8 minute read
Central Research
Do probiotics work?
It is estimated that the global probiotics market moves more than 2,500 million dollars a year, and it is estimated that this figure can easily double in the coming years. It is a sector with an upward trend: an increasingly aging population with more pathologies, a consumer increasingly concerned about their health and easily accessible products.
Probiotics are defined as “live microorganisms that, when administered at an appropriate concentration, confer some health benefit to the host.” Other related concepts are those of prebiotics (a substrate used selectively by host microorganisms), synbiotics (a mixture of both living microorganisms and substrates), or postbiotic (a preparation of dead microorganisms and/or their components). In all cases its consumption should confer a health benefit.
In the last decade, research on the gut microbiome has experienced an exponential increase and the amount of information we have accumulated is extraordinary. Today we know that we are actually a complex ecosystem filled with hundreds of millions of interactions between our own human cells and our microbes, and that our health dependso on that balance. The study of the human microbiome has been accompanied by a growing interest in probiotics as a way to manipulate or modulate our microbiota. Therefore, there are more and more reviews that try to clarify if probiotics are really useful, if they can modify our microbiota, if they have any efficacy or even some side effect.
The confusing clinical efficacy of probiotics
There are many trials that ensure that probiotics have a preventive and even therapeutic (curative) effect on some health problems: from acute diarrhea associated with antibiotic consumption or Clostridioides difficile infections, irritable bowel syndrome, neonatal sepsis and enterocolitis, Helicobacter pylori infection, respiratory infections, atopic dermatitis, cardiovascular risk, and even anxiety or depression. Many studies have suggested that probiotics modulate the immune response by affecting the expression of genes related to immunity and inflammation. Probiotics have been linked to cytokine release and IgA secretion. It has also been suggested that probiotics can modulate the original microbiota or normalize it when it is disturbed, inhibit and block the colonization of other pathogenic bacteria, stabilize the epithelial barrier, promote mucus secretion or raise the levels of some compounds such as butyrate or other short-chain fatty acids, with health benefit.
Unfortunately, for most of these cases there are similar works with negative and even opposite results at the same time. This confusion contributes to the fact that many effects have not been proven in humans or have been done with a statistically non-significant number or have only been done with some specific probiotic bacteria. There is also an enormous variability of different strains of bacteria and yeasts used in the different studies, there is no consensus in the formulations or in the methodological protocols and analysis of the results, and there is a high heterogeneity in terms of diet, age, sex, genetics, and indigenous microbiota of the individuals analyzed. In many cases, evidence is lacking and more clinical trials are needed to check whether these changes associated with probiotics are really beneficial or not. In addition, some effects observed in animal models are not necessarily transferable to humans, such as the effect of probiotics on anxiety.
To date, there is no approved and authorized health claim for any probiotic. This discrepancy creates confusion and raises the question of whether probiotics work or not. The answer is clear: it depends.
The problems of colonization and permanence
One of the problems still unresolved with probiotics is the ability of the microorganisms that compose them to lodge stably in the intestinal mucosa and whether this colonization of the intestine is necessary to have a beneficial impact on the host. Surprisingly, it has not been studied much whether the probiotics we consume actually colonize the intestinal mucosa. Most studies usually analyze the amount of probiotics that appear in the feces, but it is not usually examined if they have really colonized the intestine or have simply “passed by”. Thus, it has been suggested that there are two types of people: permissive, in which probiotic microorganisms colonize and remain for a while in their intestine; and resistant ones, in which probiotics do notcolonize the intestine and are quickly expelled in the feces. It seems that it is the pre-existing gut microbiota itself that determines whether a person is permissive or resistant to colonization. There is therefore individual variability and some people may benefit from probiotics, while others “pass by” and have no effect. This is not surprising, as different people respond differently to the same drug, food, pathogen or probiotic.
Another question we can ask ourselves is how long the probiotic microorganisms remain colonizing the intestinal mucosa, once we have stopped taking them. Several studies have been done and the answer is also not very clear. In some cases, the probiotic disappears when you stop taking it, in others it can last between one and two weeks, or even longer. In general, the results suggest that how long probiotics remain inside us depends a lot on the type of strain used in the formulation of the probiotic and, again, on each person.
So that general idea that taking a pill with “good” bacteria or yeast can crowd out the “bad” bacteria and improve my health is probably wrong: for a person who is already healthy to take probiotics to improve their overall health may not help. No one assures us that this particular probiotic will colonize our intestine.
Another question about probiotics is whether they are effective in replenishing the gut microbiota after treatment with antibiotics. On this too there are contradictory results. The effects of antibiotic treatments on the native microbiota are associated with many health problems, from infections, obesity and allergies to chronic inflammation. Antibiotics often alter the diversity of microorganisms in the original microbiota, facilitating colonization of exogenous strains of probiotics. But this can sometimes come at a price: in some people, the native bacteria of the original microbiota may take longer to return to their original situation. This suggests that perhaps, in some cases, taking probiotics delays the return to the native microbiota.
The future: new personalized probiotics
For many years, different species of bacteria (Lactobacillus, Bifidobacterium, Enterococcus, E. coli, Bacillus, Prevotella, Streptococcus ) and yeasts (Saccharomyces, Kluyveromyces, Candida, Debaryomyces, Hansenula, Pichia...). As we are seeing, the effectiveness of probiotics depends on many factors: the quality of the product, the specific strain of bacteria or yeast that has unique characteristics and may have different effects, the quantity or dose of the microorganism, viability and stability (probiotics must be alive and active at the time they are consumed so that they can have a beneficial effect), the compatibility and health status of the host, the duration of its use, the synergy with other specific components or nutrients, etc.
Modifying our microbiota is much more complex than we thought. Not all formulations or combinations of probiotic strains have been clinically validated. It is necessary to agree on rigorous and quality multicenter clinical protocols and trials, which study the efficacy and possible side effects, especially in children, immunocompromised and sick people. New recombinant strains and new combinations of bacteria and yeast species can be investigated and tested, or combined with new prebiotics or postbiotics. New administration formulas, such as microencapsulation, are also being studied to promote the viability and stability of microorganisms.
At the end of 2021, Akkermansia muciniphila, a bacterium first isolated in 2004 from human feces and whose presence has been correlated with good health, was approved as food by the European Food Safety Authority. It is the first bacteria approved as food. It is not actually a probiotic, since the bacteria is not administered alive, but dead, pasteurized. Akkermansia muciniphila is a good example of those beneficial gut bacteria from which we have a lot to learn.
The future of probiotics is exciting. Perhaps within a few years they will sequence our intestinal microbiota and according to its composition and diversity, they will prescribe a concrete and personalized cocktail of microorganisms, perhaps encapsulated and combined with other prebiotics, as a concrete remedy for certain ailments. The future of probiotics is also part of personalized medicine.
Professor Ignacio López-Goñi, PhD
PhD in Biology and Professor of Microbiology, Faculty of Medicine, University of Navarra (Pamplona, Spain). Member of the American Society of Microbiology (ASM), of the Spanish Association of Scientific Communication, and president of the Teaching and Dissemination group of the Spanish Society of Microbiology (SEM).
Lilly Foundation Scientific Dissemination Award, COSCE Award for the Dissemination of Science, and CSIC-BBVA Foundation Award for Scientific Communication (2021). In 2023 he has received the Science Communication Award in Spanish.
Some references to learn more:
Suez, J., y col. (2019). The pros, cons, and many unknowns of probiotics. Nat Med, 25(5):716-729.
Reis, D.J., y col. (2018). The anxiolytic effect of probiotics: A systematic review and meta-analysis of the clinical and preclinical literature. PLoSOne.13(6):e0199041. Zmora, N. y col. (2019). Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell, 174(6):1388-1405.
Suez, J. y col. (2019). Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 174(6):1406-1423.
Jennifer Abbasi, J. (2019). Are probiotics money down the toilet? or worse? JAMA, 321(7):633-635.
