The cross talk between microbiota and the immune system: metabolites take center stage
Introduction
The mammalian gastrointestinal tract harbors one of the highest microbial densities on Earth, a population comprising around 1000–5000 species from all domains of life. The recent recognition that intestinal microbiota exerts profound effects on many aspects of human health and disease, including the metabolic, immune, and nervous system, has led to the concept of a human meta-organism that integrates the communication between both prokaryotic and eukaryotic parts to achieve homeostasis [1]. Because of its capability for direct microbial recognition and microbial community shaping through anti-microbial pathways, the host immune system plays a key role in this communication. So far, most research has focused on the recognition of microbial surface molecules and nucleic acids by the innate immune system, and a large number of reciprocal feedback loops between the microbiota and the innate immune system has been uncovered [2, 3]. However, relatively little attention has been given to another means of communication between commensal bacteria and the immune system, namely the immunomodulatory effects of microbiota metabolites. These small molecules are intermediates and end products of diet-dependent commensal bacterial metabolism. Many of them serve as functional complementation to the metabolic capacities of the host, providing an example for bona fide mutualistic co-evolution with the mammalian part of the superorganism reducing its genomic capabilities to the extent that can be complemented by the microbiota. Other metabolites may serve as signaling molecules for inter-bacterial communication and quorum sensing. Since similar functional states of the microbiota can be reached by distinct taxonomic compositions, immune sensing of metabolites, rather than surface molecules, might allow more meaningful evaluation of microbiota function and consequences for the immune system. Here, we provide an overview about the most prominent examples of how microbiota metabolism products contribute to health and disease of the meta-organism by shaping the development and function of the immune system. As such, these metabolites integrate the functional states of food intake, microbiota ecology, and accordingly fine-tuning the host response.
Section snippets
Short-chain fatty acids
Diet dramatically influences the composition and function of the microbiota, and dietary changes can influence intestinal microbial ecology within the time scale of days [4]. Plant-derived non-digestible polysaccharides, such as cellulose, are an integral component of human diet. Bacterial fermentation of these polysaccharides produces short-chain fatty acids (SCFA) of 1–6 carbon length, including acetate, propionate, and butyrate. SCFAs have recently emerged as pivotal regulators of host
Long chain fatty acids
Long chain fatty acids (LCFAs) are an integral part of our diet. Various biochemical forms of LCFAs have been associated with health risks and benefits [16]. Like SCFA, some of the LCFA quantity and composition is modulated by the microbiota, and in turn participates in microbial-induced signaling in host cells. Dietary poly-unsaturated fatty acids (PUFA), such as various linoleic acids, are transformed into conjugated linoleic acids (CLA) and trans fatty acids [17, 18, 19]. Accordingly, mice
Bile acids
A further important element of intestinal fatty acid metabolism are bile acids, that are continuously secreted into the proximal intestinal where they have multiple physiological roles in facilitation of digestion and absorption of multiple essential food-derived particles. Bile acids are derived from cholesterol catabolism in the liver. Newly synthesized bile acids are conjugated to glycine (in humans) or taurine (in mice), and conjugated bile acids are transported into the gallbladder.
Polysaccharides
In addition to intermediates of primary microbial metabolism, structural components of commensal microbes may be involved in the cross talk between the microbiota and the host immune system. Of all bacterial carbohydrates, the capsular polysaccharide A (PSA) of the commensal Bacteroides fragilis and its impact on the host immune system has received most attention. Initially, monocolonization of GF mice with B. fragilis modulates CD4+ T cell homeostasis and cytokine production in a PSA-dependent
Vitamins
Vitamins are nutrients that are vital for multiple cellular and organ functions. Vitamin deficiency has been associated with well-defined clinical entities, and growing numbers of individuals, healthy and diseased alike, have adopted an empiric multi-vitamin usage. It has long been realized that vitamins biosynthesis can be performed or modulated by some members of the commensal microbiota [74, 75, 76]. For instance, gut Bifidobacterium and Lactobacilli synthesize the B9 vitamin folate [77, 78,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank the members of the Elinav lab for fruitful discussions. We apologize to authors whose relevant work was not included in this review owing to space constraints. Eran Elinav is supported by Yael and Rami Ungar, Israel, Abisch Frenkel Foundation for the Promotion of Life Sciences, the Gurwin Family Fund for Scientific Research, Leona M. and Harry B. Helmsley Charitable Trust, Crown Endowment Fund for Immunological Research, Estate of Jack Gitlitz, Estate of Lydia Hershkovich and the
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These authors contributed equally to this work.