OK, so just for the record I'm not actually saying that NICE (the National Institute for Health and Care Excellence) actually provide faecal microbiota transplants (FMTs) as some sort of in-house service; that's not their job. But as the BBC reported (see here) they have published guidance on the use of FMT specifically with recurrent Clostridium difficile infection in mind (see here for the full guidance). And that guidance is, as was expected, positive on the use of FMTs where and when other treatments have failed.
I'm not surprised that they have come down on the side of FMTs for recurrent C.diff infection in light of the data being presented, some of which has been previously covered on this blog. As I've mentioned before, however you perceive this type of intervention and the thought of receiving the collected bacteria from someone else's deepest, darkest recesses, FMT does seem to reach the parts that other treatments fail to do for some people.
I suppose the next question is: are there other conditions or other instances where FMT might prove to be useful? (hint: possibly... but with more research required).
Wednesday, 26 March 2014
Thursday, 12 September 2013
A true rise in pediatric coeliac disease
Consider this something of a micro blog post as I offer up your scientific TV dinner today in the form of the paper by White and colleagues* (open-access) on the numbers game when it comes to coeliac disease (even celiac disease if you prefer) in children.
On the understanding that not everyone knows about the currently known hows and whys of coeliac disease (CD) - the premier autoimmune condition linked to the protein gluten - readers might want to check out my CD mega-post over on a sister blog (see here).
Self-promotion over and done with, the paper from White et al looking at the incidence (that's incidence not prevalence) of CD is an important one, because as the authors conclude: "The significant increase in classic cases is strongly suggestive of a true rise in CD incidence". In other words, it's not just about better case ascertainment, at least when it comes to CD in Scotland.
So to the next question: 'why the increase?' We've been given a few areas that might require some further investigation (see here and here and here) but I'm not going to make any sweeping generalisations at this time.
On the understanding that not everyone knows about the currently known hows and whys of coeliac disease (CD) - the premier autoimmune condition linked to the protein gluten - readers might want to check out my CD mega-post over on a sister blog (see here).
Self-promotion over and done with, the paper from White et al looking at the incidence (that's incidence not prevalence) of CD is an important one, because as the authors conclude: "The significant increase in classic cases is strongly suggestive of a true rise in CD incidence". In other words, it's not just about better case ascertainment, at least when it comes to CD in Scotland.
So to the next question: 'why the increase?' We've been given a few areas that might require some further investigation (see here and here and here) but I'm not going to make any sweeping generalisations at this time.
Friday, 12 July 2013
Probiotic mix effective for IBS?
We are already starting to appreciate just how (a) complex and (b) important our gut microbiota are to health and wellbeing outside of the more traditional duties of food digestion and making the odd nutrient or two. Those trillions of beasties which call us home seem to be cropping up everywhere these days in research terms, based on investigations as diverse as obesity (see here) and autoimmunity (see here) even to the point of speculation about involvement in psychological development (see here) (mice, not humans, mice... so far). That and the fact that stability seems to be a good word to describe their bacterial lives* (assuming that you don't swallow a grenade).
That being said, the involvement of gut bacteria whether alone or as part of the triad of gut involvement - gut bacteria, gut permeability and mucosal / systemtic immunity** - in relation to gastrointestinal (GI) illness and/or dysfunction should not get too lost in the dialogue. Indeed, how modification of gut bacteria, whether through diet, medicine or other means (yes, yuck factor 10) remains a real point of interest when it comes to GI conditions.
With that in mind I turn today to the paper by Yoon and colleagues*** who following quite a rigourous trial (double-blind, placebo-controlled) suggested that a mix of probiotics given over 4 weeks might be able to do some positive things to the symptoms of formally diagnosed irritable bowel syndrome (IBS). The "multi-species" mix included various species and strains: Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Streptococcus thermophilus. The authors reported that more of those in receipt of the probiotic mix reported greater relief from their IBS symptoms over and above placebo, and when looking at fecal microflora, there were accompanying changes too as a result of the mix. Interestingly even in the placebo group there were some bacterial changes to be had (mind over matter?).
I know that the Yoon paper is not necessarily new news when it comes to probiotics and IBS (see here) but what this paper does add is its suggestion that rather than thinking too narrow about specific bacteria and species affecting specific conditions, we should perhaps be taking a more broad perspective and realising that the whole is greater than the sum of its parts when it comes to the intricate connections between our various passengers residing in the gut.
----------
* Faith JJ. et al. The long-term stability of the human gut microbiota. Science. 2013 Jul 5;341(6141):1237439. doi: 10.1126/science.1237439.
** Groeger D. et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013 Jun 21;4(4).
*** Yoon JS. et al. Effect of multi-species probiotics on irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Gastroenterol Hepatol. 2013 Jul 5. doi: 10.1111/jgh.12322.
----------
That being said, the involvement of gut bacteria whether alone or as part of the triad of gut involvement - gut bacteria, gut permeability and mucosal / systemtic immunity** - in relation to gastrointestinal (GI) illness and/or dysfunction should not get too lost in the dialogue. Indeed, how modification of gut bacteria, whether through diet, medicine or other means (yes, yuck factor 10) remains a real point of interest when it comes to GI conditions.
With that in mind I turn today to the paper by Yoon and colleagues*** who following quite a rigourous trial (double-blind, placebo-controlled) suggested that a mix of probiotics given over 4 weeks might be able to do some positive things to the symptoms of formally diagnosed irritable bowel syndrome (IBS). The "multi-species" mix included various species and strains: Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Streptococcus thermophilus. The authors reported that more of those in receipt of the probiotic mix reported greater relief from their IBS symptoms over and above placebo, and when looking at fecal microflora, there were accompanying changes too as a result of the mix. Interestingly even in the placebo group there were some bacterial changes to be had (mind over matter?).
I know that the Yoon paper is not necessarily new news when it comes to probiotics and IBS (see here) but what this paper does add is its suggestion that rather than thinking too narrow about specific bacteria and species affecting specific conditions, we should perhaps be taking a more broad perspective and realising that the whole is greater than the sum of its parts when it comes to the intricate connections between our various passengers residing in the gut.
----------
* Faith JJ. et al. The long-term stability of the human gut microbiota. Science. 2013 Jul 5;341(6141):1237439. doi: 10.1126/science.1237439.
** Groeger D. et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013 Jun 21;4(4).
*** Yoon JS. et al. Effect of multi-species probiotics on irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Gastroenterol Hepatol. 2013 Jul 5. doi: 10.1111/jgh.12322.
----------
Tuesday, 21 May 2013
Gut bacteria determines social development? Psychobacteriomics?
The paper by Desbonnet and colleagues* (open-access) asks some intriguing questions about how our gut bacteria - those trillions of passengers which we all carry in our deepest, darkest recesses - might have the propensity to affect the behavioural development of a mouse specifically focused on social development.
Whilst to some people this might not sound like a particularly exciting finding, to others such a suggestion might potentially signal the start of a whole new way of looking at how our (human) physiology might actually impact on our psychological development. Move over Piaget et al and make way for something rather more complex. Even possibly a new -omic..... psychobacteriomics (you heard here first folks).
OK let's not get ahead of ourselves here. This was only a small study of germ-free (GF) and conventionally colonised (with bacteria) mice measuring their mouse-like behaviours across various 'sociability tests'. Mice are mice not humans and this finding needs replication.
That being said I'm interested. I'm interested whether these findings could be crossed over to other animals and even humans. I'm interested whether different bacteria might be linked to various aspects of social development. I'm interested whether this means that taking lots of antimicrobials during early infancy could affect social development. Indeed, I'm interested if this might have implications for the arguments: breast vs. bottle, c-section vs. natural birth, even whether supplementation with probiotics during critical stages of development might show some relationship to a person social development bearing in mind I'm not making any recommendations by the way.
And then there's conditions like autism to consider...
----------
* Desbonnet L. et al. Microbiota is essential for social development in the mouse. Molecular Psychiatry. May 2013.
----------
Whilst to some people this might not sound like a particularly exciting finding, to others such a suggestion might potentially signal the start of a whole new way of looking at how our (human) physiology might actually impact on our psychological development. Move over Piaget et al and make way for something rather more complex. Even possibly a new -omic..... psychobacteriomics (you heard here first folks).
OK let's not get ahead of ourselves here. This was only a small study of germ-free (GF) and conventionally colonised (with bacteria) mice measuring their mouse-like behaviours across various 'sociability tests'. Mice are mice not humans and this finding needs replication.
That being said I'm interested. I'm interested whether these findings could be crossed over to other animals and even humans. I'm interested whether different bacteria might be linked to various aspects of social development. I'm interested whether this means that taking lots of antimicrobials during early infancy could affect social development. Indeed, I'm interested if this might have implications for the arguments: breast vs. bottle, c-section vs. natural birth, even whether supplementation with probiotics during critical stages of development might show some relationship to a person social development bearing in mind I'm not making any recommendations by the way.
And then there's conditions like autism to consider...
----------
* Desbonnet L. et al. Microbiota is essential for social development in the mouse. Molecular Psychiatry. May 2013.
----------
Tuesday, 14 May 2013
Akkermansia muci... muciniphila and diet induced obesity
It just rolls off the tongue: Akkermansia muciniphila*.
As we speak A.muciniphila is making headlines across the world based on the study by Amandine Everard and colleagues** (open-access) on what happened to mice who had or were lacking in this stalwart of the gut microbiome.
No need for me to go into great detail about the Everard trial because (a) the paper is open-access and (b) it's already received plenty of coverage as per an entry in Nature (see here) and the National Geographic (see here).
The long-and-short of it (I should perhaps rename this blog with those words) was that A.muciniphila is, as it's name suggests, a bacteria with a connection to mucin; in particular it's love of the stuff. The finding: mice who were obese and diabetic (type 2 diabetes) seemed to have lower levels of A.muciniphila, and "that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance". The speculation is whether these mouse findings might, just might turn out to be something truly remarkable for humans presenting with similar symptoms.
But as with everything in life, things are rarely so simple. My first thought when I saw the name A.muciniphila were the intriguing findings reported by Lynne Wang and colleagues*** of lower numbers of A.muciniphila in fecal samples from children diagnosed with an autism spectrum disorder and their siblings. Just in case your interested, I talked about this paper on a post for a sibling blog. So unless we are talking about children with autism subsequently being a greater risk for obesity and type 2 diabetes, I would wager that there is more to A.muciniphila than just weight loss and insulin.
Leaky gut anyone?
----------
* Derrien M. et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. IJSEM. 2004; 54: 1469-1476.
** Everard A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS. May 2013.
*** Wang L. et al. Low Relative Abundances of the Mucolytic Bacterium Akkermansia muciniphila and Bifidobacterium spp. in Feces of Children with Autism. Appl Environ Microbiol. 2011; 77: 6718–6721.
----------
As we speak A.muciniphila is making headlines across the world based on the study by Amandine Everard and colleagues** (open-access) on what happened to mice who had or were lacking in this stalwart of the gut microbiome.
No need for me to go into great detail about the Everard trial because (a) the paper is open-access and (b) it's already received plenty of coverage as per an entry in Nature (see here) and the National Geographic (see here).
The long-and-short of it (I should perhaps rename this blog with those words) was that A.muciniphila is, as it's name suggests, a bacteria with a connection to mucin; in particular it's love of the stuff. The finding: mice who were obese and diabetic (type 2 diabetes) seemed to have lower levels of A.muciniphila, and "that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance". The speculation is whether these mouse findings might, just might turn out to be something truly remarkable for humans presenting with similar symptoms.
But as with everything in life, things are rarely so simple. My first thought when I saw the name A.muciniphila were the intriguing findings reported by Lynne Wang and colleagues*** of lower numbers of A.muciniphila in fecal samples from children diagnosed with an autism spectrum disorder and their siblings. Just in case your interested, I talked about this paper on a post for a sibling blog. So unless we are talking about children with autism subsequently being a greater risk for obesity and type 2 diabetes, I would wager that there is more to A.muciniphila than just weight loss and insulin.
Leaky gut anyone?
----------
* Derrien M. et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. IJSEM. 2004; 54: 1469-1476.
** Everard A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS. May 2013.
*** Wang L. et al. Low Relative Abundances of the Mucolytic Bacterium Akkermansia muciniphila and Bifidobacterium spp. in Feces of Children with Autism. Appl Environ Microbiol. 2011; 77: 6718–6721.
----------
Wednesday, 8 May 2013
Gluten exclusion for cases of diarrhoea predominant IBS
If I had the intellect I would try and deliver this very concise entry in the form of a witty poem or ditty just to try and make things a little more entertaining for readers rather than enduring yet another dry excuse for not making a proper "chatty" post. Unfortunately, I am to poetry what chocolate is to teapot material, so won't even try.
Instead I offer a link to a potentially very, very interesting trial by Maria Vazquez–Roque and colleagues* (open-access) reporting physiological results based on the use of a gluten-free diet for cases of irritable bowel syndrome (IBS) diarrhoea predominant type. The accompanying editorial by Lowe and Moseley** does a great job of summing up what Vazquez-Roque et al found, so leaves me very little to add.
Basically, under randomised-controlled conditions, "Patients on the gluten-containing diet exhibited greater small intestinal permeability than those on the gluten-free diet. The study was able to measure significant changes that provided physiologic support for a gluten-free diet in patients with IBS-D without celiac disease".
Whilst small intestinal permeability - also known as gut hyperpermeability or leaky gut - is already discussed in coeliac disease (CD) circles, the added-value from this recent trial is the suggestion that the effect of gluten on permeability might extend slightly outside of just diagnosed CD. I'm not getting into the nitty-gritty of the MHC and those CD-related serotypes at this point even though they were important to the findings. Also too were some interesting results based on those tight junction proteins including 'General' zonulin.
I do wonder how far outside of CD and indeed IBS-D we might venture with these findings. Y'know that very interesting paper from Laura de Magistris and colleagues*** (discussed here) with autism in mind; bearing in mind of course the experimental differences between the studies and that autism is not IBS....
Maybe also at this point I'll also introduce the latest study by Jessica Biesiekierski and colleagues**** on non-coeliac gluten sensitivity (see here) in relation to FODMAPs and gluten as further fodder for consumption.
Now, 'the boy stood on the burning deck....' (scroll down the link to see the Spike Milligan parody).
---------
* Vazquez–Roque MI. et al. A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology. 2013; 144: 903-911.
** Lowe AW. & Moseley RH. Covering the Cover. Gastroenterology. 2013; 144: 859-862.
*** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010; 51: 418-424.
**** Biesiekierski JR. et al. No Effects of Gluten in Patients with Self-Reported Non-Celiac Gluten Sensitivity Following Dietary Reduction of Low-Fermentable, Poorly-Absorbed, Short-Chain Carbohydrates. Gastroenterology. May 2013.
----------
Instead I offer a link to a potentially very, very interesting trial by Maria Vazquez–Roque and colleagues* (open-access) reporting physiological results based on the use of a gluten-free diet for cases of irritable bowel syndrome (IBS) diarrhoea predominant type. The accompanying editorial by Lowe and Moseley** does a great job of summing up what Vazquez-Roque et al found, so leaves me very little to add.
Basically, under randomised-controlled conditions, "Patients on the gluten-containing diet exhibited greater small intestinal permeability than those on the gluten-free diet. The study was able to measure significant changes that provided physiologic support for a gluten-free diet in patients with IBS-D without celiac disease".
Whilst small intestinal permeability - also known as gut hyperpermeability or leaky gut - is already discussed in coeliac disease (CD) circles, the added-value from this recent trial is the suggestion that the effect of gluten on permeability might extend slightly outside of just diagnosed CD. I'm not getting into the nitty-gritty of the MHC and those CD-related serotypes at this point even though they were important to the findings. Also too were some interesting results based on those tight junction proteins including 'General' zonulin.
I do wonder how far outside of CD and indeed IBS-D we might venture with these findings. Y'know that very interesting paper from Laura de Magistris and colleagues*** (discussed here) with autism in mind; bearing in mind of course the experimental differences between the studies and that autism is not IBS....
Maybe also at this point I'll also introduce the latest study by Jessica Biesiekierski and colleagues**** on non-coeliac gluten sensitivity (see here) in relation to FODMAPs and gluten as further fodder for consumption.
Now, 'the boy stood on the burning deck....' (scroll down the link to see the Spike Milligan parody).
---------
* Vazquez–Roque MI. et al. A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology. 2013; 144: 903-911.
** Lowe AW. & Moseley RH. Covering the Cover. Gastroenterology. 2013; 144: 859-862.
*** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010; 51: 418-424.
**** Biesiekierski JR. et al. No Effects of Gluten in Patients with Self-Reported Non-Celiac Gluten Sensitivity Following Dietary Reduction of Low-Fermentable, Poorly-Absorbed, Short-Chain Carbohydrates. Gastroenterology. May 2013.
----------
Thursday, 28 March 2013
Gut bacteria - obesity and coeliac disease - stem cells
Another very quick post to bring to your attention two very interesting papers which caught my attention recently.
The first is by Ciccocioppo and colleagues* and how, quote: "allogeneic HSCT may lead to induction of gluten tolerance in patients with CD [coeliac disease]." HSCT = hematopoietic stem cell transplantation, which is indeed as controversial as it sounds. Two patients, both with CD and β-thalassemia major who at 5 year follow-up after HSCT did not appear to show a reappearance of the some of the serological and histological markers of CD following gluten consumption. I'm not making any recommendations from this (or anything else) aside from stressing the need for quite a bit more research in this area.
The second paper by Liou and colleagues** suggested that based on a mouse model, changes to the gastrointestinal (GI) bacterial population following a gastric bypass might play some role in the weight loss above and beyond the surgery itself. This paper has received gallons of media coverage from places such as the BBC (see here) to Scientific American (see here) to Nature (see here). It's an interesting idea, that our gut bacteria might actually influence our body shape and particularly pertinent to our modern day obsession with weight and its health implications. That's not to say that this is the first time such a suggestion has been made (see this and this post from a sister blog) but at least now it is in the public consciousness and potentially opens the door to lots of possibilities not least the dreaded fecal bacterial transplant...
----------
* Ciccocioppo R. et al. Allogeneic Hematopoietic Stem Cell Transplantation May Restore Gluten Tolerance in Patients With Celiac Disease. J Pediatr Gastroenterol Nutr. 2013; 56: 422-427.
** Liou AP. et al. Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity. Sci Transl Med 2013; 5: 178ra41.
The first is by Ciccocioppo and colleagues* and how, quote: "allogeneic HSCT may lead to induction of gluten tolerance in patients with CD [coeliac disease]." HSCT = hematopoietic stem cell transplantation, which is indeed as controversial as it sounds. Two patients, both with CD and β-thalassemia major who at 5 year follow-up after HSCT did not appear to show a reappearance of the some of the serological and histological markers of CD following gluten consumption. I'm not making any recommendations from this (or anything else) aside from stressing the need for quite a bit more research in this area.
The second paper by Liou and colleagues** suggested that based on a mouse model, changes to the gastrointestinal (GI) bacterial population following a gastric bypass might play some role in the weight loss above and beyond the surgery itself. This paper has received gallons of media coverage from places such as the BBC (see here) to Scientific American (see here) to Nature (see here). It's an interesting idea, that our gut bacteria might actually influence our body shape and particularly pertinent to our modern day obsession with weight and its health implications. That's not to say that this is the first time such a suggestion has been made (see this and this post from a sister blog) but at least now it is in the public consciousness and potentially opens the door to lots of possibilities not least the dreaded fecal bacterial transplant...
----------
* Ciccocioppo R. et al. Allogeneic Hematopoietic Stem Cell Transplantation May Restore Gluten Tolerance in Patients With Celiac Disease. J Pediatr Gastroenterol Nutr. 2013; 56: 422-427.
** Liou AP. et al. Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity. Sci Transl Med 2013; 5: 178ra41.
Tuesday, 26 February 2013
The science of microbiomics
A very short post to plug... well, to plug me really, and my very, very small contribution to an article featuring in the Pharmaceutical Journal titled: Microbiomics: its growing significance in the world of medicines testing. The article is only open-access for a short period of time, so if you happen to have stumbled across this post years and years into the future (today is Tuesday 26th February 2013 according to my flux-capacitated DeLorean) sorry.
But just so you don't feel to left out, a few article highlights: yoghurt and C.diff infection, the human microbiome project (HMP), gut bacteria and immune function, dysbiosis, the microbiota-gut-brain axis, fecal transplants (yuck factor 10) and pharmacometabonomics.
But just so you don't feel to left out, a few article highlights: yoghurt and C.diff infection, the human microbiome project (HMP), gut bacteria and immune function, dysbiosis, the microbiota-gut-brain axis, fecal transplants (yuck factor 10) and pharmacometabonomics.
Sunday, 24 February 2013
Gluten, guts and glory
Yep, I know. First post for several months - indeed first post for 2013 - and more apologies to readers about not keeping up with this blog. A short post on this occasion focused on an interesting opinion piece by Moises Velasquez-Manoff titled: Who has the guts for gluten?
I'll admit to being pretty entertained by the work of Velasquez-Manoff given his previous articles crossing over into topics like autism spectrum disorders (see here and also covered here). This latest piece is equally thought-provoking and alongside the opinions of people like Alessio Fasano, he of the [General] zonulin (see here), asks some potentially important questions about our relationship with gluten.
One quote in particular caught my attention from Dr Fasano: “Keep the lactobacilli high enough in the guts of these kids, and you prevent autoimmunity.” following some observations based on the onset of type 1 diabetes and coeliac (celiac) disease.
I'm intrigued and am waiting for that confirmatory peer-reviewed evidence.
I'll admit to being pretty entertained by the work of Velasquez-Manoff given his previous articles crossing over into topics like autism spectrum disorders (see here and also covered here). This latest piece is equally thought-provoking and alongside the opinions of people like Alessio Fasano, he of the [General] zonulin (see here), asks some potentially important questions about our relationship with gluten.
One quote in particular caught my attention from Dr Fasano: “Keep the lactobacilli high enough in the guts of these kids, and you prevent autoimmunity.” following some observations based on the onset of type 1 diabetes and coeliac (celiac) disease.
I'm intrigued and am waiting for that confirmatory peer-reviewed evidence.
Friday, 14 September 2012
Gut microbes and health
I'd like to apologise to my Gutness Gracious Me blog. I've neglected you and your subscribers for quite a few months now and I'm sorry. I have no excuse so please accept my humble apology.
Friends again?
OK. There's been quite a bit of new research come out in the intervening months which I need to catch up on. For this entry I'm going to list a couple of interesting papers showing how, if it was ever needed, gut bacteria really are starting to be taken quite seriously in lots of science circles.
Nature is a good starting point (the journal Nature not nature in general). A whole supplement was recently dedicated to gut bacteria which can be viewed here. Unfortunately the papers aren't open-access but I might draw your attention to two of them in particular:
Next up is another Nature journal, Nature Neuroscience, which carried an interesting piece by Cryan & Dinan***** on the potential 'mind-altering' effects of gut bacteria and everyone's favourite term: the gut-brain axis. I've kinda done bacteria potentially influencing behaviour before on a sister blog entry (see here) so don't really want to rehash that again. Suffice to say that as well as being home to quite a lot of bacteria, our gut also houses quite a few neurotransmitters and their receptors more traditionally associated with brain, so why would we expect these not to potentially serve functions other than controlling gut motility and the like. Whether there is interaction between these neurotransmitters and gut bacteria.... well I'd speculate there might very well be.
----------
* Tremaroli V. & Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012; 489: 242-249.
** Semova I. et al. Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish. Cell Host & Microbe. 2012; 12: 277-288.
*** Maynard CL. et al. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 489: 231-241.
**** Cucchiara S. et al. Interactions between intestinal microbiota and innate immune system in pediatric inflammatory bowel disease. Journal of Clinical Gastroenterology. 2012; 46: S64-S66.
***** Cryan JF. & Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews: Neuroscience. September 2012.
Friends again?
OK. There's been quite a bit of new research come out in the intervening months which I need to catch up on. For this entry I'm going to list a couple of interesting papers showing how, if it was ever needed, gut bacteria really are starting to be taken quite seriously in lots of science circles.
Nature is a good starting point (the journal Nature not nature in general). A whole supplement was recently dedicated to gut bacteria which can be viewed here. Unfortunately the papers aren't open-access but I might draw your attention to two of them in particular:
- Valentina Tremaroli & Fredrik Bäckhed* discuss the "functional interactions between the gut microbiota and host metabolism" and how gut bacteria might, just might have the ability to affect how we derive energy from our food. I suppose this crosses quite a few different issues such as 'is a calorie a calorie' and how overweight and obesity might not just be a simple 'energy in - energy out' relationship. Indeed the concept of gut bacteria potentially regulating metabolism and absorption of things like fatty acids as per this paper by Semova and colleagues** (discussed here) may very well also be relevant.
- The paper by Craig Maynard and colleagues*** highlights another important function of our gut bacteria with regards to immune function and how the communication between the two systems may have the ability to influence our health and ill-health. Other authors have similarly speculated on this process as per this study by Cucchiara and colleagues**** using pediatric inflammatory bowel disease as an example.
Next up is another Nature journal, Nature Neuroscience, which carried an interesting piece by Cryan & Dinan***** on the potential 'mind-altering' effects of gut bacteria and everyone's favourite term: the gut-brain axis. I've kinda done bacteria potentially influencing behaviour before on a sister blog entry (see here) so don't really want to rehash that again. Suffice to say that as well as being home to quite a lot of bacteria, our gut also houses quite a few neurotransmitters and their receptors more traditionally associated with brain, so why would we expect these not to potentially serve functions other than controlling gut motility and the like. Whether there is interaction between these neurotransmitters and gut bacteria.... well I'd speculate there might very well be.
----------
* Tremaroli V. & Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012; 489: 242-249.
** Semova I. et al. Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish. Cell Host & Microbe. 2012; 12: 277-288.
*** Maynard CL. et al. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 489: 231-241.
**** Cucchiara S. et al. Interactions between intestinal microbiota and innate immune system in pediatric inflammatory bowel disease. Journal of Clinical Gastroenterology. 2012; 46: S64-S66.
***** Cryan JF. & Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews: Neuroscience. September 2012.
Wednesday, 27 June 2012
General Zod? No, General Zonulin
I hold my hands up and admit that gut hyperpermeability - leaky gut - is a bit of an obsession of mine. I know to some the mere mention of leaky gut conjures up images of 'alternative medicine' and all things tree-hugging. Just for the record I've never knowingly hugged any tree and am a meat eating, petrol car driving, house dwelling regular guy who has yet to dabble in anything 'alternative' assuming that the odd vitamin D tablet and probiotic counts as regular. Still I remain very interested in how abnormal gastrointestinal (GI) permeability might be tied into quite a few conditions.
One aspect of GI permeability in particular has surfaced quite recently on my research radar, an interesting compound called zonulin.
A description first. Zonulin enjoys quite a special place in the science of the tight junctions. Tight junctions (TJs) among other roles, serve quite an important barrier function in lots of parts of the body; so making sure that things stay in and other things stay out. Zonulin seems to be part and parcel of the chemistry of tight junctions and in particular sharing quite an important relationship with the enhanced permeability of TJs.
With the gut in mind, zonulin has found quite a bit of interest. A familiar name to this blog, Dr Alessio Fasano, seems to have been present right at the beginning of interest in zonulin, with a particular focus on gut permeability tied into the presence of coeliac (celiac) disease as per this article* and write-up.
Ever since then, zonulin has just been making wave** (full-text) after wave*** (full-text) after wave**** as per its 'disassembly' activity when it comes to TJs. The initial link with coeliac disease is an interesting one given that later work suggested that gluten, or rather the gliadin fraction of gluten, has the propensity to induce zonulin release***** (at least under certain laboratory conditions).
But coeliac disease was just the starting point for zonulin, as more recent research has suggested a potential role for this protein in relation to gut permeability in type-1 diabetes (here and here), obesity (here) and potentially quite a few other conditions (here) with a specific focus on autoimmune conditions. General Zod? No, General Zonulin.
Accepting that there still remains some work to do on zonulin with regards to the methods and mode of action of zonulin on gut permeability******* this is a very interesting protein.
With my 'wondering' hat on, I have a few questions:
----------
* Fasano A. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000; 355: 1518-1519.
** Wang W. et al. Human zonulin, a potential modulator of intestinal tight junctions. Journal of Cell Science. 2000; 113: 4435-4440.
*** Fasano A. Intestinal zonulin: open sesame! Gut. 2001; 49: 159-162.
**** El Asmar R. et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002; 123: 1607-1615.
***** Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003; 52: 218-223.
****** Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012; 1258: 25-33.
******* Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Reports. June 2012
One aspect of GI permeability in particular has surfaced quite recently on my research radar, an interesting compound called zonulin.
A description first. Zonulin enjoys quite a special place in the science of the tight junctions. Tight junctions (TJs) among other roles, serve quite an important barrier function in lots of parts of the body; so making sure that things stay in and other things stay out. Zonulin seems to be part and parcel of the chemistry of tight junctions and in particular sharing quite an important relationship with the enhanced permeability of TJs.
With the gut in mind, zonulin has found quite a bit of interest. A familiar name to this blog, Dr Alessio Fasano, seems to have been present right at the beginning of interest in zonulin, with a particular focus on gut permeability tied into the presence of coeliac (celiac) disease as per this article* and write-up.
Ever since then, zonulin has just been making wave** (full-text) after wave*** (full-text) after wave**** as per its 'disassembly' activity when it comes to TJs. The initial link with coeliac disease is an interesting one given that later work suggested that gluten, or rather the gliadin fraction of gluten, has the propensity to induce zonulin release***** (at least under certain laboratory conditions).
But coeliac disease was just the starting point for zonulin, as more recent research has suggested a potential role for this protein in relation to gut permeability in type-1 diabetes (here and here), obesity (here) and potentially quite a few other conditions (here) with a specific focus on autoimmune conditions. General Zod? No, General Zonulin.
Accepting that there still remains some work to do on zonulin with regards to the methods and mode of action of zonulin on gut permeability******* this is a very interesting protein.
With my 'wondering' hat on, I have a few questions:
- Assuming the link between type-1 diabetes, gut permeability and zonulin holds up, does this mean that a gluten-free diet might be 'advantageous' for at least some people with type-1 diabetes? I'm thinking about this recent case study******* as a template. I would also add that no medical advice is given or intended by this question.
- Gut hyperpermeability, leaky gut, has been documented in other conditions including one close to my research heart, autism spectrum conditions (see here). Again noting the suggestions by de Magistris and colleagues (here) on how a gluten- & casein-free diet seemed to affect measures of gut permeability in their cohort, is it perhaps time to look at zonulin with regards to conditions like autism? How about schizophrenia also?
- Finally(!), the amino acid glutamine and its proposed tie up with gut permeability. Might glutamine affect zonulin production or even the other way around? Or am I just confusing things and heading out a step too far?
----------
* Fasano A. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000; 355: 1518-1519.
** Wang W. et al. Human zonulin, a potential modulator of intestinal tight junctions. Journal of Cell Science. 2000; 113: 4435-4440.
*** Fasano A. Intestinal zonulin: open sesame! Gut. 2001; 49: 159-162.
**** El Asmar R. et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002; 123: 1607-1615.
***** Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003; 52: 218-223.
****** Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012; 1258: 25-33.
******* Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Reports. June 2012
Wednesday, 13 June 2012
The Human Microbiome Project
13th June 2012. The Human Microbiome Project reports first results on the bacterial constitution of 242 healthy adults sampled over 15-18 body parts up to three times. Framework results can be viewed here* (full-text) alongside what they found results here** and represent a bit of a milestone in our beginning to understanding how the trillions of bacteria which inhabit the human body, either in it or on it, play an important role in our lives.
I have to say that I am pretty excited about these papers and the other results published which can all be found at the PLoS Collections site (here). There is a massive of amount of material to go through which I want to talk about in future posts. For now, browse through a moment in scientific history.
* The Human Microbiome Project Consortium. A framework for human microbiome research. Nature. June 2012
DOI: 10.1038/nature11209
** The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. June 2012
DOI: 10.1038/nature11234
I have to say that I am pretty excited about these papers and the other results published which can all be found at the PLoS Collections site (here). There is a massive of amount of material to go through which I want to talk about in future posts. For now, browse through a moment in scientific history.
* The Human Microbiome Project Consortium. A framework for human microbiome research. Nature. June 2012
DOI: 10.1038/nature11209
** The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. June 2012
DOI: 10.1038/nature11234
Thursday, 17 May 2012
Coeliac disease as a model of autoimmunity
A very short post primarily to link to a recent paper by Kumar and colleagues* (full-text, at least for the moment).
The paper is a sort of 'all you ever wanted to know about coeliac / celiac disease but were afraid to ask' type piece and jolly informative in terms of what we think we know so far about the condition regarding genes, heritability, biochemistry and the like.
Just for good measure, here also are a few other links to some interesting discussions appearing in Nature recently on our gut microbiota and the Barker hypothesis. All I will say is 'all hail our gut bacteria' and onwards with the epigenetic revolution.
Happy reading!
P.S. I know I have been neglecting this blog for a few weeks and apologise. I will hopefully devote more time to it as the year goes on. In the meantime, a link to a peculiar song which has been running through my mind for a few week now.. Gotye and 'Somebody that I used to know' (UK readers might have heard this as an advert for 2Day 2012 from BBC Radio 2).
* Kumar V. et al. From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Seminars in Immunopathology. May 2012
DOI: 10.1007/s00281-012-0312-1
The paper is a sort of 'all you ever wanted to know about coeliac / celiac disease but were afraid to ask' type piece and jolly informative in terms of what we think we know so far about the condition regarding genes, heritability, biochemistry and the like.
Just for good measure, here also are a few other links to some interesting discussions appearing in Nature recently on our gut microbiota and the Barker hypothesis. All I will say is 'all hail our gut bacteria' and onwards with the epigenetic revolution.
Happy reading!
P.S. I know I have been neglecting this blog for a few weeks and apologise. I will hopefully devote more time to it as the year goes on. In the meantime, a link to a peculiar song which has been running through my mind for a few week now.. Gotye and 'Somebody that I used to know' (UK readers might have heard this as an advert for 2Day 2012 from BBC Radio 2).
* Kumar V. et al. From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Seminars in Immunopathology. May 2012
DOI: 10.1007/s00281-012-0312-1
Monday, 19 March 2012
Gut microflora, coeliac disease and introducing gluten
A new paper by Sellitto and colleagues* (full-text) has been causing quite a bit of interest in certain circles. The paper as the name suggests is [partially] a 'proof of concept' study which includes several topics of interest for this blog with its focus on gut microflora (and dysbiosis), coeliac (celiac) disease (CD) and some interesting metabolomics science. The added value comes with the name Alessio Fasano as part of the authorship list.
There is quite a bit of details to this paper but in essence the aims were: (i) to characterise the changes from birth to 24 months in terms of gut bacteria to genetically at-risk of coeliac disease children as a function of early or delayed introduction of gluten to the diet, and (ii) to undertake a range of analytical methods to map such bacterial populations with the hope of further informing on any relationship between gut bacteria and coeliac disease.
The paper is full-text but a quick summary of proceedings and findings:
It's taken me a while to get my head around all the findings from this recent paper because there was a lot of data produced bearing in mind the small participant group and preliminary status of the paper. One of the first things that did strike me is the overlap in these findings and some fairly recent data published looking at carbohydrate metabolism and autism included in this post. Decreasing Bacteriodetes and increasing Firmicutes was the preliminary finding from Williams and colleagues*** bearing in mind the difference in samples being analysed and the lack of data on HLA DQ2 / HLA DQ8 genotype provided in the group with autism being studied. I'm not going to say too much more of this 'similarity' aside from the fact that screening for coeliac disease and/or excessive intestinal permeability perhaps ought to be much more commonly undertaken in cases of autism spectrum conditions just to rule them out.
Quite a few mentions of the word 'dysbiosis' are also recorded in the current paper which reaffirms the possibility of a connection between the various populations of bacteria that reside within us and our potential risk of disease. I like the idea that this study looked at both the metabolomic and genomic side of things even if it was just based on the HLA DQ geneotypes.
So from the starting point of a genetic susceptibility to gluten, we have preliminary data on functional changes to the microbiome in susceptible people and some interesting tools for looking at how this might be expressed functionally. I look forward to more studies of this type with greater participant numbers, and in particular how such findings might extend into other autoimmune conditions and even beyond just somatic presentation.
* Sellitto M. et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE. March 2012
DOI: 10.1371/journal.pone.0033387
** Palmer C. et al. Development of the human infant intestinal microbiota. PLoS Biology. 2007; 5:e177
DOI: 10.1371/journal.pbio.0050177
*** Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. September 2011.
DOI: 10.1371/journal.pone.0024585
There is quite a bit of details to this paper but in essence the aims were: (i) to characterise the changes from birth to 24 months in terms of gut bacteria to genetically at-risk of coeliac disease children as a function of early or delayed introduction of gluten to the diet, and (ii) to undertake a range of analytical methods to map such bacterial populations with the hope of further informing on any relationship between gut bacteria and coeliac disease.
The paper is full-text but a quick summary of proceedings and findings:
- Forty-seven infants who had one parent with biopsy-proven CD were initially recruited before weaning had commenced. All were breastfed from birth to at least 6 months of age. From 6-12 months of age, 30 infants positive for either the HLA DQ2 and/or HLA DQ8 genotypes were randomly allocated to either a gluten-free - delayed gluten exposure - group (n=13) or a gluten load - early exposure - group (n=17).
- A smaller number of children from each group (n=8 each) were selected randomly for the analytical side of the study (which is what this paper in essence reports) where stool samples were collected at various points over the study period ranging from 7 days in to 24 months.
- The results: none of the 8 infants from the delayed gluten exposure group developed CD over the course of the study. One of the 8 infants in the early gluten introduction group did go on to develop CD at 2 years of age as measured by various serological panels and went on to a gluten-free diet with a remission of serology at follow-up.
- When levels of anti-gliadin antibodies (AGA) (IgG) were examined and corrected for gluten exposure time, the early gluten introduction group showed a higher number of IgG-AGA positive results than the delayed exposure group. The authors discuss how AGA is not necessarily a particularly good measure of CD but could indicate greater levels of intestinal hyperpermeability (leaky gut) as a result of exposure to the gliadin fraction of the gluten protein in the same way that IgG levels have been interpreted in other studies (see Sutterella and autism post).
- Pyrosequencing of the various species and families of bacteria present across the groups at different time frames suggested some interesting goings-on. To quote: "the GI tract microbiota in DQ2+/DQ8+ infants appears to be lacking significant numbers of member of the phylum Bacteroidetes". That and a higher abundance of Firmicutes, implies that maturationally, the gut microflora of children at elevated risk of CD is different from lower risk groups as determined by comparison with an external dataset** (full-text).
- The application of 1H-Nuclear Magnetic Resonance Spectroscopy (NMR) to proceedings added that metabolomic touch as "..SCFA succinate, acetate, propionate and butyrate are found in the feces" following the introduction of solid foods. Having said that little distinguishing data was found to categorise the two groups in any significant, universal way.
It's taken me a while to get my head around all the findings from this recent paper because there was a lot of data produced bearing in mind the small participant group and preliminary status of the paper. One of the first things that did strike me is the overlap in these findings and some fairly recent data published looking at carbohydrate metabolism and autism included in this post. Decreasing Bacteriodetes and increasing Firmicutes was the preliminary finding from Williams and colleagues*** bearing in mind the difference in samples being analysed and the lack of data on HLA DQ2 / HLA DQ8 genotype provided in the group with autism being studied. I'm not going to say too much more of this 'similarity' aside from the fact that screening for coeliac disease and/or excessive intestinal permeability perhaps ought to be much more commonly undertaken in cases of autism spectrum conditions just to rule them out.
Quite a few mentions of the word 'dysbiosis' are also recorded in the current paper which reaffirms the possibility of a connection between the various populations of bacteria that reside within us and our potential risk of disease. I like the idea that this study looked at both the metabolomic and genomic side of things even if it was just based on the HLA DQ geneotypes.
So from the starting point of a genetic susceptibility to gluten, we have preliminary data on functional changes to the microbiome in susceptible people and some interesting tools for looking at how this might be expressed functionally. I look forward to more studies of this type with greater participant numbers, and in particular how such findings might extend into other autoimmune conditions and even beyond just somatic presentation.
* Sellitto M. et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE. March 2012
DOI: 10.1371/journal.pone.0033387
** Palmer C. et al. Development of the human infant intestinal microbiota. PLoS Biology. 2007; 5:e177
DOI: 10.1371/journal.pbio.0050177
*** Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. September 2011.
DOI: 10.1371/journal.pone.0024585
Monday, 5 March 2012
Strong intestinal barrier and the big C?
I enjoy reading the odd newspaper now and again just to find out what's going on in the world. Having said that I do take some of the headlines with a pinch of salt as evidenced by a recent UK headline about autism which has been roundly brought up on its inaccuracy.
With such things in mind, I approach this post with very much more caution than usual given the subject matter - cancer - and the propensity for such headlines to become 'over inflated'. The headline in question came from this news piece on the recent publication by Lin and colleagues* (open-access) on a possible connection between the compound guanylyl cyclase C (GC-C) and the integrity of the intestinal barrier which might have onward repercussions outside of just malabsorption issues.
Let's start from the beginning on this one. Guanylyl cyclase C (GC-C) is, as its -ase name suggests, an enzyme found in gut and brain. It plays a role in regulating intestinal fluid and balancing electolytes. For those brave souls who quite like a bit of heavy biochemsitry, quite a thorough description of the whole guanyly cyclase family can be found here. Going back to GC-C, more recently, evidence has been accumulating to suggest that GC-C might also have some connection to intestinal barrier function** based on knockout mice studies.
The recent study by Lin went one stage further suggesting that in a mouse model GC-C did indeed link to barrier integrity through its effect on various junction proteins. It also however affected oxidative DNA damage when silenced subsequently ".. associated with increased spontaneous and carcinogen-induced systemic tumorigenesis".
Some details:
There is a lot more to this paper which I unable to cover in this short post. The one obvious point to make is that this was a mouse model of GC-C deficiency and hence needs a little more investigation into whether such processes transpose so readily on to humans. GC-C already has a possible link to metastatic cancer cells as per articles like this one so one would already expect quite a bit of interest in this compound in cancer research circles.
Combined with my previous post on diabetes and leaky gut, it is heartening to see some novel research is being done on how gut barrier permeability might not necessarily just manifest in intestinal symptoms. I leave you with another quote from one of the authors: ".. if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the [intestinal] barrier.” I am certainly not advocating this or any other 'advice' at this time but perhaps this is fodder for further research and a later post methinks.
* Lin JE. et al. GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS ONE. February 2012.
DOI: 10.1371/journal.pone.0031686
** Han X. et al. Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS ONE. 6: e16139
DOI: 10.1371/journal.pone.0016139
With such things in mind, I approach this post with very much more caution than usual given the subject matter - cancer - and the propensity for such headlines to become 'over inflated'. The headline in question came from this news piece on the recent publication by Lin and colleagues* (open-access) on a possible connection between the compound guanylyl cyclase C (GC-C) and the integrity of the intestinal barrier which might have onward repercussions outside of just malabsorption issues.
Let's start from the beginning on this one. Guanylyl cyclase C (GC-C) is, as its -ase name suggests, an enzyme found in gut and brain. It plays a role in regulating intestinal fluid and balancing electolytes. For those brave souls who quite like a bit of heavy biochemsitry, quite a thorough description of the whole guanyly cyclase family can be found here. Going back to GC-C, more recently, evidence has been accumulating to suggest that GC-C might also have some connection to intestinal barrier function** based on knockout mice studies.
The recent study by Lin went one stage further suggesting that in a mouse model GC-C did indeed link to barrier integrity through its effect on various junction proteins. It also however affected oxidative DNA damage when silenced subsequently ".. associated with increased spontaneous and carcinogen-induced systemic tumorigenesis".
Some details:
- Various mouse models were used; the important ones being mice deficient in GC-C (called GUCA2A in this paper) which will be called GC-C-/- (the -/- denoting zygosity for the receptor, as in homozygous for deficiency) and mice GC-C+/+ (denoting homozygous for no deficiency).
- A few differences came to light between the -/- and +/+ mice: the -/- mice produced less tight junction proteins including occluden, claudin-2, claudin-4 and JAM-A. In English, these are some of the main constituents that keep the gut barrier in good integral health. This was confirmed when looking at intestinal permeability which was increased (more leaky) in the -/- mice.
- When trying to chemically induce intestinal barrier issues via DSS, the severity of the colitis produced was increased in the -/- mice compared with the +/+ mice; something also seen in the mortality-survival rates between the two models.
- A quote from the paper: "Impaired basal epithelial barrier integrity producing systemic genotoxicity was associated with spontaneous extra-intestinal tumorigenesis, including tumors in mesenteric lymph nodes, livers, and lungs, in 50% of Gucy2c−/− mice, but in only 10% of Gucy2c+/+ mice". Translation: more permeability in the gut of the -/- mice led to more tumours in other organs compared to +/+ mice.
There is a lot more to this paper which I unable to cover in this short post. The one obvious point to make is that this was a mouse model of GC-C deficiency and hence needs a little more investigation into whether such processes transpose so readily on to humans. GC-C already has a possible link to metastatic cancer cells as per articles like this one so one would already expect quite a bit of interest in this compound in cancer research circles.
Combined with my previous post on diabetes and leaky gut, it is heartening to see some novel research is being done on how gut barrier permeability might not necessarily just manifest in intestinal symptoms. I leave you with another quote from one of the authors: ".. if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the [intestinal] barrier.” I am certainly not advocating this or any other 'advice' at this time but perhaps this is fodder for further research and a later post methinks.
* Lin JE. et al. GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS ONE. February 2012.
DOI: 10.1371/journal.pone.0031686
** Han X. et al. Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS ONE. 6: e16139
DOI: 10.1371/journal.pone.0016139
Friday, 24 February 2012
Does diabetes start in the intestines?
The findings of an interesting paper by Wei and colleagues* (full-text) pose a question: are the origins of diabetes in the intestines?
For those that don't know too much about diabetes, here is a link that should help. The concise version (if there is such a thing) is that diabetes normally manifests as either type-1 diabetes or type-2 diabetes with insulin being the key compound in controlling blood sugar, and corresponding issues either with its production or when resistance is built up to it.
The crux of the paper by Wei et al is that an insulin-responsive super enzyme called fatty acid synthase (FAS) involved in lipogenesis is also involved in gut barrier regulation through its action on Mucin 2 (Muc2), a gel-forming component of mucus. The authors' suggestion is that becoming resistant to insulin is associated with issues with FAS and correspondingly problems with mucus in the gut, inflammation and diabetes. No pressure then.
The paper summarised (deep breath):
This is quite a complicated paper and so please do not take my summary as gospel. It is intriguing that inflammation is at the heart of their theory and in particular, inflammation as a result of not having enough FAS present in the gut with the knock-on effects on gut permeability. Indeed not for the first time has it been suggested that diabetes and leaky gut are connected as per articles like this one. Makes you wonder also about any other possible dietary inter-related connections?
* Wei X. et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin. Cell Host & Microbe. February 2012.
DOI: 10.1016/j.chom.2011.12.00
For those that don't know too much about diabetes, here is a link that should help. The concise version (if there is such a thing) is that diabetes normally manifests as either type-1 diabetes or type-2 diabetes with insulin being the key compound in controlling blood sugar, and corresponding issues either with its production or when resistance is built up to it.
The crux of the paper by Wei et al is that an insulin-responsive super enzyme called fatty acid synthase (FAS) involved in lipogenesis is also involved in gut barrier regulation through its action on Mucin 2 (Muc2), a gel-forming component of mucus. The authors' suggestion is that becoming resistant to insulin is associated with issues with FAS and correspondingly problems with mucus in the gut, inflammation and diabetes. No pressure then.
The paper summarised (deep breath):
- Several groups of mice were included for study: (a) mice with chemically-induced (tamoxifen induction of Cre recombinase) decreases of FAS protein and mRNA, (b) mice bred with inactivated FAS in the intestine and (c) control germ-free mice. For group (b) mice, diabetes was induced by administration of streptozotocin, a toxin to the beta cells which produce insulin in the pancreas.
- Assays looking at gut bacteria, intestinal permeability, cytokine release and protein S-palmitoylation were used to investigate various parameters.
- The findings: a chemically-induced deficiency of FAS in mice started a cascade of events linked to inflammation. One of the primary cytokine markers of this inflammation was elevated levels of TNF-α although animals were also noted to show weight loss and other gastrointestinal symptoms. A quarter of these mice actually died within 14 days.
- The authors deduced that although some changes were noted to the intestinal bacterial makeup of FAS reduced mice, these changes were not enough to cause the inflammation observed but rather were as a result of the inflammation. They demonstrated this via a previously discussed method on this blog, bacterial transplantation; in this case to the germ-free mice (group c) who did not show the accompanying inflammation as a result of their donor bacteria. That is not however to say that gut microbiota did not have some effect, as per the reduction in inflammation noted in the FAS deficient mice following administration of the antibiotics ciprofloxacin and metronidazole.
- The link between FAS deficiency and Muc2 was evidenced by the lower levels of Muc2 shown in FAS deficient mice and reduced inner mucus layer thickness in the colon of affected mice.
- Looking at the inactivated FAS (group b) diabetic mice, a similar pattern of issues with Muc2 and reductions in the mucus layer was seen alongside penetration of bacteria indicating intestinal hyperpermeability (leaky gut). Interestingly, insulin supplementation seemed to positively affect some of the permeability issues.
This is quite a complicated paper and so please do not take my summary as gospel. It is intriguing that inflammation is at the heart of their theory and in particular, inflammation as a result of not having enough FAS present in the gut with the knock-on effects on gut permeability. Indeed not for the first time has it been suggested that diabetes and leaky gut are connected as per articles like this one. Makes you wonder also about any other possible dietary inter-related connections?
* Wei X. et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin. Cell Host & Microbe. February 2012.
DOI: 10.1016/j.chom.2011.12.00
Monday, 20 February 2012
On gut parasites and chronic fatigue
An interesting exchange on Twitter prompted this short post regarding a paper by Naess and colleagues* (full-text) on Giardia lamblia gastroenteritis and chronic fatigue syndrome (CFS). The tweets concerned another parasitic nasty called Toxomplasma gondii which has featured quite a bit on a sister blog with regards to its link to various behaviourally-defined conditions. I thought that T.gondii was a spine-tingling protozoa until someone posted about these other chaps and their brain-eating, behaviour-changing and belly exploding antics (pass the sauce, please).
Giardia lamblia is quite a special protozoa in terms of its survival, persistence and ability to link into quite a few other health complaints particularly of the gastrointestinal variety and specifically links to lactose intolerance. The current observations by Naess et al are interesting in that based on an examination of over 1200 patients with laboratory-confirmed giardiasis following a large community outbreak in Bergen, Norway, approximately 5% of cases (58/1262) were diagnosed with CFS as classified by the CDC criteria (see here for a related post on the trials and tribulations of diagnosing CFS/ME).
Even assuming a CFS prevalence of 1% previously noted in children (not adults) in the UK, the 5% figure seems high bearing in mind correlation is not necessarily causation. What can perhaps be ascertained from this latest study is that it might be a good idea to screen for giardiasis where active functional bowel issues are present alongside fatigue-related conditions and further research on any mechanism of parasitic infection linked to long-term fatigue might be advisable.
* Naess H. et al. Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. BMC Gastroenterology. February 2012.
DOI: 10.1186/1471-230X-12-13
Giardia lamblia is quite a special protozoa in terms of its survival, persistence and ability to link into quite a few other health complaints particularly of the gastrointestinal variety and specifically links to lactose intolerance. The current observations by Naess et al are interesting in that based on an examination of over 1200 patients with laboratory-confirmed giardiasis following a large community outbreak in Bergen, Norway, approximately 5% of cases (58/1262) were diagnosed with CFS as classified by the CDC criteria (see here for a related post on the trials and tribulations of diagnosing CFS/ME).
Even assuming a CFS prevalence of 1% previously noted in children (not adults) in the UK, the 5% figure seems high bearing in mind correlation is not necessarily causation. What can perhaps be ascertained from this latest study is that it might be a good idea to screen for giardiasis where active functional bowel issues are present alongside fatigue-related conditions and further research on any mechanism of parasitic infection linked to long-term fatigue might be advisable.
* Naess H. et al. Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence. BMC Gastroenterology. February 2012.
DOI: 10.1186/1471-230X-12-13
Monday, 13 February 2012
Plasma amino acids and inflammatory bowel disease
My recent post on the application of metabolomics to food fingerprinting got me thinking about the examination of biological fluids and how our metabolome might have some interesting secrets to one day share. The 'promise' of the science of metabolomics is that one day, we should be able to look at various biological fluids across a range of conditions and based on the compounds excreted/detected determine diagnosis, disease progression and how well someone responds to intervention. I hasten to add that we are nowhere near that position yet.
In light of this, it was perhaps inevitable ('it is your destiny') that this paper by Hisamatsu and colleagues* (full-text) on possible plasma biomarkers for inflammatory bowel disease (IBD) would get some attention. I'm pretty sure that I don't have to explain this to viewers but the term inflammatory bowel disease covers quite a bit of diagnostic ground including Crohn's disease and ulcerative colitis. Diagnostic confirmation of these conditions is quite a complicated process normally involving a combination of peripheral measures (blood tests, stool analysis) coupled with more direct observation of the bowel.
Hisamatsu and colleagues reported that a previously trialed network analysis of plasma amino acid levels in patients diagnosed with IBD might provide novel, non-invasive and importantly, objective biomarkers potentially opening up some new research areas into the nature of IBDs.
The details:
The data produced by this study is interesting. OK, it is not totally 'diagnostic' either in terms of classifying IBD from controls or looking at active vs. remissive symptom presentation but it's not a bad start at all. Indeed the use of discovery and training sets takes me back to a wonderful paper covered last year on schizophrenia, which did find a perfect classification based on a handful of serum and urinary markers. It makes me wonder if they were looking at serum and urine at the same time or maybe incorporating a few more well-known markers, whether those ROC values might further approach the magical number 1 (denoting a perfect classification).
The use of statistical models allied to biochemical data is also interesting. I note that similar linkages have been used in other areas of medicine, possibly even to recreate speech from brain activity...?
* Hisamatsu T. et al. 2012 Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease. PLoS ONE. January 2012
DOI: 10.1371/journal.pone.0031131
In light of this, it was perhaps inevitable ('it is your destiny') that this paper by Hisamatsu and colleagues* (full-text) on possible plasma biomarkers for inflammatory bowel disease (IBD) would get some attention. I'm pretty sure that I don't have to explain this to viewers but the term inflammatory bowel disease covers quite a bit of diagnostic ground including Crohn's disease and ulcerative colitis. Diagnostic confirmation of these conditions is quite a complicated process normally involving a combination of peripheral measures (blood tests, stool analysis) coupled with more direct observation of the bowel.
Hisamatsu and colleagues reported that a previously trialed network analysis of plasma amino acid levels in patients diagnosed with IBD might provide novel, non-invasive and importantly, objective biomarkers potentially opening up some new research areas into the nature of IBDs.
The details:
- Fasting plasma 'aminograms' for a discovery group of 102 Japanese adult patients diagnosed with Crohn's disease (CD) and 102 patients with ulcerative colitis (UC) were initially compared against 102 healthy control participants. The majority of participants were male (70%) with disease duration ranging between an average of 7.8-11 years. A minority of participants were described as having 'active' disease (CD = 29/102; UC = 38/102). Obtained aminogram results were also validated using a validation set of participants (CD: n=63; UC: n=120; controls: n=108).
- Serum albumin levels were reported as significantly lower in the IBD groups compared to controls.
- Various differences were noted between the groups in terms of amino acid levels. The authors seemed to have concentrated on histidine and tryptophan as primary examples with a view to disease activity and correlation with C-reactive protein levels (a marker for inflammation).
- Implementing their network analysis (MIAI), the authors came up with a formula based on 6 amino acids which discriminated CD and UC groups from controls with ROC values ranging from 0.894 to 0.955 depending on whether the discovery or validation group were used and comparing across the IBDs with controls.
- Depending on whether disease was active or in remission, a formula incorporating data for 7 amino acids was suggested to have some power in discriminating disease activity with ROC values ranging from 0.894 (CD active vs. CD remission) and 0.849 (UC active vs. UC remission).
The data produced by this study is interesting. OK, it is not totally 'diagnostic' either in terms of classifying IBD from controls or looking at active vs. remissive symptom presentation but it's not a bad start at all. Indeed the use of discovery and training sets takes me back to a wonderful paper covered last year on schizophrenia, which did find a perfect classification based on a handful of serum and urinary markers. It makes me wonder if they were looking at serum and urine at the same time or maybe incorporating a few more well-known markers, whether those ROC values might further approach the magical number 1 (denoting a perfect classification).
The use of statistical models allied to biochemical data is also interesting. I note that similar linkages have been used in other areas of medicine, possibly even to recreate speech from brain activity...?
* Hisamatsu T. et al. 2012 Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease. PLoS ONE. January 2012
DOI: 10.1371/journal.pone.0031131
Tuesday, 7 February 2012
Newsflash: defining gluten-related disorders
In the style of one Homer J Simpson... can't stop... must finish for the day.. new guidance of what constitutes a gluten-related disorder just published by Sapone and colleagues*.
If there is one document that you absolutely have to look at which summarises where we are in relation to gluten-related conditions, not just coeliac disease, this is it.
It's full-text, has a myriad of gluten research names included on it (including Alessio Fasano, Marios Hadjivassiliou and David Sanders), so enjoy.
* Sapone A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine. February 2012.
DOI: 10.1186/1741-7015-10-13
If there is one document that you absolutely have to look at which summarises where we are in relation to gluten-related conditions, not just coeliac disease, this is it.
It's full-text, has a myriad of gluten research names included on it (including Alessio Fasano, Marios Hadjivassiliou and David Sanders), so enjoy.
* Sapone A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine. February 2012.
DOI: 10.1186/1741-7015-10-13
Monday, 6 February 2012
Pesticides and vitamin D deficiency
Chemistry World, the public face of the UK Royal Society of Chemistry (RSC), carried an interesting report recently discussing research linking exposure to organochlorine pesticides (OCs) with vitamin D deficiency. The research in question is this paper by Jin-Hoon Yang and colleagues* (full-text) and before you ask, yes, it is a study of 'association', so we tread carefully.
Before wading into this study it is interesting to note that vitamin D is currently enjoying quite a trendy following in many areas. Important discussions are underway to determine whether a resurgence of conditions like childhood rickets means supplementation needs to be more closely inspected.
I digress. A summary of the paper in question:
As I said, this is a study based on association. Controlling for factors such as gender, age, race and vitamin D supplementation is an admirable quality of the study but association is normally only a guidepost to a possible relationship, not a dead cert. That and the fact that little information has been provided on why the results came out as they did, leaves the door open to further study in this area.
Noting that this blog is primarily concerned with the gut, I do wonder about these recent findings and how they may (or may not) fit into a past post on gut bacteria and organochlorine pesticides. It's a bit of a long shot but how about testing the suggestion that OCs affect gut bacteria which in turn affects other systems including vitamin D and its receptors?
* Yang J-H. et al. Associations between organochlorine pesticides and vitamin D deficiency in the U.S. population. PLoS ONE. January 2012. DOI:10.1371/journal.pone.0030093
Before wading into this study it is interesting to note that vitamin D is currently enjoying quite a trendy following in many areas. Important discussions are underway to determine whether a resurgence of conditions like childhood rickets means supplementation needs to be more closely inspected.
I digress. A summary of the paper in question:
- An analysis of plasma levels of 7 OCs (including DDE and DDT) was undertaken for 2,337 people aged 12 and above recruited as part of the US National Health and Nutrition Examination Survey (NHANES). After exclusion of those where accompanying 25-hydroxyvitamin D (25(OH)D) were not available alongside other exclusions (e.g. pregnant women, being under 20 years old), the final participant group number was N=1275.
- The results: based across various grouping on concentrations of OCs, there were quite a few significant inverse relationships reported. That is, for the OCs - p,p′-DDT, p,p′-DDE, and β-hexachlorocyclohexane - elevated plasma levels of these compounds individually and collectively were associated with lower vitamin D levels. Plasma levels of DDT in particular showed quite an enduring association with vitamin D levels.
- There is a suggestion that the relationship may also be dose-dependent up to a certain point; that is up to a value of 200 ng/g lipid of DDT, vitamin D levels dropped, but increasing levels of DDT after that seemed to be linked with increasing vitamin D levels bearing in mind that most participants presented below this 200 ng/g lipid threshold.
As I said, this is a study based on association. Controlling for factors such as gender, age, race and vitamin D supplementation is an admirable quality of the study but association is normally only a guidepost to a possible relationship, not a dead cert. That and the fact that little information has been provided on why the results came out as they did, leaves the door open to further study in this area.
Noting that this blog is primarily concerned with the gut, I do wonder about these recent findings and how they may (or may not) fit into a past post on gut bacteria and organochlorine pesticides. It's a bit of a long shot but how about testing the suggestion that OCs affect gut bacteria which in turn affects other systems including vitamin D and its receptors?
* Yang J-H. et al. Associations between organochlorine pesticides and vitamin D deficiency in the U.S. population. PLoS ONE. January 2012. DOI:10.1371/journal.pone.0030093
Subscribe to:
Posts (Atom)