cell and/or B-cells? depends who you talk to...) direct immunological destruction of central nervous system myelin. Most patients go through a relapsing remitting stage in the disease, in which neurologic deficits are eventually restored, presumably through the regenerative process known as remyelination. Then, after repeated immune attacks, permanent disability occurs and the patient moves to a progressive form of the disease. It is now well established that disability is due to axon transection and irreparable damage to neurons. Functional recovery early in the disease could be due to (in addition to remyelination) neural plasticity in the adult brain. After the neural reserve is used up over time, progressive neurologic disability then occurs.

The cause of MS is still unknown. I think there is definitely an immunological component to MS, but whether the immune system is the PRIMARY problem or a SECONDARY aspect of the disease is a hot issue of debate. All current MS therapies are immunomodulatory drugs. Also, acute MS attacks are treated with methylprednisolone, a potent anti-inflammatory drug. However, these drugs are not curative, they are preventative. Some of these drugs have become remarkably efficient at preventing attacks in MS patients. But are these drugs simply masking the real, underlying problem?

Evidence is beginning to emerge that MS may not be a primary immunopathology. In 2004, Prineas and Barnett examined very early MS lesions using histological procedures. In an unusual case, an MS patient died just 17 hours after the beginning of an attack. In these early lesions, researchers found apoptotic oligodendrocytes (the cells which produce central nervous system myelin) without evidence of infiltrating lymphocytes. Is it possible that some insult to oligodendrocytes kicks off the disease, independent of the immune system? And then later on, the immune system becomes sensitized? It could also be possible that the primary insult is to neurons, and oligodendrocyte death and myelin destruction are both indirect effects.

Prineas and Barnett article:
http://onlinelibrary.wiley.com/doi/10.1002/ana.20016/abstract;jsessionid=D01FDD81E1736A59DEC3F3090B6910CC.d03t02

Relevant review article:
http://www.annualreviews.org/doi/abs/10.1146/annurev.neuro.30.051606.094313?url_ver=Z39.88-2003&rfr_dat=cr_pub%3Dpubmed&rfr_id=ori%3Arid%3Acrossref.org&journalCode=neuro

Diet Soda leading to stroke?

Can diet soda possibly cause stroke?

There have been multiple amounts of studies conducted in order to confirm whether or not diet sodas are the source of certain diseases.  The fact is, diet sodas have been scrutinized due to the fact that it was designed to be a healthier alternative to the sugary carbonated drinks.  Although diet sodas are supposed to help with weight loss, there is that possibility that it could induce worse conditions.  The alternate sweetener utilized in diet sodas, also known as aspartame, has been shown to cause cancer. However, the question is, can it cause stroke, which is a disruption of blood flow to the brain?

During the American Stroke Association’s International Stroke Conference in 2011, research findings were reported with the answer to this question.  2564 participants were divided into groups based on soda consumption: no consumption, regular soda consumers, or diet soda consumers.  There were other groups formed: people who consumed both regular and diet soda moderately and people who drank a mixed amounts of regular and diet soda everyday. 

It was found that people who drank diet soda everyday had 48% increased probability of having a stroke or other vascular event in a nine year span.  This is including certain lifestyle factors and medical history.  It was found that people who drank diet soda suffered some sort of vascular event including strokes, heart attacks and/or death. 

Certain limitations to this study were admitted.  The data in this experiment were self-reported, which in any experiment, can be somewhat biased.   It was also found that the participants who did drink diet soda tended to have a high fat/high cholesterol diet which can be a high risk factor for any cardiovascular disease.  This factor can skew the data by the simple fact that diet can be reason why diet soda consumers are suffering some sort of vascular incident.  
Another point that is a weakness in this article is the fact that they do not point out the reason why diet soda could be a cause of stroke.  There is the possibility of the carbonation of the soda that could increase carbon dioxide in the blood, which could be detrimental for oxygen transport to the brain.  It could also be aspartame which is the sweetener found in diet soda.  Because it is found to cause cancer, it could also cause some other conditions within the body.  
Overall, the lesson learned from this article is that we cannot be too careful as to what we put in our bodies.  We may try to consume something as a healthier alternative, or to prolong survival, but overall we cannot be too sure of everything that we humans create.  All that one can do is just cautious of the ingredients found in what we consume and hope that we are consuming foods that will benefit ourselves.  

http://healthland.time.com/2011/02/11/diet-soda-may-lead-to-stroke-risk-really/

What really is an autoimmune disease?

One of the first things that struck me as I was looking autoimmune diseases was how vague the criteria was at times. Autoimmune diseases must be classified by Witebsky Postulates. The postulates have been modified from Witebsky's initial 1957 criteria. Witebsky's Postulates include:

• Direct evidence from transfer of pathogenic antibody or pathogenic T cells. 
• Indirect evidence based on reproduction of the autoimmune disease in experimental animals
• Circumstantial evidence from clinical clues

There so many suspected autoimmune diseases that do not fulfill all of the postulates. I personally have a major problem with the last criteria. Essentially, the last criteria bases diagnosis on pretty circumstantial clinical evidence. We can't convict someone based on circumstancial evidence, so why are we using circumstantial evidence from clinical clues to diagnose a disease as autoimmune? For example narcolepsy is a suspected autoimmune disease (See more in Mignot, E (2001). "A commentary on the neurobiology of the hypocretin/orexin system". Neuropsychopharmacology 25 (5 Suppl): S5–13) By constrast some are question whether Multiple Sclerosis is truly and autoimmune disease. Some people have argued that cancer, to some extent has some autoimmune qualities.

Autoimmune diseases can also be classified by hypersensitivity based on types II, III or IV. The reason I posted this blog was to reexamine how we as scientist see as autoimmunity, and whether autoimmunity can really be narrowed down because autoimmunity is so broad and can include so many things. For more on these criteria, check out a paper by Rose and Bona called Defining criteria for autoimmune diseases (Witebsky's postulates revisited). I know the paper is a bit old, but the link can be seen at http://www.ncbi.nlm.nih.gov/pubmed/8216719.

What kind of transplant?!

As I was reviewing the daily news, an article title caught my eye, “Little-known fecal transplant cures woman's bacterial infection”, which led me to further explore this topic.  In short, we can call this Wednesday night. 

In 2011, Ms. Kaitlin Hunter had been in a severe car accident, in which she suffered a fractured lower spine, lacerated liver and colon, and broke all her toes.  After being discharged, she suffered from abdominal pain leading to her rehospitalization where she was diagnosed with Clostridium difficile infection (CDI).  This bacterium can cause watery diarrhea up to 15 times a day, as well as other unpleasant symptoms.  The Centers for Disease Control and Prevention estimates that, annually within the U.S., approximately 14,000 individuals die due to CDI.  Furthermore, within the past couple of decades; CDI has reached epidemic proportions with a recurrence rate between 30-65%, along with associated frequent treatment failures of multiple courses of antibiotics.  Her story was very similar to this trend as she received nine regimens of antibiotics, but there appears to be hope with regard to a very intriguing approach to CDI treatment known as fecal microbiota transplant (FMT).

Dr. Lawrence Brandt is a pioneer with regard to FMT for the treatment of CDI.  He performed his first transplant in 1999, but points out that this procedure had been around long before that, indicating that the first transplant occurred in 1958 in humans and had been performed in animals for more than a century.  He feels that FMT is gaining popularity because antibiotics disturb intestinal microflora, and when altered, dysbiosis (i.e. when natural flora of the gut are thrown out of balance) results and the organisms in the intestinal tract can no longer prevent CDI.  In general, FMT is performed through a colonoscopy; thus, the risks of transplantation are fairly equivalent.  Furthermore, Dr. Brandt states, “By reintroducing a healthy diversity of bacteria, fecal transplantation can re-establish colonization resistance to prevent CDI from gaining a foothold and becoming a dominant organism in the environment of the gut.”

Now that the biologic mechanism has been briefly explained, what about the empirical evidence?  Currently, there are no controlled trials supporting FMT; however, there are over 27 published case series, one multi-center follow-up study and one single site follow-up study.  Not surprisingly, the multi-center study was led by Dr. Brandt. 

All participants for this study had recurrent CDI and were treated with FMT.  Participants completed questionnaires through postal mail or telephone and were asked about primary cure and secondary cure rates (actually proportions, not rates).   Primary cure rates were based on resolution of symptoms within 90 days following FMT and secondary cure rates were based on resolution of symptoms after one additional regimen of antibiotics with or without repeat FMT.  The results displayed that the primary and secondary cure rates were 91% (70/77) and 98% (76/77), respectively.  There doesn’t appear to be significantly associated adverse events to this procedure; however, 4 of the 77 study patients developed immune diseases consisting of: idiopathic thrombocytopenic purpura, peripheral neuropathy, rheumatoid arthritis (RA) or Sjögren syndrome.  Nevertheless, skepticism remains based on the procedure being attributable to the development of these factors, as all subjects in the study were already in poor health status.

The single site follow-up study also analyzed patients with recurrent CDI (N = 26) and found that FMT was 92% effective at preventing further symptoms or CDI recurrence.   

In closing, Dr. Brandt is trying to secure approval (and funding of course) of a controlled study involving the treatment of CDI by FMT.  This would be paramount in order to prove its effectiveness, as well as potentially gain FDA approval.  Dr. Brandt also hypothesizes that it is likely that only a few organisms and their metabolic products found in stools may be necessary to treat CDI and in the future, rather than performing FMT, if these factors can be isolated, patients may simply be exposed to just those.  Lastly, to end on a positive note, as the title of the original article suggests, after a long battle with CDI, Ms. Hunter was cured with this increasingly popular, yet still esoteric procedure. 

References

Brandt LJ. Gastroenterol Hepatol (N Y). Fecal Transplantation for the Treatment of Clostridium difficile Infection. 2012 March; 8(3): 191–194.
Brandt LJ, Aroniadis, OC, Mellow M, Kanatzar A, Kelly C, Park T, et al. Am J Gastroenterol. 2012 Jul;107(7):1079-87. doi: 10.1038/ajg.2012.60.
Centers for Disease Control and Prevention. Healthcare-associated Infections (HAIs): Clostridium difficile Infection. 6, Mar. 2012.  Accessed on September 27, 2012. Available at http://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html
Hudson, W. “Little-known fecal transplant cures woman's bacterial infection.” cnn.com. CNN, 26, Sept. 2012. Accessed on September 26, 2012. Available at: http://www.cnn.com/2012/ 09/ 26/health/fecal-transplant/index.html?hpt=hp_c2.
Kelly CR, de Leon L and Jasutkar N. Fecal Microbiota Transplantation for Relapsing
Clostridium difficile Infection in 26 Patients: Methodology and Results. J Clin Gastroenterol. 2012 Feb;46(2):145-9.
Mayo Clinic. C. difficile. 3, Nov. 2010. Accessed on September 26, 2012. Available at: http://www.mayoclinic.com/health/c-difficile/DS00736.
WebMD. Digestive Disorders Health Center: C. diff. N.d. Accessed on September 26, 2012. Available at: http://www.webmd.com/digestive-disorders/clostridium-difficile-colitis.

Pictures:
http://www.usatoday.com/news/health/2010-03-20-c-diff-bacteria_N.htm
http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and reports/?pageaction=displayproduct&productid=891
http://www.sodahead.com/living/have-you-hear-of-the-cdiff-bactera-it-has-killed-30000-americans/question-3109465/?link=ibaf&q=&imgurl=http://my.telegraph.co.uk/wpcontent/blogs.dir/1/user/paultoner/20071012020742.jpg

Side effect of Angiotensin II

Angiotensin II (ANGII) is a hormone that can cause problematic changes in the heart such as inflammation, thickening of the walls of the heart, high blood pressure and fibrosis (excessive scar tissue).  One pathological change the lab I work for studies is cardiac fibrosis (excessive scar tissue) caused by angiotensin II. The heart consists mostly of two types of cells: myocytes and fibroblasts. Fibroblasts are cells in connective tissue that are involved in tissue repair.  They are located between myocytes and contribute to the structure and mechanical properties of the heart.  Fibroblasts have a receptor called angiotensin type I receptor (AT1R).   When Angiotensin II binds to the angiotensin type I receptor, a signaling pathway is activated in the cardiac fibroblasts.  This leads to an increase production of cytokines in the fibroblast.  Cytokines are signal proteins. One cytokine that is made is the transforming growth factor beta (TGFβ).  TGFβ is secreted from the cardiac fibroblast to recruit other fibroblasts to this area in the heart.  The fibroblasts also secrete extracellular matrix (complex network of proteins), that are rich in collagen.  This creates a scar.  Many types of immune cells are recruited to this area too.  This cascade of events leads to fibrosis (excessive scar tissue).  Below are two pictures of a section of a mouse heart that has angiotensin II induced fibrosis from my lab. 

 The red in this section of mouse heart is the fibrotic regions made up of the extracellular matrix.  The heart section is stained with Picro Sirius Red that binds to collagen and turns it red.

 The arrows point to white blood cells (red nuclei) in the fibrotic area of a mouse heart.  

I work for a lab that looks at the effects certain drugs have on the angiotensin II signal pathway in the heart.  We implant pumps into mice that release angiotensin II and expose them to different drugs by injections.  Then we look at cardiac fibrosis by staining sections of the mice’s hearts (as seen in the pictures above).  We also look at the quantity and type of immune cells in the heart and venous blood from the mice.  I have many questions from the experiments my lab has done such as: What is the mechanism that triggers the immune response in the fibrotic areas of the heart?  Where do the immune cells come from (lymph nodes, bone marrow)?  Where do the fibroblasts come from that are recruited by the cytokine TGFβ (bone marrow, other surrounding tissues next to the heart)?

Sources:

Leask A. TGFβ, cardiac fibroblasts and the fibrotic response.  Cardiovascular Research 2007;74:207-212.

Mehta P, Criendling K.  Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.  Am J Physiol Cell Physiol 2007;292:C82-C97.

Mckinsey lab in the division of cardiology.