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:

• 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.

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* 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.

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

Metabolomics and the food fingerprint

I've touched upon the beautiful science of metabolomics previously on a sister blog; that is, looking for 'chemical fingerprints' in various biological fluids to garner further information on underlying biological processes related to health. Already metabolomics has provided us with a few preliminary clues in relation to more behaviourally-led conditions such as autism and schizophrenia (AUC=1), but as the technology gets smarter and smaller (and cheaper), I foresee great things ahead for this flourishing branch of biochemistry similar to the genomic high-throughput screening technology carried out at places like the Sanger Institute.

When a story recently appeared on the BBC website discussing a food 'fingerprints' test, it was therefore always going to attract my attention. Indeed so much so that after a few quick emails to one of the people involved with the research, I was very satisfied to receive some of their peer-reviewed papers on the details behind the headlines. 

The BBC story discusses some collaborative research based on the notion that what we eat leads to the production of various chemical metabolites and that detecting those metabolites in fluids like urine means we can objectively find out what someone has consumed recently and if necessary promote any dietary changes. Food diaries are the normal way of collecting information on what people have eaten recently but recall is often not as accurate as you think.

My take on this work was slightly different in terms of the fact that the researchers are in effect, building up a large bank of information based on very controlled eating habits about what comes out when we eat certain foods. 

This paper by Favé and colleagues* (full-text) sums up the research aims and objectives; also providing a great overview of the various techniques used in metabolomics and importantly the statistical analyses required (normally PCA or some variant). The researchers have been very methodical in their approach to this issue. This paper again by Favé and colleagues** (full-text) details how they went about clearing a few potential interfering variables such as the fasting period and some information on the reproducibility of findings over various testing occasions. In short, they wanted to make sure that interesting collected metabolites were food derived and were consistent.

So what have they got so far?

Well, according to this paper by Lloyd and colleagues*** when compared to a standard breakfast made up of orange juice, tea with skimmed milk and sugar, butter croissant, and cornflakes with milk, an alternative dietary schedule made up of either salmon, broccoli, whole-grain wheat cereal or raspberries produced some notable differences in urinary metabolites. The differences were even more notable when the alternative dietary schedule was compared against fasting urine samples.

Looking more specifically at individual compounds formed as a result of dietary intake, a few interesting snippets were reported including:

• Smoked salmon intake was associated with increased levels of 1-methylhistidine and anserine (b-alanyl-L-methylhistidine), metabolites of the amino acid histidine, probably derived from fish skeletal muscle. Also alongside were findings of TMAO, a degradation product from carnitine (remember that?).
• Broccoli and raspberry were both associated with increased ascorbate and individually, xylonate/lyxonate and polyphenols.
• For each of these three dietary components, there were at least 7 putative biomarkers of intake reported although nothing was reported on for the wholegrain cereal consumption.

Another paper by Lloyd and colleagues**** reported that proline betaine was associated with citrus exposure, with detected levels using the same technology and methods explanatory of both acute and habitual exposure to citrus containing foods (makes it sound like an illicit drug or something).

Appreciating that this and related work is still an emerging area of investigation, subject to all manner of confounders that we as human beings do to ourselves every day, I am suitably impressed that there are groups out there looking at our food and how we metabolise it. I can envisage many applications for this kind of work, ranging from a non-invasive test of recent food consumption, to measuring adherence to certain kinds of dietary intervention, to examining whether there are any differences in the metabolism of certain foods as a function of say gut bacteria which might cast some light on the biology behind lots of conditions.

To finish how about a bit of artistic interpretation through the medium of dance from Kate Bush...

* Favé G. et al. Measurement of dietary exposure: a challenging problem which may be overcome thanks to metabolomics? Genes & Nutrition. 2009; 4: 135-141

** Favé G. et al. Development and validation of a standardized protocol to monitor human dietary exposure by metabolite fingerprinting of urine samples. Metabolomics. 2011; 7: 469-484

*** Lloyd AJ. et al. Use of mass spectrometry fingerprinting to identify urinary metabolites after consumption of specific foods. American Journal of Clinical Nutrition. 2011; 94: 981-91.

**** Lloyd AJ. et al. Proline betaine and its biotransformation products in fasting urine samples are potential biomarkers of habitual citrus fruit consumption. British Journal of Nutrition. 2011; 106: 812-824.

Greens, glutathione and the mucosal barrier

'Eat your greens' is a phrase most of us will have heard on several occasions when growing up. I have to admit to being a bit of a 'goody two-shoes' in this respect, having had a lasting affection for things like Brussels sprouts and broccoli. Indeed, sprouts still tend to be on my menu several times a week (boiled with a drop of Greek olive oil).

I say all this because an interesting article published a few years back has caught my eye recently. The paper by Hoensch and colleagues* (open-access) looked at the various factors potentially affecting the functioning of the gastrointestinal glutathione system with some interesting observations.

I will admit that glutathione (GSH) is something which I am becoming very interested in at the moment. Over on my autism research blog, I recently discussed the pretty remarkable findings emerging in some cases of autism with regards to plasma GSH which might (might!) eventually have some diagnostic usefulness in combination with other factors. The Hoensch paper talks about GSH levels in the upper gastrointestinal mucosa and how factors such as diet, some medications and even gender seemed to affect levels of GSH and accompanying enzyme activity (glutathione S-transferase, GST).

The particulars:

• Biopsy pinches taken from two sites (antral and duodenal mucosa) for 202 adults (104 males: 98 female) undergoing endoscopy were analysed for GSH and GST activities. Various background information was also taken from participants including details of family history, medication and current dietary habits via a food frequency questionnaire.
• The findings: different biopsy sites reflected different levels of GSH and enzyme activity. Female participants showed higher levels of GSH and GST activity in their antral mucosa samples than males. High intake of vegetables (more than 3 days a week) seemed to enhance aspects of GST activity.
• A subsequent author reply to a suggestion that Helicobacter pylori infection might also have had an effect suggested that indeed, one aspect of GST activity was negatively affected by H.pylori infection.

Bearing in mind that GSH and its related sub-systems represent an important part of our defences against those dastardly free radicals among other things, making sure that the system is in tip-top condition is probably quite important. I don't want to make sweeping gender generalisations but the fact that females seemed to be in a slightly more advantageous position compared with male participants leads me back to some interesting work on the fragile male. Having said that, let's not be too defeatist here; greater vegetable consumption seemed to have an enhancing effect as per other results so one could argue, guys in particular, eat more greens - especially more brassica vegetables to support your mucosal antioxidant defence system.

* Hoensch H. et al. Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system. Gut. 2002; 50: 235-240.

Gut bacteria and heart health?

Happy (belated) New Year! Welcome back to Gutness Gracious Me in 2012. I start this year with a post on something pretty central to the ethos of this blog: gut bacteria.

I should perhaps first apologise to Alex Gazzola (#HealthJourno) who very kindly asked if I would be discussing the new Codex standards for labelling foods and gluten-free and the 20 parts per million threshold introduced. I did say I would have a look at this and I am still looking. I do however think that Alex has done a wonderful job of covering this topic on his own blog (see here) as per the reader response he has received.

Back to task. Despite being only 13 days into the New Year (Friday 13th...mmm?), already the research is coming thick and fast. Over at my Questioning Answers blog, the big news recently has been on the bacteria Sutterella and its detection via various methods in quite a few biopsy samples from children with autism and gastrointestinal (GI) issues. I say big news but in among the very detailed explanation of how that team came to find Sutterella, the main story for me is the suggestion that gut hyperpermeability in some cases of autism might be a route through which the immune system meets gut bacteria in places it really shouldn't and onwards formulates an antibody response. The template for this is Crohn's disease and leads into some interesting suggestions about whether gut bacteria itself might not necessarily be the bad guy but rather what happens when it is allowed to roam.

The other quite interesting news is from this paper by Vy Lam and colleagues* suggesting that different amounts and varieties of gut bacteria might influence the severity of and recovery from heart attacks in rats. I am well used to seeing papers talk about gut bacteria in relation to GI issues and conditions, even conditions like autism where functional and more systemic bowel disorders have been noted in some cases. This is however one of the first times that I have come across gut bacteria potentially so directly influencing the physical health of an organ like the heart.

So what did the researchers do?

• Three groups of rats were fed three different types of diet: a standard diet, a standard diet plus quite a powerful antimicrobial (vancomycin) and a standard diet plus a probiotic very aptly named GoodBelly. 
• The primary probiotic constituent of GoodBelly is Lactobacillus plantarum 299v quite commonly found in fermented foods like sauerkraut and subject to a few claims. One of those claims is that the bacteria might be able to reduce the production of leptin among other things.
• Both the vancomycin and GoodBelly supplemented groups showed a decrease in circulating leptin levels (38% and 41% respectively) alongside some changes to gut bacteria as one might expect.
• The vancomycin and GoodBelly supplemented groups also showed evidence of smaller heart attacks and improved recovery after heart attack compared with the standard diet group.

Whilst the authors describe this as a 'proof-of-concept' study, there are potentially many implications from this work not least that our gut bacteria might do far more than call us home and help digest our food. I have previously (jokingly) referred to gut bacteria as being our 'masters'. Assuming the results from this study are pertinent to humans as well as rats, I might well be offering a sacrifice to 'those who must be obeyed' in the near future.

Should we be surprised that the human body is interconnected? No probably not, although it might take a while and a few more bits of evidence of effect before cardio health care professionals start giving probiotics to help treat (prevent?) myocardial infarction (please note I am not giving any medical advice about this). Going back to the Sutterella post and the proposed link between bacterial translocation and gut permeability, I do wonder whether research should also be looking more closely at gut permeability and lots of other conditions just to see if findings such as these might provide a few more clues about health and illness.

*Lam V. et al. Intestinal microbiota determine severity of myocardial infarction in rats. The FASEB Journal. January 2012

The leaky gut and chronic fatigue syndrome

I've mentioned the TV programme called the Food Hospital before on this blog in a post not so long ago about Crohn's disease and the LOFFLEX diet. Having watched the episodes so far as well as the various social networking chatter about the series, my conclusion is that it is rather a brave programme to broadcast in terms of 'treating' various medical conditions simply with adjustments to diet. I will perhaps lay my stall out to you in that I am swayed by some of the arguments that food, certain foods, do place certain people at a health disadvantage outside of known food-related conditions such as coeliac (celiac) disease and PKU. The emerging data, albeit preliminary, on some cases of autism and ADHD seems to be pointing in that direction for example.

The latest programme aired on Tuesday 13 December (2011) again presented some interesting 'cases' and the potential link to food. One particular cases was that of a woman diagnosed with Chronic Fatigue Syndrome (CFS). I don't want to get too bogged down with a description of CFS (and CFS/ME) because it is quite complicated. Without blowing my own trumpet, I was involved in a paper on trying to describe CFS a while back which suggested that quite a few symptoms might be variably expressed including physical, somatic features alongside other more cognitive issues. The bottom line is that CFS/ME is a real and very often complicated condition.

The Food Hospital suggested a few things in terms of diet which might be useful for the particular lady with CFS in question. Outside of chocolate being suggested (and not doing particularly well in this case) I thought I also heard the suggestion that a glutamine-rich diet might also be something to try. My attention was grabbed by this suggestion for a very good reason: glutamine (also called L-glutamine) has some interesting effects on the gastrointestinal (GI) tract and in particular, intestinal permeability.

Maybe I should back up a little here. Glutamine is an amino acid, a building block of protein. For quite a few years, glutamine has been finding some favour in relation to improving the structural integrity of the intestinal barrier in both humans and animals and potentially relieving the so-called 'leaky gut'. Leaky gut is a bit of a misnomer because everyone has leaky gut to some degree; the better description would perhaps be gut hyperpermeability or excessive leakiness.

With regards to CFS/ME, as with other conditions, leaky gut has been reported in the research literature and commented on elsewhere. One name seems to crop up quite a lot in this area of investigation, Dr Michael Maes and not just with regards to CFS/ME. It seems leaky gut might have the potential to do all manner of things. So putting leaky gut, CFS/ME and glutamine together might make some sense? Aside from the paper from Maes, I have been unable to find any other published trials of glutamine for CFS/ME which is a shame really, given that a double-blind, placebo-controlled trial of a solitary supplement like glutamine should be a pretty straight-forward experiment to do (he says with a straight face). Any budding researchers out there with a few hundred thousand pounds to spare could do a lot worse than put such an experiment to their boss and local ethics committee.

I would finally add that as per the tenets of this and my other blogs, I don't give out medical advice and am not suggesting for one minute that glutamine is a cure-all for CFS/ME. I do however reiterate that for a condition like CFS/ME where more questions are being asked than answered, every experimental and research avenue should be explored.

Crohn's disease and the LOFFLEX diet

A short post this one following a very interesting series airing here in the UK called the Food Hospital. 'Let food be your medicine' was the mantra of a certain Greek gentleman called Hippocrates (or perhaps according to Bill and Ted, 'Hippo-crates') and that is exactly what this series is suggesting.

In the programmes so far we have seen conditions ranging from migraine to obesity discussed. Tonight's programme featured a particularly brave young woman called Laura who presented with quite a serious case of Crohn's disease. For those who want more information about Crohn's see here. The long and short of it is inflammation, discomfort and quite a few 'peripheral' symptoms; no recognised cure and a life of medication and possibly surgery. Certainly one of the more serious gastrointestinal (GI) conditions.

Anyhow true to the name, the Food Hospital investigated whether it was possible the manage some of the symptoms of Crohn's disease through dietary changes. The plan in question is highlighted here and included a 3-step dietary intervention beginning with a cessation of food intake and reliance instead on a liquid feed containing all the necessary nutrients, followed a few weeks later by the implementation of the LOFFLEX (LOw Fibre, Fat Limited EXclusion) diet finally followed by dietary challenge/rechallenge in the hope of identifying problem foods related to symptoms.

It was interesting to see that some success was reported whilst on the regime in terms of symptom reduction following a flare-up. This is not proof of anything but certainly an interesting case study (n=1). Looking at the scientific literature for the LOFFLEX diet, things seem to be a little bit sparse at the moment. I found this trial from Addenbrookes Hospital which was the first place to look at the diet (I think). I also noted an interesting name on the authorship list, Prof. John Hunter, who is quite an expert on all things gastroenterology and particularly a role for gut bacteria in various bowel conditions.

I await more research on this very interesting regime and its potential applications to other conditions.

The gut virome

Our gastrointestinal tract is alive. Teaming with all sort of weird and wonderful compounds and organisms, it truly is a world within a world. Metabolites from food, various neurotransmitters, digestive juices and enzymes; all swimming merrily around doing things which we have only started to understand, not just in the gut but also connected to lots of other systems in the body.

Our gastrointestinal bacteria constitutes a large portion of this 'biochemical soup' and has started to receive quite a lot more research inquiry recently as a result. What is perhaps only now starting to be realised is that our gut also house a lot more than just bacteria, it is also home to quite a few viruses also.

Think viruses and people automatically assume infection and bad things like bird flu. Even today, alerts are cropping up suggesting that bird flu might be making a comeback and this time with even more lethal strains. Viruses do not have a great reputation despite the fact that perhaps not all are the devil incarnate as exemplified by this recent advance in a potential anti-cancer virus.

A recent paper by Minot and colleagues* published in Genome Research suggests that our gut might house quite a few viruses and that what we eat has the potential to affect both the bacterial and viral signature in our gut.

The paper which has been summarised here suggests the gut virome, similar to the gut bacterial microbiome is both unique to a person and dynamic; in this case, changing the fibre and fat content of a persons diet resulted in changes to the gut virome.

I await more investigation on this topic. Investigation into how our gut virome interacts with our health and disease and how potentially other environmental factors might affect our viral world within a world.

* Minot S. The human gut virome: inter-individual variation and dynamic response to diet. Genome Research. August 2011.

Food and irritable bowel syndrome

Irritable bowel syndrome (IBS) has always seemed like a bit of an odd term to me. Odd because whilst it is used to describe various symptoms related to the bowel, 'irritable' to me implies angry and annoyed. Assuming that a similar meaning is denoted for IBS, various notions perhaps acquire new meaning. If for example, we assume that the gut is the second brain, and our first brain (the one in our head!) is the part of us that becomes irritable, angry or annoyed in response to whatever, then one can see some sense in its use when applied to the gut.

I digress. There is quite a lot of speculation as to what causes IBS and what are the most effective ways of reducing or managing symptoms. Outside of psychological factors such as stress, diet and food have been consistently related to some cases of IBS and the suggestion that sensitivity or intolerance might be tied into symptoms. I wrote a post about this not so long ago following the publication of quite an important piece of research where non-celiac gluten intolerance seemed to be linked to some cases of IBS. Removing gluten, or rather reintroducing gluten after having previously been excluded from the diet, seemed to be linked to the appearance of various IBS symptoms over placebo.

A recent article adds to the dietary connection. The paper by Carroccio and colleagues* suggested that a quarter of their participant group were found to have a food hypersensitivity to cow's milk protein and/or gluten wheat protein. Furthermore levels of tryptase, an enzyme normally released as part of an allergic-immune response, and fecal eosinophil cationic protein (ECP), related to inflammation, were higher in those participants with IBS and food hypersensitivity. This indicating some possibility of identifying those cases of IBS with a potential dietary effect involved.

Whilst complicated, dare I say spectral, conditions such as IBS are never going to be caused by one factor and one factor alone, there is some reliable evidence emerging implicating a dietary effect as being involved. Much like lifestyle and stress-reduction treatments and pharmacotherapy, such a dietary effect if linked, provides another possible intervention route to potentially alleviating symptoms, at least for a proportion of those affected.

* Carroccio A. et al. Fecal assays detect hypersensitivity to cows milk protein and gluten in adults with irritable bowel syndrome. Clinical Gastroenterology & Hepatology. August 2011.