Probiotics have a range of documented effects on human health, with hundreds of studies from the past several decades showing their ability to alter physical or behavioural phenotypes in humans. These human efficacy trials provide the necessary evidence to guide probiotic use. In designing a trial, however, the researchers often wonder how to select the best strain for the task in order to increase the likelihood of success. In this context, preclinical testing—using in vitro, ex vivo, and animal models—becomes highly important. Controlled studies of this kind provide a window into the mechanisms involved in a probiotic-mediated health effect.
In this manner, many probiotic mechanisms of action have been uncovered. According to the 2014 International Scientific Association for Probiotics and Prebiotics (ISAPP) expert consensus document on the definition of probiotic, some mechanisms seem to be rare among different strains, but others are widespread among strains of the same species (Hill et al., 2014). For instance, some Lactobacillus species can act through immune modulation: specifically, by depleting pro-inflammatory Th17 immune cells systemically through the production of tryptophan metabolites, which activate the aryl hydrocarbon receptor (Zelante et al., 2013). But individual strains may have multiple mechanisms of action and a comprehensive understanding of these mechanisms does not yet exist for traditional probiotic strains (Lebeer et al., 2018).
From the perspective of the host, the mechanisms of action of traditional probiotics may include (but not exclusively) the following:
|Mechanism of action||Further reading|
|Producing metabolites such as short-chain fatty acids and histamine||(Gao et al. 2017; Sanders et al., 2018)|
|Modulating composition and/or activity of host microbiota (e.g., through pili-mediated colonization)||(Hemarajata & Versalovic 2013; O’Connell Motherway et al., 2011)|
|Enhancing epithelial barrier integrity||(Rao & Samak, 2013)|
|Modulating the host immune system||(Yan & Polk, 2011)|
|Central nervous system (CNS) signaling (e.g., neurotransmitters)||(Wang et al., 2016)|
|Modulating gene expression in host tissues at distance from the gastrointestinal tract (e.g., liver, adipose tissues)||(Plaza-Diaz et al., 2014)|
|Influencing hormone levels||(Clarke et al., 2014)|
|Adhering to the mucosa and epithelium, inhibiting pathogen adhesion and/or growth||(Bermudez-Brito et al., 2012)|
|Inhibiting pathogen virulence factor expression||(Corr et al., 2009)|
|Producing enzymes (e.g., lactase to promote lactose digestion in the small intestine)||(de Vrese et al., 2001)|
|Synthesizing vitamins||(Gu & Li, 2016)|
|Producing bacteriocins||(Corr et al. 2009; Spinler et al., 2017)|
Research that has looked deeper at each of these mechanisms has found that many are actively mediated by various probiotic effector molecules—likely numbering in the thousands. Examples of probiotic effector molecules in Lactobacillus and Bifidobacterium strains include surface-located molecules, metabolites related to tryptophan and histamine, as well as CpG-rich DNA and various enzymes (e.g. bile salt hydrolases) (Lebeer et al. 2018).
Great potential lies in harnessing novel human-derived microbes to perform specific health functions; for each candidate, however, regulators must evaluate many factors: the microbe’s beneficial properties, its antibiotic resistance profile, history of safe use (where it exists), publication of its genomic sequence, toxicological studies in agreement with novel food regulations, and qualified presumptions of safety (Brodmann et al., 2017). As these next-generation probiotics may open up new therapeutic possibilities, understanding their mechanisms of action is no less important than for traditional probiotics. In the two leading next-generation probiotic candidates, studies to date show they may share mechanisms of action with traditional probiotics, but they may also have novel mechanisms—the details of which will emerge with further investigation.
Akkermansia muciniphila appears to be an important bacterium in metabolic health; levels of these bacteria in the human gut are negatively correlated with obesity, diabetes, cardiometabolic diseases, and low-grade inflammation (Cani & de Vos 2017). Our preclinical work found pasteurized A. muciniphila reduced fat mass development, insulin resistance, and dyslipidemia in mice; the bacteria also modulated both the host urinary metabolome and energy absorption in the intestines. The mechanism appeared related to immune modulation through a protein (called Amuc_1100*) on the outer membrane of A. muciniphila, which interacted with Toll-like receptor 2. And speaking of immunity, this impact of A. muciniphila seems to be of great importance not only in the context of the metabolic syndrome but also for reducing the onset of type 1 diabetes (Hänninen et al. 2017). Even more strikingly, a series of recent papers (Jobin, 2018; Kaiser, 2017; Routy et al., 2018; Matson et al., 2018) have shown that the gut microbiota—and key bacterial species in particular—may influence the outcomes of immunotherapy for cancer, such as anti–PD-1 treatment. For example in humans, responders (as compared to non responders) revealed an increased relative abundance of A. muciniphila and favorable drug response; interestingly, poorly responding mice could be turned into responders by treating them with A. muciniphila.
Strains of another next-generation probiotic candidate, Faecalibacterium prausnitzii, may initiate a complex anti-inflammatory pathway in the host, with recent reports showing short-chain fatty acid (butyrate) production probably plays a role in the strains’ ability to induce the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells.
Toward therapeutic precision
The past several decades have seen many data emerge on the applications of probiotics in human health, and a continually increasing understanding of probiotic mechanisms will lead us into a new era of therapeutic possibility. Ongoing rigorous investigative work will help us achieve a comprehensive understanding of the ‘personality’ of each probiotic bacterium, including the ways in which each one succeeds in affecting host health—and this will ultimately help us move toward personalized medicine.
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Brodmann, T. et al., 2017. Safety of Novel Microbes for Human Consumption: Practical Examples of Assessment in the European Union. Frontiers in Microbiology, 8, p.1725. Available at: http://journal.frontiersin.org/article/10.3389/fmicb.2017.01725/full [Accessed January 9, 2018].
Cani, P.D. & de Vos, W.M., 2017. Next-Generation Beneficial Microbes: The Case of Akkermansia muciniphila. Frontiers in Microbiology, 8, p.1765. Available at: http://journal.frontiersin.org/article/10.3389/fmicb.2017.01765/full [Accessed January 9, 2018].
Clarke, G. et al., 2014. Minireview: Gut Microbiota: The Neglected Endocrine Organ. Molecular Endocrinology, 28(8), pp.1221–1238. Available at: https://academic.oup.com/mend/article-lookup/doi/10.1210/me.2014-1108 [Accessed December 21, 2017].
Corr, S.C., Hill, C. & Gahan, C.G.M., 2009. Chapter 1 Understanding the Mechanisms by Which Probiotics Inhibit Gastrointestinal Pathogens. In Advances in food and nutrition research. pp. 1–15. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19389605 [Accessed December 20, 2017].
Gao, C. et al., 2017. Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production. The American journal of pathology, 187(10), pp.2323–2336. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28917668 [Accessed January 4, 2018].
Gu, Q. & Li, P., 2016. Biosynthesis of Vitamins by Probiotic Bacteria. In Probiotics and Prebiotics in Human Nutrition and Health. InTech. Available at: http://www.intechopen.com/books/probiotics-and-prebiotics-in-human-nutrition-and-health/biosynthesis-of-vitamins-by-probiotic-bacteria [Accessed December 20, 2017].
Hänninen, A. et al., 2017. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut, p.gutjnl-2017-314508. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29269438 [Accessed January 9, 2018].
Hemarajata, P. & Versalovic, J., 2013. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therapeutic advances in gastroenterology, 6(1), pp.39–51. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23320049 [Accessed December 21, 2017].
Hill, C. et al., 2014. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology, 11(8), pp.506–514. Available at: http://www.nature.com/doifinder/10.1038/nrgastro.2014.66 [Accessed March 17, 2017].
Jobin, C., 2018. Precision medicine using microbiota. Science (New York, N.Y.), 359(6371), pp.32–34. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29302001 [Accessed January 9, 2018].
Kaiser, J., 2017. Gut microbes shape response to cancer immunotherapy. Science (New York, N.Y.), 358(6363), p.573. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29097525 [Accessed January 9, 2018].
Lebeer, S. et al., 2018. Identification of probiotic effector molecules: present state and future perspectives. Current Opinion in Biotechnology, 49, pp.217–223. Available at: http://www.sciencedirect.com/science/article/pii/S0958166917301829?via%3Dihub#tb0010 [Accessed December 20, 2017].
Matson, V. et al., 2018. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science (New York, N.Y.), 359(6371), pp.104–108. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29302014 [Accessed January 9, 2018].
O’Connell Motherway, M. et al., 2011. Functional genome analysis of Bifidobacterium breve UCC2003 reveals type IVb tight adherence (Tad) pili as an essential and conserved host-colonization factor. Proceedings of the National Academy of Sciences, 108(27), pp.11217–11222. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21690406 [Accessed January 5, 2018].
Plaza-Diaz, J. et al., 2014. Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics. World journal of gastroenterology, 20(42), pp.15632–49. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25400447 [Accessed December 21, 2017].
Rao, R.K. & Samak, G., 2013. Protection and Restitution of Gut Barrier by Probiotics: Nutritional and Clinical Implications. Current nutrition and food science, 9(2), pp.99–107. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24353483 [Accessed December 21, 2017].
Routy, B. et al., 2018. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.), 359(6371), pp.91–97. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29097494 [Accessed January 9, 2018].
Sanders, M.E. et al., 2018. Shared mechanisms among probiotic taxa: implications for general probiotic claims. Current Opinion in Biotechnology, 49, pp.207–216. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29128720 [Accessed December 20, 2017].
Spinler, J.K. et al., 2017. Next-Generation Probiotics Targeting Clostridium difficile through Precursor-Directed Antimicrobial Biosynthesis V. B. Young, ed. Infection and Immunity, 85(10), pp.e00303-17. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28760934 [Accessed January 5, 2018].
de Vrese, M. et al., 2001. Probiotics–compensation for lactase insufficiency. The American journal of clinical nutrition, 73(2 Suppl), p.421S–429S. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11157352 [Accessed December 20, 2017].
Wang, H. et al., 2016. Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review. Journal of neurogastroenterology and motility, 22(4), pp.589–605. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27413138 [Accessed December 21, 2017].
Yan, F. & Polk, D.B., 2011. Probiotics and immune health. Current opinion in gastroenterology, 27(6), pp.496–501. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21897224 [Accessed December 21, 2017].
Zelante, T. et al., 2013. Tryptophan Catabolites from Microbiota Engage Aryl Hydrocarbon Receptor and Balance Mucosal Reactivity via Interleukin-22. Immunity, 39(2), pp.372–385. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23973224 [Accessed December 20, 2017].
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