Incredible claims of some probiotic manufacturers are sometimes not backed up by incredible evidence. It is particularly a problem when such products are targeted at vulnerable groups. This includes children with autism. A recent review says it is now time to run proper trials on the efficacy of probiotics in autistic children. Let’s take a look.

Max’s Note: In the interests of full disclosure, approximately 10 years ago I was involved in some research about gut microbes and autism. This was during my PhD at The University of Reading. We had some success. Here is the paper.

Incredible Claims

Selling probiotics to treat medical conditions is a big, controversial business. The claims (particularly the ones plastered on the internet) are often not backed up by evidence, the prices can be wild and if swallowing a capsule containing “250 billion cfu of 25 scientifically proven probiotic bacteria and 88 clinically proven herbal extracts” is enough to replace actual drugs that do work, then this business can even be dangerous.

Where it gets very interesting is when medical science fails to provide answers on causes and treatments for diseases. This is exactly the position we find ourselves in with autism. Effective treatments are few and far between which means ‘alternative’ therapies are everywhere. One ‘treatment’ being flogged to rightfully desperate parents of autistic kids is probiotics. Gastrointestinal complaints are commonly reported in autism and probiotics are then often recommended (often by other parents or so-called experts). Assuming that the product is safe, this probably won’t do much harm except perhaps act as a self imposed taxation.

Scientific Consensus?

There is however a growing scientific consensus that there might, might be something in this approach. Writing in the open access journal “Gastroenterology Research and Practice” a group of scientists from the US, The Netherlands and UK now suggest it’s time to run clinical studies to validate whether probiotics can help with gastrointestinal symptoms in autistic children. They suggest that the prevalence of these symptoms in autism and the point that a significant minority of US physicians recommend giving probiotics to autistic children really now warrants proper investigation.

Reviewing the evidence

Setting out the evidence J. William Critchfield and team suggest that there are now four strands of evidence on which to base clinical studies. The first is the similarity between gastrointestinal symptoms in autism and IBS and that in certain circumstances certain strains of bifidobacteria have shown promise in clinical trials for IBS symptoms. Next, there is growing evidence (although there would appear to be more work needed here) that gut microbiota composition could be altered in autistic children and that probiotics might be useful here. Finding evidence of widespread issues with the way the gut actually functions in autistic children is a controversial topic (think vaccines and autism). Wisely, they suggest that proper studies should be performed to firmly establish this. Interestingly they point towards some studies suggesting that probiotics might stabilise the gut mucosa (this is the surface of the gut wall), stimulate immunity and improve gut barrier function. We should be cautious here as most of these studies are in animals or in a dish.

Behaviour Bugs

Finally, the review raises a significant point about gut microbes and behaviour. It suggests that compounds from the diet and from cell walls of bacteria can cross from the gut into the central nervous system and finally the brain… affecting behaviour. This is a story that has been around for a while. What is significant now is that in the past few years studies have shown that administration of probiotics can affect various parameters of behaviour in both rats and humans. Specifically we learn of a study revealing a positive effect of a probiotic drink on mood and cognition. Whilst it is unclear how this works, this has to be of some significance to autism. The concluding comments of the authors says it all:

“There is a range of indications that alterations in the intestinal microbiota in the gut might contribute to the disorder in a substantial number of individuals. Probiotics can be useful to restore the microbial balance in the intestine, to relieve gastrointestinal problems and to attenuate immunological abnormalities. Whether the use of probiotics by children with autism can lead to improvements in behaviors needs to be established in well-controlled trials with sufficient group sizes. Important for these trials is the choice of the bacterial strains, as effects of probiotic bacteria can be highly strain specific.”

Now, I am not suggesting with all this that there is concrete proof that probiotics have a proven role to play in helping autistic children and their symptoms. This is all about specific strands of evidence that point towards a possible role in the future. That is why we need clinical studies.

Trials?

The obvious thing to shout now is “Max… surely you can tell us where the clinical studies are!” Sorry to disappoint you, but there are none registered in any clinical trial database. The only strand of hope I can bring you is that two of the authors are from Winclove Bio Industries in Amsterdam who make probiotics for various applications. I have contacted them to ask for more details and I will update the post if I hear back. I can guarantee you that if clinical studies are planned we will not be seeing any proven probiotic product for gastrointestinal symptoms in autism for sale any time soon. Trials take time.

There is also one more intriguing point to all this. In 2006, Prof Glenn Gibson of The University of Reading reported that a trial of probiotics with autistic was so successful that the trial ultimately failed. Dropouts from the study were so high that no meaningful conclusion could be drawn. Now, when you hear about high dropout rates in studies we should normally get worried as it could mean patients are getting worse because of the study. Not in this case. The reports that emerged suggested that parents were withdrawing their children because the effects were so good in terms of mood and behaviour. They realised that their child was on the active treatment and then refused to cross over to the comparison placebo. Through no fault of the scientists, the trial became unblinded as a result of its success. The only option… another study. And, that has never happened to date. You can read the study report here… or at least the abstract on page 3.

Reference

Critchfield JW et al (2011). The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterology Research and Practice 2011: 161358. DOI: 10.1155/2011/161358

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.

Each week linked up for your reading pleasure. This week, it’s all about erm.. well.. everything. We learn that it’s really complicated that fat and eczema is not solved just yet. IBS might, might be related (again) to gut microbes and that it’s really expensive to learn about diarrhoea. Bogs are also happily full of bog bugs… and sink bugs and… hand bu… What a relief! 

Here we go then…

A veeeeery complicated dissection of a relationship between gut microbes, immunity and fat (paywalled) at Nature Medicine.

A clinical Study in infants and atopic dermatitis: no effect of prebiotics in infant formula.

and while we are there… no effect of two probiotic strains in eczema in another clinical study.

IBS: Differences in gut microbes uncovered in IBS via two studies (pay-walled), discussed in an editorial and picked over here by yours truly.

and while we are there… IBS discussed again in a review.

Prebiotics and Probiotics for skin (paywall) and it looks like an article might appear on skin/microbiome/cosmetics via @kellydobos (here’s the tweet, and I’ll update when/if it appears… could be interesting).

Bog bugs: Survey of public toilets confirms gut bugs associated with toilets and skin microbes associated with the sink. Well, at least we now have that nugget confirmed.

Clinical perspectives on acute diarrhoea. However, how the publishers can possibly justify $86 for 24 hours access is beyond belief – expect a response @ maxbingham.com).

Dodgy probiotic claims targeted at IBD patients discussed. But again, buyer beware, I hope you have some sort of access… a bargain at $42.

And finally… rocking through the guts of, well everything and more, we are introduced to the concept of ‘Microbial Resource Management‘. If there is anything in this, you can expect a comment next week.

Odd ‘omic’ word competition (which I might start running weekly) – new for this week… Probiogenomics…

Have a good weekend!

Big is not something you would immediately place in the same sentence as microbe. However if your ambition is to catalog all microbes on earth it is probably wise to think very big. That is exactly what the Earth Microbiome Project aims to do in what we can rightly call massively collaborative science. Here’s a brief run down of the project and what we might expect when completed.

Here is their description of the project:

“The Earth Microbiome Project is a proposed massively multidisciplinary effort to analyze microbial communities across the globe. The general premise is to examine microbial communities from their own perspective. Hence we propose to characterize the Earth by environmental parameter space into different biomes and then explore these using samples currently available from researchers across the globe. We will analyze 200,000 samples from these communities using metagenomics, metatranscriptomics and amplicon sequencing to produce a global Gene Atlas describing protein space, environmental metabolic models for each biome, approximately 500,000 reconstructed microbial genomes, a global metabolic model, and a data-analysis portal for visualization of all information.”

You can read more about the project’s ambitions here.

Ok, that is really, really ambitious. The process is fairly straightforward: divide the earth into different ecological areas (biomes; i.e. soil, sea, human, insect, animal, town, city, atmosphere… you name it), find samples from them, extract and sequence the DNA and then use the information to piece together what’s there, microbially speaking. The project actually promises to go much further by looking at what the microbes might be doing too. The scale of this project though is absolutely mind blowing with the amount of data being generated dwarfing any previous microbial ecology project.  The guarantee from all this is that we are certainly going to discover new species and strains of microbes and learn a great deal about what they might be doing. The other neat point is that all the data and the tools to analyse it will be available freely on the web. You, me or anyone else can get involved (if you know what you are doing) and get stuck in. This is bound to result in spin off research and most likely spin off technologies that will be relevant to daily life. Quite what, we will have to wait and see.

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.

Each week, linked up for your reading pleasure. Actually, this week we cover the last 2 weeks as I had a short week off. Topics include the usual mix of health related stories, microbes doing Twitter, bumble bees eating poo and surveys of gut microbes of the world’s largest rodent and the Panda (just in case you’ve ever wondered).

Microbe implicated in colorectal cancer: Checking this out here via this… and now posted here.

“Probiotics effective in combating antibiotic-associated diarrhea.” – 4 studies discussed at ACG Annual Conference. Would be great if they could publish the papers.

Immune benefits (well, increases in antibodies but nothing else) of two probiotic strains in new clinical study.

Reviewing the evidence: prebiotics, probiotics and obesity.

Social networking for microbes, raising concerns about antibiotic resistance. Read all about it with another great article from Ed Yong.

Interesting discovery! The humble bumble bee eats poo for protection against infections (including the one that’s causing population collapse).

The Capybara (Source: Wikipedia CC BY 3.0)

Just in case you’ve ever wondered: gut microbes surveyed in the world’s largest rodent, the Capybara (see right).

IBS: Significant differences again reported in gut microbes. Still wondering about causes and consequences here.

Melting permafrost, methane and climate change, we now at least know that there are some microbes present that can consume methane.

Microbes and mood disorders. Review suggests gut microbes and immune function play a role.

Interesting link between gut microbes and type 1 diabetes revealed by some super advanced sequencing.

And finally, I’ve always wanted to know… Panda’s survive on bamboo because of special mix of gut microbes.

In the first of an ongoing series, Last week in Links will bring together links to research and other content that are interesting from the perspective of microbes and us. It might simply be content that I have not had a chance to cover in more detail. It might also be content that is interesting but that I have not (yet) weaved into a full article. It might also be content that is locked up behind a paywall and that I have not got my hands on yet. I hope you find them useful.

Research

Should we worry? large RCT shows prebiotics in infant formula do not affect fever episodes… in infants.

Woh! This study and this one suggest viruses might need a helping hand from gut microbes to wreak havoc.

Clever… Multiple Sclerosis is blamed on intestinal microbes (the lot) but don’t worry, it’s in mice genetically pre-disposed to developing MS when they have microbes in their gut. Interesting!

Gum disease only develops when normal mouth bacteria are present, suggesting they could be altered to prevent it. It is a long way off.

One to watch: getting around antibiotic resistance by disabling the needle.

Believe it when it’s published: More cranberry anti-infection claims.

… Oh? published today but locked up in a journal that does not even publish its table of contents (tick, tick, tick).

Cause or consequence? Type 1 diabetes, allergies in infants and altered gut microbiota composition.

Don’t read this having your lunch: Faecal transplantation effective in getting rid of C.difficile infection in 87% of cases (although the report might be positively biased).

Blame the weather: Infection rates climb in summer months; but what about climate change asks Maryn Mckenna?

A lead worth watching: Keeping bacteria at a small distance (50μm) in small intestine via antibacterial proteins.