Yeast β‐Glucans and Immunity

Structural Diversity with Varied Health Impacts

β‐Glucans are naturally occurring polysaccharides of d‐glucose monomers linked by β‐glycosidic bonds. They serve as energy stores and structural components of plant, algal, fungal, and bacterial cell walls. β‐glucans show a very defined structure–activity relationship: research to date demonstrates that varied source and structure lead to varied biological activity. For example, although oat‐derived β‐glucans act as effective dietary fibers that improve metabolic health parameters, including dyslipidemia and insulin resistance; yeast‐derived β‐glucans behave as immunomodulators, specifically targeting the innate immune response. The chemistry of β‐glucans is well characterized; they all share a β‐1,3‐glucan backbone; however, among β‐glucans, there is variation regarding source as well as extraction and purification methods used in their commercial preparation, which gives rise to great diversity in branching pattern, insertions, and impurities. This yields a wide range of molecular structures within the β‐glucan family to ultimately determine a range of health effects . Long side chains along the β‐1,3 backbone confer insolubility in the case of some yeast and fungal β‐glucans. The formation of purely linear β‐1,3‐glucans in fungi and yeast is highly uncommon; however, these are present in soluble extracts of S. cerevisiae .Interestingly, only β‐glucans with a high molecular weight and degree of branching, like those from fungi and yeast, have been reported to exert an immunomodulatory action. In fact, it was the preliminary work of Pillemer and Ecker on Fleischmann's Yeast that emerged during the 1940s which first suggested the connection between β‐glucans and immunity. Several decades later, evidence has accumulated relating to the immunomodulatory activity of both research‐exclusive and commercially available forms of β‐glucans derived from various sources, and by various extraction and purification methods; however, the translation of any nutritional immunomodulatory agent from cellular and/or pre‐clinical models to use in humans is a great challenge. This specifically applies to β‐glucans, since aside from their wide structural variability leading to diverse biological activities, there are differences between β‐glucan receptors in humans and mice, immune health markers are ambiguous, and variation in administration route, dose, populations studied, and time points between studies are likely to contribute to inconsistent results relating to the health impact of β‐glucans. As such, the first aim of this review is to collate and interpret the existing pre‐clinical research on β‐1,3/1,6‐glucan with regard to immunity in order to clarify its molecular mechanism of immunomodulatory action. This will be achieved by considering its binding to immune receptors and the downstream signaling events leading to trained immunity and cytotoxic activity. The second aim of this review is to collate and evaluate the literature in order to provide a comprehensive overview of the human studies assessing the effect of supplementation with high quality, well‐characterized β‐1,3/1,6‐glucan from commercially available sources on immunity across multiple populations. For this, inclusion criteria consist of randomized, double‐blind, placebo‐controlled human studies that investigated the efficacy of orally administered β‐glucan with a purity of over 75% (obtained by stripping β‐glucan from the external mannoprotein layer, the interlinked chitin in the cell wall, and the components inside the cell membrane). Exclusion criteria include β‐glucan formulations that lack human studies or are used in combination with other active ingredients (e.g., β‐glucan and monoclonal antibodies in cancer research). Overall, no adverse events were detected, and no major safety concerns were presented in response to any of the selected intervention studies. Statistical significance was set at p < 0.05, and all results included are by default significant unless otherwise stated. All β‐glucans covered herein are by nature β‐1,3/1,6‐glucans, and the term β‐glucan will refer to β‐1,3/1,6‐glucan unless otherwise specified.