Bacterial transplantation: undesirable but effective

We have a term common to certain parts of the UK: 'where there's muck, there's brass'. The more usual interpretation of this phrase is that where there is a dirty job to be done, so there is money to be made. In the case of this post on probably the most undesirable therapy ever, bacterial transplantation, money might be replaced with health.

The paper in question is this review by Ethan Gough and colleagues* (available full-text not anymore). I'm not going to go through the whole paper because it is was free to view to everyone. The bottom line is that following the identification of various literature on other-person derived stool infusions, 27 reports fulfilled author criteria for review, of which over 90% of patients reported on showed 'resolution' of their problems of Clostridia difficile infection or pseudomembranous colitis following a bacterial transplant. Perhaps more importantly, the reported rate of side-effects including the ultimate side-effect of death, whilst present, could not be directly attributed to the transplant but rather the disease transplant was attempting to treat.

I note the authors also discuss the likelihood that bacterial transplantation might also be useful for other bowel-related conditions including inflammatory bowel disease and irritable bowel syndrome (although I offer no endorsement for anything on this blog).

Despite the subject matter, I have to say that I am interested in the combined results of bacterial therapy. There are lots of questions to answer about the hows and whys of this method and importantly, what are we transplanting aside from bacteria, the gut virome for example? Assuming that gut bacteria or pathogens affecting gut health are non-responsive to more traditional anti-microbial forms of treatment, and looking at the success rates included in this review, I wonder also how many GI-related conditions might benefit from such an intervention. Extending GI disease to cover other conditions as a comorbidity also, such as autism and the bacterial work being done there or even Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), does this mean we should be looking at this measure a little more closely rather than just squinting our eyes in disgust?

* Gough E. et al. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. August 2011.

Cytokines and gut motility

A relatively short post this one.

I think most people would understand why gastrointestinal motility is important to our health and wellbeing. Too fast or too slow a transit time is likely to lead to some pretty uncomfortable symptoms and indeed could signal the presence of one of a number of complications.

A recently published review paper on motility in gastrointestinal disorders by Akiho and colleagues* (full-text here) caught my eye. I was interested in this paper because it reviews the association between gastrointestinal motility and the expression of cytokines as a function of which way the immune system might be skewed.

I should perhaps back-up slightly here and provide some commentary on the way the immune system can be poised (according to our current knowledge) and in particular the concepts of Th1 and Th2. A good overview of the T helper cells is here. In brief, it's all to do with different kinds of immunity and how our immune system attempts to strike a balance between cell-mediated immunity (Th1) and humoral immunity (Th2) depending on what particular pathogen the immune system is up against.

The Akiho review paper lists a number of the most common GI disorders currently in the medical dictionary and details what particular types of response and cytokines are tied into the disease state. So for coeliac (celiac) disease and Crohn's disease there is a predominantly Th1 skewed cytokine profile either associated with disease onset or perpetuation. In ulcerative colitis, it is more of a Th2-like response in terms of cytokines associated with the condition. The authors do make mention also about Th17-mediated inflammation (possibly linked to autoimmunity) but this is still very much an emerging area of investigation.

The authors then proceed to review the evidence that Th1-related cytokines seem to show more of an affinity with hypocontractality of inflamed intestinal smooth muscle (slowing down) and Th-2 show a more hypercontractility (speeding up).  This is perhaps too simplistic a view to take, one linked to one but not the other, given the number of cytokines tied into various GI states and the complexity of the whole thing. But their analysis of the current evidence base is an interesting one.

What work like this serves to show is that the our immune system is a fantastic piece of engineering constantly trying to strike a balance between fighting off pathogens and infections and invaders, whilst at the same time keeping the host (us) in working order, trying not to destroy us also. The presentation of GI conditions, many GI conditions, seem to reflect the inner workings (and malfunctions) of the immune system and when establishing how the immune system manifests itself in individual conditions, offers some tantilising insights into potential therapies.

* Akiho H. et al. Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders. World J Gastrointest Pathophysiol. October 2011

The emergency exits are here and here

The title of this post has very little to do with steward / stewardess instructions delivered just before take-off, despite my recently watching the very funny Walliams/Lucas series 'Come Fly With Me'. Rather, with a straight face, I refer to your route into the world and whether Mother Nature required a helping hand in bringing you from the comfort of your watery cocoon into the real world. Could your route of entry alter your risk of developing certain things in later life... say coeliac (celiac) disease?

I am going to keep this post brief because this is a question that I have tackled before on a sister blog post: caesarean section and coeliac disease? The crux of that entry was the emerging suggestion that people born via caesarean section (c-section) were at greater risk of coeliac disease than those who were pushed through the bacteria-filled birth canal.

Further evidence has now emerged concerning a possible relationship in this paper by Marild and colleagues*. The details summarised:

• A case-control study where recorded pregnancy information was collected via a central database between 1973 and 2008.
• Biopsy-verified coeliac disease (CD) was determined for 11,749 participants compared with 53,887 age- and gender-matched non-CD general population controls.
• There was a positive significant association between elective c-section delivery and later CD diagnosis (p=0.005) but none for emergency c-sections.
• Small for dates babies were over 20% more likely to develop CD also.
• No other pregnancy variables showed an association with CD.

I quote from the author's final sentence of their abstract: ".. consistent with the hypothesis that the bacterial flora of the newborn plays a role in the development of celiac disease".

I must point out that whilst bacterial colonisation of the infant gut may be a variable in determining your risk of CD, it is most probably not the only important variable. I don't want anyone reading this entry and taking it to their healthcare provider as 'proof' of anything; it is not. Likewise I am not trying to overturn any 'too posh to push' arguments.

What however can be inferred from this paper is that there may consequences to every action; some consequence might be positive (such as getting a breech presenting infant out of mum and avoiding any very serious complications), some of them might be not-so positive. The trick is to see where this research leads and, just a suggestion, whether an early bacterial 'transplant' from mum to baby one day becomes the norm for those babies who don't end up traversing the birth canal. Just a suggestion.

* Marild K. et al. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology. October 2011.

I, claudin

There is no way that I can blog about the gastrointestinal (GI) tract without making mention of that wonderful barrier separating gut contents from the other recesses of our body. Without being too dramatic, I could probably say that I owe my livelihood to the gut barrier; as a consequence of much of my research career heading towards some involvement for the gut barrier at least in some cases of autism spectrum conditions.

A recent paper brought all the years of reading on this subject back to me with the suggestion of a link between intestinal inflammation and claudin-1. The paper by Poritz and colleagues* describes how key tight junction proteins like occludin and zonula occludens-1 (ZO-1) are decreased in inflammatory bowel diseases and how treatment of intestinal epithelial cells with the inflammatory cytokine TNF-alpha (sorry about the lack of Greek characters) seems to increase permeability (leaky gut). With all due respect to the authors, these findings are nothing new.

What was slightly more interesting from Poritz however were the findings in relation to the ratio of claudin-1 and occludin (C:O) as a consequence of cell treatment with TNF-a and what this ratio looked like in real life when comparing different intestinal diseases like Crohn's disease (CD) and ulcerative colitis (UC). Answer: decreased occludin and increased claudin-1 in diseased UC vs. non-diseased UC and normal colons and nothing spectacularly different in different disease-states of CD or controls.

Even to an interested amateur like me, this data indicate some things potentially very important: (a) ratios between multiples rather than independent statistics might yield more diagnostic information, and (b) there may be some underlying differences in the way that tight junctions might be affected in UC vs. CD.

I will come back to the leaky gut and various other things related to it at some point in the future no doubt. But for now if you really, really want some extra credits bedtime reading, here is an article that I always found invaluable on the subject (long yawn, adjust reading glasses and reach for that glass of scotch on the bedside table).

* Poritz LS. et al. Increase in the tight junction protein claudin-1 in intestinal inflammation. Dig Dis Sci. October 2011.

Gluten, bacteria and mouthwash

Peptides. Those short-ish chains of amino acids, are interesting characters. Therapeutically, certain peptides have the propensity to do great things as exemplified by compounds such as the glucagon-like peptides and speculation on a therapeutic role in conditions like diabetes and intestinal disease.

In terms of 'disease' and ill-health, other peptides have a slightly less desirable side; something which I have been interested in for a few years speculatively in relation to conditions such as autism and schizophrenia. Peptides, such as those immunogenic epitopes derived from gluten, in relation to coeliac (celiac) disease (CD) also perhaps show a less speculative negative side in terms of effect.

What can be done about these immune-stimulating gluten peptides? Well, you could try and break them down via enzymes such as endopeptidases. There are also lots of products on the market which claim to do similar things (bearing in mind that I offer no endorsement). A recent paper by Zamakchari and colleagues* also offers another potential solution: certain enzymes produced by bacteria with the propensity to degrade gluten.

Before you go scouring the Internet for some commercial bacterial supplement, know that the authors suggested that we might already have such bacteria in our 'oral cavity' (mouth in plain speak); in our saliva and dental plaque.

The paper summary:

• Human dental plaque and saliva were collected from willing volunteers and the various oral micro-organisms cultured. Those bacteria with gliadin-degrading activity were identified by 16S rDNA analysis, a sort of molecular fingerprinting service.
• Various bacterial strains were added to synthetic immunogenic peptide sequences from gliadin and the subsequent effects separated and characterised by a combination of reversed-phase HPLC and mass spectrometric detection (MS/MS).
• The results: 27 aerobic and 30 anaerobic bacterial strains capable of metabolising gluten were found. All the final anaerobic strains cultured (n=10 fastest growing) were of the Bifidobacterium genus. The final aerobic strains (n=5 fastest growing) included bacteria of the Rothia genus.
• Several tri-peptide combinations appearing in the greatest frequency within the larger gluten peptides were broken down by individual bacterial strains. Rothia mucilaginosa and Rothia aeria seemed to come out top in terms of their hydrolysing abilities in terms of amounts and time taken. This effect was also noted when the larger immunogenic epitopes were exposed to the Rothia strains. 

There are a few important points to be taken from this research. First is the suggestion that digestion starts in the mouth and that all important motherly advice 'chew your food properly'. Masticating (or chewing to us mere mortals) is an important first step in presenting the food we eat to the rest of our hard-working gastrointestinal (GI) tract. Second is the suggestion that dental plaque (alongside saliva) might actually serve some purpose rather than just being something associated with poor oral hygiene and bad breath. I am not for one minute suggesting that we should all stop our regular tooth cleaning routine; but perhaps just step back and think about when you clean your teeth and what products you might use in your dental hygiene routine. Finally (finally!) I am already a big fan of the idea that our relationship with bacteria, some strains of bacteria, is an important one. A primary implication from this work is that 'addition' of bacteria to food or whilst eating certain foods (bearing in mind the effect of pH on these bacteria) might actually serve as another tool in the arsenal against conditions like coeliac disease, and even gluten sensitivity when it comes to degrading those very difficult gluten peptides. Please note that I am not recommending anything from this point given the slightly more negative press from these strains; just speculating.

* Zamakhchari M. et al. Identification of Rothia bacteria as gluten-degrading natural colonizers of the upper gastro-intestinal tract. PLoS ONE. September 2011.