Designing synbiotics for improved human health

A synbiotic is the combination of a microorganism shown (or thought) to have some beneficial effect when consumed (i.e. a probiotic) and a compound that specifically favours its growth (i.e. a prebiotic), having a synergistic effect when paired together. Many probiotic supplements are currently marketed as synbiotics. These products typically contain a combination of Bifidobacterium, Lactobacillus or Streptococcus species, and a carbon substrate (e.g. lactose, lactulose or inulin) supporting growth of these organisms. Historical use of probiotics in foods and beverages and marketing towards digestive health has favoured food companies as producers of these products. The largest market share for probiotics comes from companies like Danone, Nestl e and General Mills, which are currently investing in R&D to expand their probiotic and prebiotic portfolios. Examples of growing interest in probiotics can be found among recent patents, containing claims of probiotics for reduction of belly fat (Grompone et al., 2014) or prebiotic fibre formulations for the treatment of inflammatory bowel disease (Boileau et al., 2015). In coming years, focus on the microbiome may shift the market share of probiotics towards pharmaceutical companies, which have infrastructure and revenue models to accommodate clinical trials. Indeed, both existing pharmaceutical companies (e.g. Johnson and Johnson, Merck, Pfizer and Novartis) and recent start-ups (e.g. Vedanta, Eligo Biosciences, Finch Therapeutics) have begun to target probiotics from the human microbiota for treatment of a broad range of diseases. Currently available probiotics sample a limited diversity of bacteria that does not include most dominant gut microorganisms positively associated with host health. The use of these established probiotics stems from their historical association with improved digestive health. Today, probiotic, prebiotic and synbiotic products are marketed towards use in gynaecology, urology, anti-ageing, gastroenterology, immunology, cardiology, skin care, dietetics and oral care. The broad applications of this limited clique of organisms suggest that there is a need for more extensive clinical and epidemiological evaluation of probiotics and their efficacies in the treatment of a variety of conditions. In general, for probiotics to be marketed as pharmaceutical products, the burden of proof for efficacy will be much greater than for similar formulations marketed as functional food products, similar to vitamins or other over-the-counter supplements. For well-studied probiotic species, we have some understanding of the mechanisms by which they impact host health. Some Lactobacillus species, in particular, are thought to deplete systemic pro-inflammatory Th17 immune cells through the production of tryptophan metabolites, which activate the aryl hydrocarbon receptor (AHR; Zelante et al., 2013). Many of their other downstream effects on host health have yet to be elucidated, but there are indications that certain Lactobacillus species may affect brain (Bravo et al., 2011), reproductive (Linhares et al., 2011) and epithelial barrier function (Levkovich et al., 2013). Ongoing research on the diverse and understudied members of the human gut microbiota likely will propel pharmaceutical investment in clinically relevant probiotics and synbiotics. By contrast, food and probiotics companies will likely invest in formulations that incorporate well-studied, previously identified probiotics to promote their non-clinical use in different settings. Recent studies analysing the effects of introduced bacteria on the host suggest that several commensals have generic and redundant effects on immunity (GevaZatorsky et al., 2017). However, these effects may change in the presence of an intact microbial community and likely interact with diet and host health (MaldonadoG omez et al., 2016). Some of these interactions may be desirable: e.g., some probiotics show competitive exclusion of pathogenic organisms (Caballero et al., 2017), support the growth of native bacteria helpful for host health (Belzer et al., 2017; Caballero et al., 2017) and provision nutrients from the diet otherwise inaccessible to the host (Marcobal and Sonnenburg, 2012). The