A recently published review has again highlighted the progress being made in unravelling a possible relationship between gut microbes and obesity. Although controversial, there is a suggestion that specific species and groups of bacteria might be associated with being obese and that they might prove worthy targets for intervention (possibly via probiotics or prebiotics).

This begs a question – where are the clinical trials? We take a look at some studies that are ongoing or remain unpublished in this area.

First things first. Obesity is a complex topic. Apart from the obvious issue of body weight, obesity is also associated with numerous other complications including type II diabetes and systemic inflammation. It is a major concern as it has the potential to prematurely kill a lot of people, rates are on the rise and it is probably largely preventable.

Gut microbes have been in the picture for a while following a series of experiments showing that they are likely to be involved in fat storage, nutrient availability, and the low grade inflammation associated with obesity. If you want to get the full picture I point you directly to the review by Nathalie Delzenne and company.

Their conclusion? Numerous potential mechanisms and variations in gut microbe composition might be involved although it is too early to safely conclude which bacteria are involved. Also, any role for probiotics and prebiotics in the management of obesity and associated conditions still needs to be evaluated further. The few clinical studies that have been completed have turned up mixed results.

So, let’s have a look at the studies that are currently ongoing to see what we might learn in the coming years.

Weighty question

Let’s start with probiotics and the most obvious target – body weight. That’s the aim of this study, led by Dr Angelo Tremblay at Laval University, Canada. According to the trial registration:

“The primary objective of the clinical trial is to investigate whether a consumption of a probiotic formula when compared to an intake of a placebo, is associated with a greater reduction of body weight.”

Given that the study involves Nestlé (or at least they are mentioned as a “collaborator”), there is clearly some sort of an agenda of potential health claims here. There is no mention of which specific strain of probiotic is being used (although we’re guessing it might be one of the ones (here or here) used in the animal studies that preceded the study) or what might count as a clinically relevant weight reduction. Nevertheless, the study is fairly large so it should give us a good idea of whether this approach has a future. It will certainly be interesting to see what comes out of it. The end date for the study is December 2011 so we should expect reporting towards the end of next year, if not 2013.

A question of risk

Next, Denmark and we move on from weight management to obesity related metabolic problems and satiety. The University of Copenhagen has four studies of interest here (two on metabolic issues and two on satiety, see below). The first study involves feeding a probiotic or flax seed fibre notionally to alter the composition of gut microbes, then to look at the effects on a variety of markers related to insulin resistance (risk factor for heart disease), inflammation, body composition (i.e. amount of fat) and then try to find correlations with the changes in the composition of gut microbes. Unravelling whether the changes are a cause or consequence of each other will be hard and it’s a fair bet that the work will generate a hell of a discussion. Nevertheless, we should expect to see this appear well into 2013 at the earliest.

The next study, again at The University of Copenhagen, and this time supported by the Danish Medical Research Council and Danisco, has the following hypothesis:

“This study will examine if overweight in children is associated with a different intestinal microbiota and if a change in microbiota caused by probiotics can modify inflammation and risk factors for the metabolic syndrome.”

According to the registration, the study was due for completion in January 2011 although, as of November 2011, it appears to not have been published. Given the number of analyses described this is perhaps not a surprise. It will certainly be interesting if a positive result comes from this. For the moment though, we just have to quietly wait.

Staying with modifying gut microbe composition and risk factors for metabolic syndrome, there is a similar study currently running at the German Diabetes Center looking at probiotic supplementation and insulin resistance. It’s due for completion in December 2011 and we should expect these findings to be reported sometime next year.

Meanwhile, the microbe used in Yakult is under investigation at the Medical University of Graz, Austria in a small study looking at its effects on various markers associated with obesity and metabolic syndrome. With a completion date of December 2010 we should expect publication of the results of this study hopefully soon.

Yet another study, this time running in Chile, reports it is looking at the effects of a combination of probiotics and prebiotics on low grade gut inflammation in people with obesity. Again, with an expected completion date of December 2010, we might get to hear about those results sometime soon.

Feeling full

Obesity is often associated with over-eating. So, if it’s possible to modify when we feel full after a meal (satiety) then this could be of interest in tackling obesity. That’s exactly the aim of the ProSat study at The University of Copenhagen (again) which is, or was, all about feeding probiotic capsules to see if appetite fell. It would appear that it has taken place in two stages with this part being completed in 2009 and this part (the bigger one) apparently being completed June 2011. It is not entirely clear what the status of these studies are and they do not appear to be reported yet. Again we will just have to wait and see. It will be an interesting result if there is a positive effect. How they will explain the mechanism will be very interesting indeed.

…and finally

Most of the studies ongoing are about probiotics being used to alter gut microbe composition and induce a variety of effects related to obesity. We are certain that with the eventual publication of these studies we will learn more about whether any of this is worth following. It is perhaps surprising that prebiotics have not featured more in the ongoing studies. The evidence for effects in animal models suggests it might be time to try it all out in humans. Well, some studies have been published with mixed results. And… there is one study looking at a prebiotic in over-weight adults and risk factors for metabolic syndrome. It completed in December 2010 and it would not surprise me if we hear about that study fairly soon.

A large clinical study looking at the prevention of fever episodes by prebiotics (specific ingredients to help selected ‘healthy’ microbes grow in your gut) in infant formula has turned up a negative result. The addition of prebiotics made no difference to the number of episodes of kids getting sick. The obvious thing to do right now would be to ask some searching questions of the infant formula companies that continue to claim that their products will prevent your children getting sick.

We are not going to go there though. National and European Authorities have already had their substantial say about that sort of thing. No, this study points to a different future, informing us just how difficult it is to prove that a food is ‘functional’ and just why we should expect to see very, very few health claims cruising the aisles of the local supermarket in the next few years. Here’s the analysis.

Fever Episodes

Clinical studies tend to be worth taking note of when they have study populations that are big. This is because they tend to give answers that are rather more believable about effects that are in fact quite small. This is the case with a recently published study that looked at the effect of prebiotics added to infant formula on fever episodes at five different study centres from across Europe. Involving well over 1000 infants, we learn that the number of episodes of fever did not differ between infants receiving formula with prebiotics (specifically in this case a blend called Immunofortis, which appears in numerous brands owned by Nutricia/ Danone), and infants receiving formula with nothing added. Comparing this to infants receiving exclusive breast milk, the study also reveals that breast-feeding resulted in a very, very small higher risk of a fever. Note this though >

If you are breast-feeding, please do not stop based on that result. The evidence for the benefits of breast feeding for your child is absolutely overwhelming. Small deviations from the scientific body of evidence do happen and it’s the whole lot of evidence you should take note of… not just one result (which incidentally has some specific weaknesses). 

Healthy Infants

Now, where this study becomes very interesting is when the scientists start to discuss the meaning of the study. Led by Margriet van Stuijvenberg of UMC Groningen, The Netherlands, the team reveal in their analysis a number of intriguing points. For example, they note that their study was performed with healthy infants. This contrasts with the previous studies they quote that involved infants at increased risk of respiratory infections (and that found an effect). The study also revealed a very low rate of fever episodes which they suggest could mean that the study was under-powered.

When we talk about the ‘power’ of a study, that refers, statistically speaking, to the chances that the study actually had to detect the effect it was looking for. A hat-tip to the authors for suggesting this is really deserved. It’s worth looking at why they think this. According to van Stuijvenberg (and company):

“… if much more participants would be necessary to find an effect, the clinical relevance would be very small.”

You can probably draw your own conclusions on that statement. They go on. Finding a very small difference in favour of prebiotic intake after the first 6 months, they then rip into the finding both statistically and noting that it is probably clinically irrelevant. Then, looking at the variation between study centres, they note differences in fever episodes and specifically that breast feeding at some centres seemed to result in higher rates (please, please see my note above). Even more intriguingly they suggest that if your kid is white or happens to be a boy, you might expect a higher number of fever episodes. Happily, if you have a furry pet in the house, you might expect a lower rate of fever episodes. All that appears to be irrelevant of whether prebiotics are given or not.

Do take some care with these observations. I have previously picked over the difference between correlation and causation. I suspect this might be true here too.

What all this highlights is that running a study in the wild (i.e. making it as realistic as possible) also makes finding effects of an intervention, in this case with infant formula containing prebiotics, very hard to pin down. The real difficulty is that, at least in Europe, the regulatory authority, EFSA, has started to ask for proof that a product making a claim works in a general population. This study was performed in a general population and as far as I can tell, was performed very well.

Detecting effects that are small in healthy populations is very hard. Making health claims that are based on such evidence and that stick in the mind of the consumer is really very, very hard. As of next year (2012), it will be illegal in Europe to make health claims that are not substantiated and approved.

A final thought

Where it will get interesting is when the general population becomes an unhealthy population. I’m looking at the US and obesity… and there is some really fascinating work going on about that little issue… microbes are probably involved.

Clinical studies represent the pinnacle of scientific endeavour in terms of proving whether a treatment has the effect we are all expecting. There are some very large studies that are ongoing and worth keeping a check on. The results could prove decisive for the future of any products or drugs that might make it to your local supermarket or pharmacy. So, in the interests of keeping a track on these, here is the (growing) list of clinical trials worth watching.

Max’s Note: I will update this list as and when I receive new information. It’s a work in progress…

Role of Probiotics in Preventing Antibiotic Associated Diarrhoea Including c.Difficile

Taking antibiotics might result in diarrhoea, with the result being anything from inconvenient to life threatening. It happens because the resident gut microbes are also largely eradicated by the antibiotics. Some microbes however, are spore formers and their spores are not affected by the antibiotics. They can rapidly over run the gut which is a problem because many also produce toxins (and these cause the diarrhoea). Clostridium difficile is a particular worry because of the severity of the diarrhoea it can produce and the risk of developing a form of gut inflammation (which is the life threatening part). It has received a considerable amount of attention because of the rates of infections reported in hospitalised patients. Probiotics have widely been touted as a potential solution from the perspective of repopulating the gut with so-called “friendly” microbes to out compete these spore-forming toxin-producing microbes. The hypothesis has a basis and some success has been reported previously in hospitalised patients.

This study then, is worth taking note of. It is being led by The University of Sussex. This is the aim according to the trial registration:

“The aim of the present study is to find out whether the use of one of these Probiotics in hospitalised patients taking antibiotics will result in less diarrhoea, less Clostridium difficile infection, as well as cost saving. The study will also analyze the effects of probiotics on quality of life and length of hospital stay.”

…and it is notable for the size of the study population: 1200. This is big and presumably needed to ensure the effects they are testing (diarrhoea reduction) can be detected.

The estimated trial completion date is October 2012. In the meantime you can read all about the study here.

The effect of Lactobacilli on the immune system of healthy adults

Whilst we are on the subject of enormous studies and probiotics, here is another one to watch. This time it is about whether probiotics can influence specific immune responses to influenza vaccination. It involves 1058 subjects split between treatment and placebo. This is the hypothesis:

“The study was designed to investigate the immune modulating properties of the probiotic strain L. casei 431® in an influenza vaccination model.”

There is no mention in the registration whether the study will look at the incidence of colds and ‘flu. The study is notable for its size, the fact that it will be carried out in multiple centres (in Denmark and Germany), in healthy subjects and will use methods that are normally the reserve of pharmaceutical studies. By the end of the study, we will have a very strong piece of evidence that either supports the notion that this particular microbe has an influence on the immune system… or not.

You can read all about the motivations of the study sponsor in this report (hint: it is about product claims). The study is being led by the University of Copenhagen and is due for completion end April 2012. You can inspect the registration for yourself here.

Last updated: October 31st 2011.

Sources: clinicaltrials.gov; controlled-trials.com