The limits of probiotics: ‘Not all are good for everything, and some are good for nothing’

The millions of microbes that live in our bodies usually coexist with us peacefully and in a sensible balance for the common good. This harmony is what we call health. However, the entente cordiale between the good and the bad is sometimes broken by external interference — such as taking antibiotics, the appearance of other pathogens or deregulation of the internal ecosystem known as microbiota — and health problems arise. One of the strategies used to restore this microbiota is to take probiotics, live microorganisms that confer a health benefit when administered in the correct amounts. Some of these products are used, according to scientists, to treat diarrhea caused by taking antibiotics, and a recent scientific review indicates that they could also be used to prevent colds. But the scientific evidence on their potential is still very limited and their alleged benefits are running faster on the street than science is advancing to prove them. Probiotics are not good for everything, experts warn.

They have always been with us. For example, breast milk contains probiotic bacteria with beneficial effects in promoting the maturation of the baby’s immune system. And in yogurts, explained Francisco Guarner, gastroenterologist and member of the International Human Microbiome Consortium’s scientific committee, there are also recognized probiotic bacteria, such as Streptococcus thermophilus, “which helps digest the lactose in milk.” The bacteria in lactic acid, and bifidobacteria are, in fact, the most commonly used microorganisms.

This strategy, of using live microorganisms to improve health, has been refined and its potential for action has expanded to the point where the shelves of pharmacies and drugstores are filled with combinations of microbes. The vast majority are sold not as drugs, but as food supplements that are presumed to have health benefits. But all that glitters is not gold: “Probiotics are useful, but not all of them are good for everything and some are good for nothing,” said Guarner. According to health consultancy IQVIA, Spaniards spent around €75 million ($82.1 million) on probiotics in pharmacies in 2022.

For a microorganism to be considered a probiotic it has to meet various criteria: “It has to have special characteristics, be held in an international culture collection, and there have to be randomized trials demonstrating its benefit to health.” That is why kefir, kombucha and yogurts in general cannot be considered probiotics in the strict sense: “Traditional ferments are considered beneficial, but they are not probiotics if you have not done a study of the benefits,” said Guarner.

The American Gastroenterological Association (AGA) maintains that “much evidence to support the use of probiotics to treat digestive diseases is lacking,” and identifies only three feasible scenarios: they may serve to prevent necrotizing enterocolitis in low-birth-weight premature infants; they may help prevent C. difficile infection in adults and children taking antibiotics; and for the management of pouchitis, a complication of ulcerative colitis.

The AGA, however, does not recommend their use in children with gastroenteritis to treat diarrhea, a position not shared by the World Gastroenterology Organization (WGO). Guarner, who has participated in the organisation’s latest clinical guidelines, argues that certain types shorten diarrhea in children by at least one day: “The AGA guidelines give advice to their doctors, but there are half a million children in the world who die each year from acute diarrhea. If it reduces the severity and duration of diarrhea, it does make sense,” he argued.

Probiotics in the doctor’s office

The WGO notes that there is “evidence of efficacy” of some probiotics in preventing antibiotic-associated diarrhea in adults or children and, in line with the AGA, also in preventing C. difficile infection in people taking antibiotics and in preventing pouchitis. Probiotics have not been found to be useful for Crohn’s disease or for the prevention of systemic infections. The international scientific society also adds that in colorectal cancer, although an improvement in some tumor-associated biomarkers has been seen in animal models, in humans the data is “limited.”

With irritable bowel syndrome and ulcerative colitis, the AGA rejects the use of probiotics (except in clinical trials) and even suggests patients with these ailments stop taking them “as there are associated costs and not enough evidence to suggest lack of harm.” The WGO points out, however, that in irritable bowel syndrome, certain strains can alleviate pain.

Manolo Romero, a gastroenterologist at the Virgen del Rocío Hospital in Seville, Spain, does not usually recommend probiotics in his practice. “I need things to be demonstrated and evidence-based. They are assumed to be safe, but what worries me is proving that they are good for something,” he said. And he admits the difficulties in “quantifying and monitoring the changes” that these products can potentially produce.

“I need things to be demonstrated and evidence-based”

Manolo Romero, Virgen del Rocío Hospital in Seville, Spain

There are many variables at play. The effect or influence on a gut microbiota is not the same as on a vaginal or respiratory microbiota, with very different compositions and ecosystems. And the impact on adults, with a mature microbiota, is also not the same as that which probiotics can cause in neonates, for example, with an undeveloped microbial ecosystem.

Several Cochrane reviews (an independent network of researchers that analyzes scientific evidence) conclude that there is low or insufficient evidence to support the benefits of probiotics for urinary tract infections, infant colic, gestational diabetes or eczema. Recent research suggests that consumption of probiotics “taken with yogurt or dairy products or in food supplements, possibly helps prevent colds and other acute upper respiratory infections,” although Romero calls the evidence “weak.” For childhood otitis, the Cochrane investigators did see a slight benefit in children who are not prone to this condition. In antibiotic-associated childhood diarrhea, the authors see “a moderate protective effect of probiotics for prevention.”

Guarner defends their use, stating that “the problem with probiotics is that they are not all good for the same thing.” It depends on the species, the strains and even the dosage. It also depends on the baseline situation of each individual. The physician pointed out that Cochrane reviews, although they are “very careful,” analyze studies with different preparations. “You can’t lump everything into the same category. Not all of them are good for everything and most of the products on the market do not meet the scientific criteria to be a probiotic,” he said.

Lack of sound scientific basis

In the absence of robust scientific evidence on where, how, and why a probiotic works, the role of the placebo effect becomes relevant, as advocated by researcher Martin J. Blaser in his book Missing Microbes: “The theory behind probiotics, prebiotics, and synbiotics is appealing, but the current ways they are used smacks of placebo effects [...] . When you go to a health-food store looking for probiotics, the very act of walking in suggests you are seeking something to make you feel better. By buying the product, you are ready to be helped, and the placebo effect kicks in.” The scientist clarifies that he does not reject probiotics, but “we won’t know if these products are doing any more good than placebos until we conduct blinded clinical trials,” he claims.

Refining the actual goodness of probiotics is no simple task. In addition to the great heterogeneity of the preparations, there is the difficulty in measuring some parameters within the microbiota and other variables that are difficult to determine at the outset (such as the course of a disease) which vary according to the patient. “The fundamental problem is that gut bacteria are in continuous interaction, talking to each other. And we have no guarantee that that bacterium that we encapsulate and give to the patient is going to have the same effect everywhere in the world. The bacteria will also depend on their environment, the microbiome, and intestinal permeability [to allow nutrients to pass through]: if it is high, everything will pass through with no problem and our bacteria will be accompanied by other things that can change their effect,” said Romero.

Rocío Puig, an endocrinologist at Hospital Sant Pau in Barcelona, also stresses the difficulty of “finding the perfect combination” of microbes or strains for a given pathology. “In obesity, for example, we don’t give probiotics. No combination of microorganisms has been found to work,” he admitted.

Research is progressing slower than expected. “We’ve been researching probiotics for 30 years and the studies are below expectations. It was thought that the dose was not important, but it is. And it has not been possible to see what aspects of the microbiota influence [probiotics] to respond better. Ecology is more difficult than pharmacology. There are a lot of interactions that we don’t control,” admitted Guarner. And another limitation, he added, “is that there are a lot of [marketed] products that are possibly useless, and that muddies the water.”

The scientific community, however, is expectant. Both with probiotics and prebiotics — compounds that serve as food for the bacteria in the intestine and generate a health benefit — and synbiotics (a mixture of probiotics and prebiotics). But also with psychobiotics, which are probiotics whose mental health benefits have been conferred through interacting with the gut microbiota.

The fact that not all the potential benefits of probiotics have been demonstrated so far does not mean that they do not have them. Guarner points out that a new generation of probiotics, the so-called live biotherapeutics, with curative potential, is already under way. That is, microorganisms selected for a specific application, almost à la carte to treat a specific ailment. A study published in the journal Nature Reviews Gastroenterology & Hepatology also points out that new microbes susceptible to becoming probiotics will increase, although in that field, they admit, “the precision, accuracy and repeatability of microbial composition measurements, leading to genuine and not misleading interpretations, need to be improved.”

For the time being, experts call for patients to exercise caution and to seek information from doctors and pharmacists before consuming any products. “At the moment, many commercial probiotics or psychobiotics are more of a marketing strategy than a real therapeutic agent: an Actimel [drink] is not going to activate your defenses or make you happier,” summarizes microbiologist Ignacio López-Goñi in his book Microbiota: los microbios de tu organismo [Microbiota: your body’s microbes] (Almuzara, 2018). Romero assumes, however, that these products will be fine tuned and will find their place: “They won’t be useful for everything, but they are gaining ground. After all, there are more bacteria in the gut than there are cells in our body.”