Probiotics

Did you know? Our ancestors took the ancestors of today’s probiotics!¹ From Neolithic times, fermentation of certain foods has been seen to hold incredible virtues. Milk, wheat, or vegetables became easier to preserve, tastier, easier to digest… and better for health.^1,2

From the beginnings of time, at least 5000 years ago, the Egyptians, Romans and Hindus already appreciated fermented milk,² and the Turks considered it to be the elixir of life. Is it the secret to their legendary strength? Three centuries before our era, Chinese workmen building the Great Wall of China ate fermented cabbage to keep healthy.² The famous Hippocrates, “father of medicine” recommended that Olympic athletes eat cheese.¹ Even the soldiers of the terrifying Genghis Khan found fermented milk to be a source of vigor that allowed him to win battles!³ But it was not until the beginning of the 20th century, particularly after Louis Pasteur’s work, that we discovered that these virtues were due to beneficial microorganisms.¹

What is a probiotic? 

Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host”. ^4,5
Do you need explanations for this original expert version?

A probiotic is not… 

• … an antibiotic, quite the contrary! The term “probiotic” (for life) was suggested by researchers in the 1960s, as opposed to “antibiotic” (against life).¹
• … a microbiota, which describes all the microorganisms present in a given environment - such as the gut. The microbiome, is simply the genome (all the genes) of all these microorganisms!⁷
• … a prebiotic, consists of special, non-digestible food fibers that specifically nourish the good bacteria in the microbiota and, thereby, are beneficial for health.⁸ When they are added to probiotics in specific products, they are called symbiotics.⁹
• … a fermented food, which is a food that has been elaborated with certain living microorganisms and via certain enzymatic transformations—such as yogurt, cheese, fermented cabbage—is not necessarily a probiotic even though it has health benefits.¹⁰
• … fecal microbiota transplantation (FMT) is a treatment consisting of treating the microbiota of a sick person by transplanting that of a healthy donor. Currently, FMT is only used in cases of relapsing intestinal infections caused by a bacterium called “Clostridioides difficile”.¹¹

What are probiotic microorganisms? 

Commonly called “microbes” or even “germs”, microorganisms are “microscopic” living beings, that means that they cannot be seen by the naked eye.¹² They often consist of only one cell! 

Microorganisms include bacteria, which are ubiquitous in our environment: they can be found in the earth, water, and even on and in our bodies!^{12, 13} Microscopic fungi can also be found: yeasts (from Saccharomyces, the baker’s yeast, to Candida, which causes fungal infections) or molds (like Penicillium, which gives Roquefort cheese its “blue” color, but also penicillin, the famous antibiotic).^12,14,15,16 Viruses are also microorganisms, but as they cannot survive without infecting a cell, they are still not considered as “living beings”.^12,17 There are also amoeba, microalgae, etc.^18,19 This little world is actually gigantic: there is already a billion bacteria in a teaspoon of earth! But fear not! Over 99% of them are harmless for humans.^12,20

The microorganisms that are most commonly used as probiotics are:

• bacteria from the human microbiota or from fermented dairy products, lactobacilli (sidenote: Lactobacilli Rod-shaped bacteria whose main characteristic is the production of lactic acid, from where they get the name “lactic acid bacteria”.  Lactobacilli are present in the oral, vaginal and gut microbiota of humans, but also in plants and animals. They are found in fermented foods, such as dairy products (e.g. certain cheeses and yoghurts), pickles, sauerkraut, etc. Lactobacilli are also found in probiotics, with certain species recognized for their beneficial properties.   W. H. Holzapfel et B. J. Wood, The Genera of Lactic Acid Bacteria, 2, Springer-Verlag, 1st ed. 1995 (2012), 411 p. « The genus Lactobacillus par W. P. Hammes, R. F. Vogel Tannock GW. A special fondness for lactobacilli. Appl Environ Microbiol. 2004 Jun;70(6):3189-94. Smith TJ, Rigassio-Radler D, Denmark R, et al. Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis ssp. lactis BB-12® on health-related quality of life in college students affected by upper respiratory infections. Br J Nutr. 2013 Jun;109(11):1999-2007. ) (Lactobacillus) and bifidobacteria‎ (sidenote: Bifidobacterium A genus of Y-shaped bacteria, most species of which are beneficial to humans. They are found in the gut of humans, and in some yogurts.
  
  They:
  - Protect the gut barrier 
  - Participate in the development of the immune system and help fight inflammation 
  - Promote digestion and improve symptoms of gastrointestinal disorders Sung V, D'Amico F, Cabana MD, et al. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics. 2018 Jan;141(1):e20171811.  O'Callaghan A, van Sinderen D. Bifidobacteria and Their Role as Members of the Human Gut Microbiota. Front Microbiol. 2016 Jun 15;7:925. Ruiz L, Delgado S, Ruas-Madiedo P, et al. Bifidobacteria and Their Molecular Communication with the Immune System. Front Microbiol. 2017 Dec 4;8:2345. ) (Bifidobacterium); ^3,21
• yeasts, such as Saccharomyces boulardii, isolated from the skin of lychees.^3,15

Have you forgotten your Latin?

Think of a fruit salad with plums, cherries, peaches and nectarines. They all come from the same genus of tree, the Prunus. For example, the species Prunus avium gives cherries, while Prunus persica gives peaches - of which there are even more varieties: yellow, white, smooth or fuzzy, round or flat, etc.²²

How are probiotics chosen?

Finding the “chosen ones” among the billions of species of microorganisms: that is the hard task that researchers face! Probiotic species often bear the names of their researchers, to commend their efforts: Saccharomyces boulardii was isolated by Henri Boulard²³ and Lactobacillus reuterii (which is now called Limosilactobacillus reuteri²⁴) by Gerhard Reuter²⁵. 

Regardless of whether they come from milk, fruit, or the human body, potentially beneficial microorganism species are studied from every conceivable angle in order to find the most promising strains.

• The first stage consists in identifying them, following the characteristics of their genome. The microorganisms are classified. They are given a name and a strain number.^4,26 
• The second stage consists in gradually reducing the potential candidates on the basis of their beneficial properties, such as anti-pathogenic, anti-cholesterol, or bowel-regulating actions.^4,26 
• The third stage consists in verifying their safety, i.e., whether there are any health risks; researchers therefore check whether they contain antibiotic-resistant genes, toxins, and whether they cause any undesirable effects. They also check whether the candidate probiotics are capable of surviving in certain extreme conditions, such as the gut (temperature, pH, bile acids, etc.).^4,26
• The fourth stage is not to be taken light-heartedly. It is when the efficacy of the probiotic is validated in humans, in what are called “clinical trials”, which should follow precise recommendations from the local or national health care authorities. It is at this stage that the tested microorganism can be classified as a probiotic.^4,26
• In the last stage, researchers ensure that the probiotic is alive and remains at the effective dose throughout the product’s shelf-life. The probiotics are then stored in an “international microbial strain bank”.^4,26

What are probiotics for? 

Our bodies contain several microbiota. The most important one is in the gut (that is, the “intestinal flora”), but there is also a microbiota of the skin, the vagina, the mouth, the respiratory tract, etc.^28,29 Billions of microorganisms work together within these microbiota.^28,30 The majority is harmless or beneficial for health.³¹ Some are potentially pathogenic; in other words, they could cause diseases, but their development is impeded by “friendly” microorganisms³². For different reasons, such as unhealthy eating, stress, disease, or a course of antibiotics, the equilibrium of the microbiota can be disrupted. This is called “dysbiosis (sidenote: Dysbiosis Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors. Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.   ) ”.^28,30 The composition of the microbiota is changed; it becomes weaker, beneficial microorganisms are less abundant, and pathogens seize the opportunity to colonize the space and multiply…³³

By reinforcing the microbiota, probiotics can help it to maintain or regain its equilibrium, acting on our immune defense system by reducing inflammation, protecting us by attacking pathogens (sidenote: Pathogen A pathogen is a microorganism that causes, or may cause, disease. Pirofski LA, Casadevall A. Q and A: What is a pathogen? A question that begs the point. BMC Biol. 2012 Jan 31;10:6. ) or their toxins. They thus prevent or correct the disorders or diseases associated with dysbiosis.^34,35,34 Nonetheless, depending on the strain, probiotics have different modes of action, and a specific beneficial effect may not be extrapolated from one strain to another.³⁷

Why take probiotics? What are the benefits? What is in it for me?

Probiotics have several benefits for our health. However, according to the efficacy that each probiotic strain has shown in studies conducted on humans, they have proven their worth in very specific situations.^5,38

• Digestive system disorders, such as antibiotic-associated diarrhea,³⁹ C. difficile diarrhea,⁴⁰gastroenteritis,⁴¹ traveler’s diarrhea,⁴² functional bowel disorders (or “irritable bowel”),^43,44 lactose digestion disorders,²¹ inflammatory bowel diseases (IBDS)⁴⁵ etc
• Winter respiratory tract infections⁴⁶
• Skin conditions⁴⁷
• Urinary tract infections⁴⁸
• Vaginal infections⁴⁹

How are probiotics made?

Probiotics are manufactured using a delicate technical process with strict quality controls at every stage of the production line. In fact, they must be produced in a way that guarantees the end product meets all quality and safety standards. The probiotic micro-organisms must stay alive, in a sufficient number and stable until the end of the product’s shelf life, be in the correct dose to produce the stated benefits, and be free from contaminants.^5,6,51

This infographic is a simplified and non-exhaustive illustration of the process for selecting and manufacturing probiotics with theoretical examples of quality controls.

Stages of manufacture^6,52

This step-by-step process is a simplified and non-exhaustive illustration of the process for manufacturing probiotics.

At each stage of the manufacturing process - even sometimes at several points during a single stage - samples are taken and analyzed to ensure that the product is compliant, in other words to check for optimal quality and purity.⁶ The micro-organisms must still be alive and safe to consume.⁶ So that consumers can have complete faith in the quality of their products, some laboratories use not only internal checks but external independent assessors to ensure that the entire manufacturing and quality control process complies with regulations and best practice.²⁷

What does science have in store for us?

There has been a lot of research into human microbiota and probiotics over the past several years. Driven by technological advances in biology, it provides us with new and sometimes surprising scientific insights into the subtle and complex interactions within microbial ecosystems. For precision probiotics, microRNAs, probiotic consortia, postbiotics, etc., research is paving the way for new and promising proposals to meet the current and future health needs of us all.

Science has already revealed some of the secrets behind how probiotics affect our health. We now know that the beneficial effect of a probiotic depends both on the strain and on certain characteristics of the individual consuming it, such as age, diet, state of health, medication and microbiota. ⁵⁴ As a consequence, this effect can vary between individuals. ⁵⁵ In recent years, major scientific advances have been made in understanding the interactions between microbiota and the human body. They suggest that modulating these microbial ecosystems could provide new solutions to major nutritional and health issues. ⁵⁶

So how can we ensure that future probiotics are more effective, more targeted and better adapted to each individual's microbiota? Many teams of scientists have already delved into this vast field of research. The tools they use to gain a better understanding include:

• The omics sciences of today’s biology

Genomics (sidenote: Genomics Study of all of a person's genes (the genome), including interactions of those genes with each other and with the person's environment. https://www.genome.gov/about-genomics/fact-sheets/A-Brief-Guide-to-Genomics ) , transcriptomics (sidenote: Transcriptomics Study of all the RNA molecules within a cell. RNA is copied from pieces of DNA and contains information to make proteins and perform other important functions in the cell. Transcriptomics is used to learn more about how genes are turned on (how they are regulated and expressed) in different types of cells. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/transcriptomics
https://www.nature.com/subjects/transcriptomics ) , proteomics (sidenote: Proteomics Study of the proteins present in a cell, tissue or organism (proteome), and the structure and function of a protein. https://academic.oup.com/chromsci/article/55/2/182/2333796   ) , metabolomics (sidenote: Metabolomics Comprehensive study of all metabolites, i.e., substances produced by biological processes during metabolism, to obtain their specific chemical fingerprint. Clish CB. Metabolomics: an emerging but powerful tool for precision medicine. Cold Spring Harb Mol Case Stud. 2015;1(1):a000588. ) , ⁵⁶ etc. Together, these disciplines cover all the processes and cellular exchanges involved in the functioning of a body system, such as the human microbiome. In addition, bioinformatics (sidenote: Bioinformatics Computer analysis of biological data Cunningham M, Azcarate-Peril MA, Barnard A et al. Shaping the Future of Probiotics and Prebiotics. Trends Microbiol. 2021;29(8):667-685 ) enables the enormous volumes of data generated by these new tools to be processed.

• Identifying key microorganisms in microbiota

The scientific knowledge provided by these new methods has enabled researchers to gain a much more detailed understanding of the organization of the microbiota, namely how it works, how the microorganisms interact with each other and with the individual that harbors them, etc. ⁵⁶ What is the goal? To identify the microorganisms that are key to its balance. In doing this, researchers are able to isolate specific strains and target them for their potential benefits for the microbiota and health. They can also observe the mode of action of these future probiotics within their cells, their interactions with the microbiota and the host's response ^{54, 57}.

• Next generation probiotics

These new scientific and technological approaches have led to the emergence of what is referred to as next generation probiotics (NGP) (sidenote: Next Generation Probiotics (NGP) Live microorganisms identified based on comparative analyses of the microbiota which confer a health benefit to the host, when administered in adequate amounts. Martín R, Langella P. Emerging Health Concepts in the Probiotics Field: Streamlining the Definitions. Front Microbiol. 2019;10:1047. ) . Among the most recently identified are Roseburia intestinalis, Faecalibacterium prausnitzii, Akkermansia muciniphila. These strains, which come from species that are key for the human microbiota, are thought to act on physiological processes (metabolism, immunity) that are not necessarily affected by conventional probiotics ⁵⁶ and on certain specific pathological mechanisms involved, for example, in cancer, obesity, diabetes, cardiovascular, inflammatory and auto-immune diseases, pain, etc. ^56,58,59,60 They could therefore be classified as Live Biotherapeutic Products or "LBPs" (sidenote: Live Biotherapeutic Product (LBP) Biological product containing living microorganisms, such as bacteria, and intended to prevent or treat disorders and diseases (vaccines do not fall into this category). Rouanet A, Bolca S, Bru A, et al. Live Biotherapeutic Products, A Road Map for Safety Assessment. Front Med (Lausanne). 2020;7:237. ) , i.e., medicinal products containing live organisms . Next generation probiotics primarily refer to those strains which do not have the history of use as probiotics. But they may also be previously known probiotics that are genetically modified to produce specific molecules of interest, such as short-chain fatty acids (SCFAs), to increase their survival in the digestive tract and improve their metabolism, immunomodulatory properties, ability to fight certain pathogens, etc. ⁶⁰

Precision probiotics for personalized medicine

The days of "precision probiotics” are already upon us. And by taking advantage of the variability of the host response, the era of personalized probiotics is dawning! As the concept of personalized medicine is based on factoring in the specific characteristics of each patient in order to overcome the disease, "next generation" probiotics can naturally be integrated into this approach due to their ability to modulate the host microbiota depending on its characteristics. ⁵⁴ Researchers are now devising ways of analyzing the gut microbiota of anyone who might benefit from a probiotic in order to determine the most suitable one beforehand. The development of miniaturized devices that can be ingested and take a flora sample in order to characterize it is already being considered. Scientists also believe that thanks to the democratization of high-speed sequencing, each of us could soon have access to the genome of our microbiota and thus be able to obtain personalized recommendations for staying in good health through nutrition, probiotics or prebiotics. ⁵⁴

New public health applications

Probiotics are currently being considered as a response to public health issues, particularly in situations where conventional therapeutic options are lacking. For example, in light of the worrying increase in antibiotic resistance worldwide, probiotics with antimicrobial or immunomodulatory activity are being studied as alternatives to antibiotics. The therapeutic potential of probiotics to treat other major health problems, such as obesity, liver disease, fertility problems, high cholesterol and mood disorders, is also being tested. ⁵⁶ Lastly, probiotics are thought to help improve cancer treatment as certain strains appear to optimize treatments (and/or reduce their toxicity) for colon, lung and kidney cancers, etc. ^60,62

Consortia pack an even bigger probiotic punch

Probiotics are also undergoing change as scientists are experimenting with them in groups... and in pieces! The balance of the microbiota depends on the interactions between its microorganisms, and several species may be abnormally underrepresented in the event of dysbiosis. Inspired by the success of fecal transplantation (sidenote: Fecal transplantation This therapeutic procedure consists in placing stool from a healthy donor in a patient’s digestive tract in order to restore the balance of their intestinal flora. For the time being, it is only approved for the treatment of recurrent Clostridioides difficile infections. Quigley EMM, Gajula P. Recent advances in modulating the microbiome. F1000Res. 2020;9:F1000 Faculty Rev-46. ) which incorporates an entire bacterial ecosystem, researchers are currently testing consortia of probiotics, i.e., formulations of several strains acting as a 'network' and in synergy ⁵⁶ to achieve a defined therapeutic effect. ⁶⁶

Have you ever heard of postbiotics?

Post bio...what? Postbiotics! ⁶⁷ These are not whole, live microorganisms, as probiotics must be, but microbial fragments, inactivated strains (the cell is dead and no longer multiplying) or bacterial metabolites (proteins, enzymes, etc.) capable of providing benefits to the host. They are beneficial because they are easy to produce and preserve, and they are said to have similar or even superior effects to their probiotic counterparts. ^56,68 Further studies are needed to confirm these encouraging initial results.

Bacteriophages: viruses that can kill bacteria....

But that's not all... Research into phage therapy, i.e. viruses that specifically attack certain pathogenic bacteria in the microbiota, is being resumed after decades of dormancy. Recent research suggests that phages could become part of the therapeutic arsenal for fighting multidrug-resistant infections. They could also help to correct the dysbiosis associated with certain diseases or serve as a 'means of transport' for targeted drugs. Further scientific work and clinical trials are once again needed before phage therapy can become one of the new, effective and safe options for tomorrow's medicine. ⁶⁹

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