β-1,3/1,6-Glucans and Immunity: State of the Art and Future Directions

Abstract

The innate immune system responds in a rapid and non-specific manner against immunologic threats; inflammation is part of this response. This is followed by a slower but targeted and specific response termed the adaptive or acquired immune response. There is emerging evidence that dietary components, including yeast-derived β-glucans, can aid host defense against pathogens by modulating inflammatory and antimicrobial activity of neutrophils and macrophages. Innate immune training refers to a newly recognized phenomenon wherein compounds may "train" innate immune cells, such that monocyte and macrophage precursor biology is altered to mount a more effective immunological response. Although various human studies have been carried out, much uncertainty still exists and further studies are required to fully elucidate the relationship between β-glucan supplementation and human immune function. This review offers an up-to-date report on yeast-derived β-glucans as immunomodulators, including a brief overview of the current paradigm regarding the interaction of β-glucans with the immune system. The recent pre-clinical work that has partly decrypted mode of action and the newest evidence from human trials are also reviewed. According to pre-clinical studies, β-1,3/1,6-glucan derived from baker's yeast may offer increased immuno-surveillance, although the human evidence is weaker than that gained from pre-clinical studies.

Keywords: diet and inflammation; innate immunity; metabolic-inflammation; trained immunity; yeast β-glucan.

Figure 1

β‐Glucan structure–activity relationship. Variability in β‐glucan structure is due to differences in source and extraction and/or purification methods, which likely explains the divergent functionalities that exist among β‐glucans. Depending on the source, differences arise such as the nature of molecular linkages and the degree of branching, together with variability in mass, charge, solubility, and configuration in solution (single helix, triple helix, or random coil), as well as in impurity levels and content. These variabilities will result in different interactions with the host. Bacterial β‐glucans represent the most basic form of the polysaccharide with a linear β‐1,3 structure; cereal β‐glucans follow the same pattern with dominant β‐1,4 stretches; fungal (e.g., mushroom) and yeast (i.e., single cell fungi) β‐glucans have frequent β‐1,3‐d‐glucose side chains at β‐1,6 branching points that are short and spaced in fungal species (e.g., mushroom) and longer in yeast species. Further variations to these general structures are common. Only highly purified β‐1,3‐1,6‐glucans with a high degree of branching along the β‐1,3‐glucan backbone and a high molecular weight are able to exert immunomodulatory properties.

Figure 2

Immune response overview. The immune system has the ability to recognize and eliminate pathogens by first activating the innate response, which, without prior antigen exposure, acts in a fast and un‐targeted manner to phagocytose and kill the invader. APCs use PRRs to recognize pathogens directly (e.g., β‐glucan recognition by dectin‐1) or indirectly (e.g., β‐glucan recognition by CR3 by binding to iC3b opsonized β‐glucan). After PRR‐pathogen binding, APCs proceed with an antimicrobial response followed by an inflammatory response with a complex intracellular signaling cascade that culminates in the activation of transcription factors to produce inflammatory mediators and antigen presentation aided by MHC Class I and II molecules.

Figure 3

Dectin‐1 structure and signaling. Murine and human dectin‐1 consist of an extracellular C‐type lectin domain (which recognizes β‐1,3‐glucans) joined to a short stalk that continues into a single transmembrane domain followed by an intracellular ITAM‐like motif signaling domain (hemITAM). Upon whole glucan particle (WGP) attachment and Src phosphorylation, CD45 and CD148 are isolated from the contact site of dectin‐1‐WGP to allow hemITAM signaling. The downstream responses include 1) a rapid antimicrobial response lead by ligand uptake, phagocytosis, and oxidative burst, and 2) a consequent pro‐inflammatory response that is mediated by the production of cytokines and chemokines as a result of gene transcription modulation, together with antigen presentation to T and B cells to further continue with adaptive cell differentiation to the specific antigen. The binding to both dectin stalks is necessary to induce downstream Src activation and Syk recruiting.

Figure 4

CR3 signaling. Dual ligation of the α‐chain (CD11b) by complement iC3b and soluble glucan (SG) is needed to activate CR3. iC3b coats the antigen and attaches to the I‐domain, while SG, derived from the fragmentation of its parent β‐glucan by phagocytes, attaches to the lectin‐1 domain.

Figure 5

Oxidative burst. β‐glucan primed immune cells produce reactive oxygen species within the lysosome by activating NADPH oxidase; however, the activation of NADPH oxidase is achieved via different molecular signaling according to the form of β‐glucan, that is, WGP, SG, or focal adhered β‐glucan.