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A Deeper look into Probiotics

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Probiotics have a dubious reputation. That’s not entirely justified. In this prepublication from his new book Allemaal beestjes (All small animals) science journalist Jop de Vrieze searches for an answer to the question of what we can expect from these so-called good bacteria.

Yakult used to claim that they were healthy on the product itself, but this was banned by the European Food Safety Authority (EFSA).

They are about ten metres high and at least five in diameter: the seven shiny stainless steel drums in which the bacteria grow. They eat a diet of milk powder, sugar, glucose syrup and water, until they are enough to be drained, carried through, packed, transported and finally consumed. The barrels are stored in the European factory of the world’s largest producer of probiotics: Japanese Yakult. The handful of staff downstairs in the hall are dressed in white clothes and adorned with hairnets and mouth caps.

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We let as few people as possible into the production area’, explains PR manager Martine van der Velde of Yakult Netherlands. Only our strain of bacteria is allowed to end up in the bottles. She talks about Lactobacillus casei Shirota, a lactic acid bacteria, like all bacteria that are sold as probiotics. Bacteria that can also be found naturally in yoghurt. Innocent but beneficial, is the idea.

“I can tell you anything,” says Van der Velde, “but then it would only be for your information. You shouldn’t attribute anything I say to me. The application for a health claim on Yakult has been rejected by the European Food Safety Authority (EFSA). If we say something about intestines, defence or good bacteria, we run the risk of being fined a hefty fine.’

Van der Velde is referring to a decision taken by the European Commission in 2006: companies should only be allowed to place health claims on their product packaging if they can substantiate them scientifically. Increases resistance’ is such a health claim, or ‘improves digestion’.

In just a few years, the food market had been flooded by products with these kinds of promises, as a result of which the consumer no longer knew what he could and could not believe. Companies such as Yakult were also annoyed by the claims of others, and applauded the introduction of clear rules. These would separate the wheat from the chaff. Things went differently. In July 2011, the scientific committee rejected all claims to probiotic products.

Probiotics with a positive effect

Do all probiotics products fall under the heading of quackery? That’s too quick a reasoning, says Canadian Professor of Microbiology and Immunology Gregor Reid. There are many substances on the market that are not worthy of the name probiotics’, says Reid, the world’s leading authority on probiotics. They’ll ruin the rest of it.

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A drug can only be a probiotic, Reid emphasises, if it has a demonstrable beneficial effect on humans in the form that you ultimately use. Even if you test it in a capsule and then put it in a drink, those studies are already worthless. That’s how sensitive probiotics are.

In theory, probiotics can contribute to our health in four ways: by breaking down food components that our ‘own’ bacteria have difficulty with, such as lactose, by competing in the colon and fighting harmful bacteria, by strengthening the intestinal mucosa and the intestinal wall and by stimulating the immune system in the small intestine. They do this temporarily, because they are unable to conquer a place in the intestine.

Wageningen researchers showed that probiotics can indeed activate immune cells in the small intestine. These immune cells send signals to the rest of the body. You tickle your immune system’, says microbiologist Michiel Kleerebezem. This allows it to react better to harmful microorganisms’, says Kleerebezem. The question is, of course, whether this alertness of the immune system really increases your resistance, just as it is doubtful whether those few billion lactic acid bacteria are strong enough to suppress harmful bacteria and strengthen the intestinal mucosa.

In any case, the effects vary between probiotic strains. There is no ultimate probiotic strain, just as there is no soccer player who is the best at everything. The properties of the bacteria determine which interactions they are capable of. Companies such as Yakult, Danone (France) and Valio (Finland) have been doing and funding research into the functioning of their own bacterial strains since the 1960s. It is difficult to appreciate the value of this research. It is designed in such a way that the chance of favourable results is high. Moreover, it is not clear how many negative results disappear in a drawer. Nevertheless, we are dependent on it. Because one probiotic is not the same as another, you want to know what effects you can expect from specific products.

Diarrhea

Yet not all studies are worthless. A major retrospective study published by the Cochrane Collaboration in 2013 showed that probiotics reduced the risk of diarrhoea caused by antibiotic treatments in hospital patients by 64 percent: from 5.5 percent in placebo to 2 percent in probiotics. A probiotic can also help against traveller’s diarrhoea: 85 percent of diarrhoea cases could be prevented, according to another survey study.

There are also indications that probiotics can help to improve the symptoms of chronic intestinal infections and irritable bowel syndrome, although in both cases the effectiveness depends strongly on the strain of bacteria used and varies from patient to patient. In any case, both ailments do not definitively change over from probiotics.

Less convincing is the evidence that probiotics would strengthen the immune system and thus help to prevent colds and inflammations of the trachea and larynx, among other things. The strengthening of the immune response to the flu shot in the elderly has also not been demonstrated.

It is possible that probiotics can help to stop babies crying endlessly. Many crying babies suffer from intestinal cramps and sometimes intestinal infections. Treatment with Lactobacillus reuteri only made these children cry for 80 minutes, compared to 170 in the control group, according to a survey study that appeared last year in JAMA Pediatrics.

All in all, probiotics can do quite a lot. Why, then, are the manufacturers unable to convince the European Assessment Committee? There are various explanations for this. First of all, the EFSA’s requirements prior to the evaluation were unclear. In the end, it turned out that EFSA was expecting clinical studies of the level required for medicines as well. The producers had not expected this.

All submitted dossiers were weighed and found to be too light. However, the lack of proper research is not the only reason for the rejections. Indeed, EFSA allows very few health claims for food products. A specific claim aimed at remedying or preventing a disease, such as diarrhoea, is not permitted, because the product would then be regarded as a medicine, and that is not a matter for the food authority but for the medicines authority. The situation is different in countries such as the United States and Canada. Drinks containing Lactobacillus rhamnosus GG (LGG) in Canada carry the claim ‘helps to manage acute infectious diarrhea’.

In Europe, manufacturers must demonstrate that they can make healthy people even healthier, so that they are less likely to fall ill, or recover sooner if they do. Or that they feel even better or perform even better than usual. For the time being, the sector is not allowed to claim anything, and even the word ‘probiotics’ is no longer permitted, because that word already suggests a health-promoting effect.

Manufacturers deal with the setback in different ways: some focus on the medical market and work directly with doctors and dieticians – who are allowed to administer products without a medical or health claim as a supplement to medicines. Some manufacturers have switched to vaguer claims such as ‘Feel good from the inside’. Others have added Vitamin D to their product because the health claim ‘supports the immune system’ has been approved for it. Yakult hasn’t given up yet. We will certainly get that certification, sighs van der Velde. But we don’t know when.

Akkermansia muciniphila

Whether or not certified, the effectiveness of lactic acid bacteria will be limited. During the short period that they stay in the intestines, they play a supporting role. For the real clappers, we need to focus on the key players in the intestine’, says Willem de Vos, professor of microbiology at the University of Wageningen. Species with important functions and a major impact on the entire ecosystem.

In January of this year, a leading American research group in Science Translational Medicine published a whole list of superbacteria that will form the second generation of probiotics. Bacteria that affect fat burning, the regulation of the immune system and the production of favourable metabolites.

One of the superbacteria is Akkermansia muciniphila, which was discovered in 2004 in the group of De Vos. Akkermansia is a kind of helper that maintains the mucus layer in exchange for shelter and food. This mucus layer is important for the barrier between the internal body and the populations in the intestines. The Wageningen researchers showed that the administration of Akkermansia to large mice can restore the mucus layer and thus the barrier between the intestinal bacteria and the internal body. As a result, the mice lost weight and their metabolism began to function normally again.

Akkermansia muciniphila

For healthy people with a few excess kilos, Akkermansia will not make the difference, because they probably already have this bacterium. He may be able to give people with metabolic syndrome a push in the right direction, although they will have to eat healthily to maintain the change.

The ultimate goal is a range of bacterial cocktails for a variety of purposes, from a good development of the child to a balanced immune system in asthma. This is not an easy task, because these species are not on the list of probiotic bacteria that are considered safe. They do not occur naturally in food and have to go through an authorisation process. This is difficult, because these bacteria on their own often do not do what they can do together with others’, says De Vos.

However, De Vos also believes that this second generation of probiotics will be introduced. The potential is so great that the rules will probably be adjusted to make admission possible. In the meantime, a third generation of probiotics is already being developed, which links the knowledge from microbiology to synthetic biology, building and encrypting organisms. In the lab of Justin Sonnenburg at Stanford University, for example. We want to design these bacteria in such a way that under certain circumstances, for example when inflammations occur in the intestines, they will perform specific tasks, such as releasing a toxic substance or an anti-inflammatory agent,’ says Sonnenburg. The bacteria will then become sensors, medicine factories and transport vehicles at the same time.

In order to get to grips with this, we will have to understand a lot more about the behaviour of bacteria and the complex interactions between them in the intestine. For the time being, we will have to make do with the drinks from the supermarket.