IBS: Pointing the finger at gut microbes

Max Bingham — Wed, 23 Nov 2011 19:15:20 +0000

A combination of new technologies and some recent discoveries has led many to point the finger at gut microbes as a predisposing factor in irritable bowel syndrome (IBS). Let’s run this one through to see what it might mean.

Recognise this? ‘Aaaaaaaaaaaaaaaargh!’, run, slam, ‘aaaaaaaaaaaaaaaahhhhhh’, flush, smile. That is the sound of someone with an overwhelming desire to sit on porcelain and let go. For some, all of this is a characteristic of irritable bowel syndrome (IBS) which, if you will forgive my understatement, can really ruin your day, week in, week out. The symptoms are well recognised. And yet, despite affecting as many as 20% of the population, we know surprisingly little about the cause of IBS. Therapies at best only provide transient relief and there is still no universal cure.

A gut feeling

There are plausible views that IBS might be caused directly in the gut and specifically be the result of subtle inflammation of the gut wall (other hypotheses are available). There are suggestions, for example, that some develop IBS after infection and gastroenteritis and that residual antigens kick off an inflammatory cascade, resulting in IBS.

Some have also pointed the finger at the composition of the gut microbiota as a whole and asked whether it could be a pre-disposing factor to IBS.

Well, a number of studies have appeared this year that suggest there might be something in this. Technology has been the key here, with some very exciting developments in sequencing technologies, meaning we can now get a view of the gut microbiota in unparalleled detail.

It’s called microbiology by numbers (or technically, microbiomics) and basically involves extracting and sequencing DNA in a sample, piecing it all together and producing an individualised catalog of what’s there.

The idea then is to compare samples from different groups (in our case patients with IBS and others without), and tease out the differences, getting an idea of what might cause what. With such an ecological system, the devil is likely to be in the detail and this approach can really, really get into that detail.

Now, it is not as if this relationship between gut microbes and IBS hasn’t been explored before. Many studies have proposed that different species might or might not be associated with IBS.

It’s just that across these studies no round consensus has ever emerged. This is probably due to the ‘depth’ of analysis, or lack of it, that has previously been possible.

What makes the following two studies important then is both the level of detail described and the agreement between the studies despite one being performed in Finland in adults (Rajilić–Stojanović et al) and the other in kids in Texas (Saulnier et al).

Significant similarities included, for example, an association between Dorea and IBS (which, incidentally has also been associated with stress in an animal study). As expected, it is not completely clear cut with some significant differences in associations also reported in the studies. In the case of the Finnish study a signature profile of bacteria could be identified to discriminate patients with IBS and those without. Equally the Texan study could also reveal signatures associated with different types of IBS.

An accompanying editorial by Talley and Fodor (published in the November edition of the journal Gastroenterology) gets into a very engaging discussion about all this.

What does all this mean for IBS?

One of the aims of this type of research is to define a set of bacteria that might be diagnostic of IBS. That is to say, a set of microbes that are always associated with IBS. Now, diagnosing IBS is easy. It often doesn’t even require a diagnostic lab test.

On the face of it then, it is fair to ask where the value is?

Again, it is in the detail and specifically in subtypes of IBS. It is entirely possible that a certain set of microbes is related to the diarrhoeal type of IBS; another with constipation etc etc. If, and it is a big if, this is the case, it suggests that therapy might be achieved through some sort of targeted intervention with probiotics, prebiotics, antibiotics or some other approach.

Probiotics and antibiotics have already shown some potential in this area. If these signatures can be identified, (and causality proved) it provides a target for treatment.

We are, however, still a long way from that sort of personalised vision of the future. I have discussed this sort of thing before when the drugs don’t work. These studies are a first step that, more than anything else, illustrate the potential of the technology and its future application.

Featured Study References

Rajilić–Stojanović et al (2011). Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. Published online 8th August 2011. DOI: 10.1053/j.gastro.2011.07.043

Saulnier et al (2011). Gastrointestinal Microbiome Signatures of Pediatric Patients With Irritable Bowel Syndrome. Gastroenterology. Published online 11th July 2011. DOI: 10.1053/j.gastro.2011.06.072

Probiotics: functional but not as we thought

Max Bingham — Thu, 27 Oct 2011 13:17:40 +0000

Probiotic yoghurts are popular mainly because they come labelled with claims that they are good for you. Whether this is true or not is the focus of a considerable number of studies that are ongoing at the moment. A small study, published yesterday, suggests that the impact of these yoghurt cultures on the composition of bacteria already present in our gut is negligible, they do not replace them, but that they might induce microbial activities involved in digestion. Let’s discuss.

Max’s Note: Before I get into this rather complicated little story, I have to note that the research paper is behind a paywall at Science Translational Medicine. If you want to read it you will need to hand over $15 or find a friend with access. For that reason I am going to keep this fairly short and explain just the topline implications of the research.

In one short sentence: Go and read this article by Ed Yong in Nature News about the research. There is no point in me re-inventing the news wheel for you. Go, go…

Whistles…

Ok, seen any issues yet? Let’s dissect this carefully. The major result indicates that the composition of gut microbiota does not change very much when probiotic bacteria are ingested but that their activity might be altered. That is a very interesting finding.

The actual mechanisms by which probiotics affect health have actually remained a bit of a mystery for many years despite considerable research efforts. Various hypotheses exist (i.e. changing composition to a more “beneficial” mix, competitive inhibition of pathogens, modulation of innate immunity and the list go on). So, this result might add just that bit more to our understanding of the function of gut microbes and the properties of probiotics.

Next, the design of the study is worth looking at in more detail as it could open the door to more significant discoveries later on. The authors report they used identical twins (in the test and control groups) which would remove confounding factors from the analysis such as human genetic variation. This makes the result more robust. Next, verifying the result in mice with identical genetic makeup and very defined microbial communities in their guts under tightly controlled laboratory conditions adds more weight to the evidence. Then, using some very advanced molecular approaches (variously described under the monikers of microbiomics and more specifically metatranscriptomics, should you care to know) to unravel what are very complex communities of bacteria and their metabolic pathways and come to the conclusion they have is an impressive technical achievement. The finding would have been very difficult to verify without these checks, controls and techniques.

But, what of the result? What are the implications? Naturally there has been some caution towards the result, including from the lead author and other scientists and these all seem to be fair. The study is small and appears to have some technical limitations (given the comments of Dusko Ehrlich in Yong’s piece). What is interesting is the impact that this approach might have on future studies and on the perennial difficulty of manufacturers of probiotic products to prove their claims. Verifying effects seen in humans in animal models is on the face of it a bit backwards, but in this case it seems appropriate because of the super complexity of the systems involved. We can expect to see studies like this appear again in the future.

It is interesting, but not surprising, that this work has been partly funded by Danone, who are one of the largest manufacturers of probiotic products. They would naturally have an interest in any new approaches or technologies that help boost the strength of evidence behind probiotic bacteria. What is unclear is whether such evidence and approaches will be sufficiently robust to meet the strict requirements of regulatory authorities such as EFSA (who have recently been very critical of the quality of evidence used to support probiotic claims in general). We will have to wait and see on that tricky little area.

Microbes.Me » Probiotics

IBS: Pointing the finger at gut microbes

A gut feeling

What does all this mean for IBS?

Featured Study References

Probiotics: functional but not as we thought