Finding a needle in a haystack: Bacteroides fragilis polysaccharide A as the archetypical symbiosis factor

: Starting from birth, all animals develop a symbiotic relationship with their resident microorganisms that benefits both the microbe and the host. Recent advances in technology have substantially improved our ability to direct research toward the identification of important microbial species that affect host physiology. The identification of specific commensal molecules from these microbes and their mechanisms of action is still in its early stages. Polysaccharide A (PSA) of Bacteroides fragilis is the archetypical example of a commensal molecule that can modulate the host immune system in health and disease. This zwitterionic polysaccharide has a critical impact on the development of the mammalian immune system and also on the stimulation of interleukin 10-producing CD4+ T cells; consequently, PSA confers benefits to the host with regard to experimental autoimmune, inflammatory, and infectious diseases. In this review, we summarize the current understanding of the immunomodulatory effects of B. fragilis PSA and discuss these effects as a novel immunological paradigm. In particular, we discuss recent advances in our understanding of the unique functional mechanisms of this molecule and its therapeutic potential, and we review the recent literature in the field of microbiome research aimed at discovering new commensal products and their immunomodulatory potential.