Updated: Feb 3, 2022
The human gut is colonized by approximately 1014 bacteria, which exceeds the number of cells in the human body by a factor of ten , so it seems natural that the gut microbiome can have an impact on human health. The colonization of the human gut occurs postnatally, from mother to infant and through the consumption of food; within a couple of years, it reaches an adult-like state .
Bacteria play an important role in the gut: they help with the digestion and absorption of food and help to keep the colonization of pathogenic (harmful) microorganisms to a minimum [1,3]. Throughout the lifetime of a human, the microbiome in the gastrointestinal (GI) tract remains relatively stable, but can be influenced by diet and the use of antibiotics . Foods contain bacteria naturally (fermented foods) or they are added as food ingredients. These probiotics can be beneficial in human health.
But does this relate to other aspects of human health? In recent years, studies have shown that bacteria are part of a bidirectional system referred to as the brain-gut axis by which the brain and gut jointly contribute to the maintenance of an organism’s health . Changes to the gut microbiome can have consequences to overall health, including autoimmune, GI, metabolic, and brain disorders. This bidirectional system works directly and indirectly via the immune system, neuroendocrine system, the central and enteric nervous systems, and through the modulation of neurotransmitters [2,5]. While all of these systems are relevant, neurotransmitters play an important part in (mental) health  by chemically transmitting nerve impulses across synapses. This chemical transmission links the brain and the spinal cord to the rest of the body, affecting every cell, tissue, and system; therefore, an imbalance of neurotransmitters can have widespread health effects . Several rodent studies have shown that probiotic consumption can prevent stress-induced increases in levels of adrenocorticotropic hormone, adrenaline, corticosterone, and noradrenaline, indicating a possible link between the gut and the brain. The reduction of these markers, which are linked to stress, suggests that the use of probiotics in depressed patients could have a therapeutic effect, by attenuating the hypothalamic-pituitary-adrenal axis, which is hyperactive in depressed patients . An imbalance of neurotransmitters can cause insomnia, mood disorders (e.g. depression) and anxiety .
Probiotics and prebiotics have been in the news making people aware of the health benefits of consuming them. A prebiotic is a food that is high in fiber and aids in the growth and maintenance of beneficial microorganisms. Probiotics as defined in 2001 by the Joint Food and Agricultural Organization (which is part of the World Health Organization) as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” . Some of the strains associated with health benefits are strains of the following genera: Bifidobacterium, Bacillus, Enterococcus, Escherichia coli, Lactobacillus, Leuconostoc, Pediococcus, Saccharomyces and Streptococcus . Probiotics can be consumed by eating fermented foods, foods that have been seeded with beneficial bacteria, and as dietary supplements.
The regulation of probiotics by the FDA depends on how the probiotics are being administered (food, dietary supplement, or drug) and if a claim (structure function claim or health claim or, a therapeutic claim, in the case of a drug) is being made.
When the probiotic is intentionally added to foods and has not already been determined safe for its intended use through a pre-market review (i.e., a food additive petition), a generally recognized as safe (GRAS) determination can be conducted, under sections 201(s) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) . This will allow the ingredient to be added to food for a specific use, at an amount that will confer a specific utility and that is safe for consumption.
Probiotics can also be consumed as dietary supplements. If the probiotic has not been marketed in the United States in a dietary supplement before October 15, 1994 (Section 413(d) of the FD&C Act, 21 U.S.C. 350b(d))  the FDA must be notified of the probiotic as a new dietary ingredient (NDI).
In order for the probiotic to be used as a drug, which is defined by the FDA as a “product that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and that its intended use affects the structure or any function of the body” . Clinical trials have to be conducted that show utility and safety of the drug and an IND will have to be filed with subsequent drug approval; the bacteria would be considered a biologic.
Claims can be made regarding the benefit of the probiotic as a structure function claim informing the consumer of the benefit of the consumption of probiotic on various systems of the body such as mood, gastrointestinal system and endocrine functions. A health claim or qualified health claim can make reference to the reduction in incidence of a specific disease.
According to the FDA, a structure function claim can be made if the “effect that a substance has on the structure or function of the body and do[es] not make reference to a disease”. A structure function claim can’t be misleading and must be truthful, it does not have to be pre-reviewed or authorized by the FDA, under 21 U.S.C. 343(r)(6) and21 CFR 101.93 . However, to substantiate structure function claims, publically available literature on human trials and animal trials as supportive information must support the truthfulness of such claims and must show the benefit of using the probiotic.
Health claims are limited to “claims about disease risk reduction, and cannot be claims about the diagnosis, cure, mitigation, or treatment of disease” . They are required to be reviewed and evaluated by the FDA prior to use and require a Significant Scientific Agreement based on the all the scientific evidence publicly available (see 21CFR 101.14) . If the publically available information does not confer Significant Scientific Agreement a Qualified Health Claims can be made which is also “limited to claims about disease risk reduction, and cannot be claims about the diagnosis, cure, mitigation, or treatment of disease” , the total amount of publicly available evidence does not have to be as rigorous as that for Health Claims . During the review process of the submission the FDA evaluates the scientific evidence provided and determines whether the available evidence meets the Significant Scientific Agreement. If the FDA agrees that the scientific evidence supports the claim, it is considered a Health Claim. However, if the provided scientific evidence does not meet the agreement, it could be considered a Qualified Health Claim . The FDA utilizes an evidence-based review system to assess the strength of claims. It involves the evaluation of the scientific evidence supporting a proposed claim about the substance/disease relationship .
The scientific information that is available on the probiotic use and its utility for the brain-gut axis can open up the development of products that probiotics can be added to as food and dietary supplements. Companies can use various regulatory pathways to bring these probiotics to market and can decide if they want to add claims to inform the public of the health benefit of the probiotic on mood disorders and other health issues. Future research on probiotics may show which combination of microorganisms should be used for specific health issues.
Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol (Lond ). 2004;558(1):263-275.
Dash SR. The microbiome and brain health: What is the connection. http://www.medscape.com/viewarticle/841748. Updated 2015. Accessed March 28, 2017.
Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burne PWJ. Psychobiotics and the manipulation of bacteria–gut–brain signals. Trends in Neurosciences. 2016;39:763-781.
Cryan JF, O’Mahony SM. The microbiome-gut-brain axis: From bowel to behavior. Neurogastroenterology and Motility. 2011;23(3):187-192.
Wallace CJK, Milev R. The effects of probiotics on depressive symptoms in humans: A systematic review. Annals of General Psychiatry. 2017;16(1).
Integrative Psychiatry. Neurotransmitters. http://www.integrativepsychiatry.net/neurotransmitter.html. Updated 2017. Accessed March 29, 2017.
FAO. Probiotics in food: Health and nutritional properties and guidelines for evaluation. http://www.fao.org/3/a-a0512e.pdf. Updated 2006. Accessed March 30, 2017.
Fijan S. Microorganisms with claimed probiotic properties: An overview of recent literature. International Journal of Environmental Research and Public Health. 2014;11(5):4745-4767.
FDA. Generally recognized as safe (GRAS). https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/. Updated 2017a. Accessed March 30, 2017.
FDA. New dietary ingredients in dietary supplements – background for industry. https://www.fda.gov/Food/DietarySupplements/NewDietaryIngredientsNotificationProcess/ucm109764.htm. Updated 2016. Accessed March 30, 2017.
FDA. Drug approval process. https://www.fda.gov/downloads/drugs/resourcesforyou/consumers/ucm284393.pdf. Updated 2017b. Accessed March 30, 2017.
FDA. Guidance for industry: A food labeling guide (8. claims). https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm064908.htm. Updated 2013. Accessed March 30, 2017.
FDA. Guidance for industry: Evidence-based review system for the scientific evaluation of health claims – final. https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm073332.htm. Updated 2009. Accessed March 30, 2017.