Elsevier

Current Opinion in Immunology

Volume 30, October 2014, Pages 54-62
Current Opinion in Immunology

The cross talk between microbiota and the immune system: metabolites take center stage

https://doi.org/10.1016/j.coi.2014.07.003Get rights and content

Highlights

  • Host and microbiota communicate by recognition of metabolic mediators.

  • Microbiota metabolites influence the development and function of the immune system.

  • Immunomodulatory function of microbiota metabolites impacts inflammatory disease.

The human meta-organism consists of more than 90% of microbial cells. The gastrointestinal tract harbors trillions of commensal microorganisms that influence the development and homeostasis of the host. Alterations in composition and function of the microbiota, termed dysbiosis, have been implicated in a multitude of metabolic and inflammatory diseases in humans. Thus, understanding the molecular underpinnings the cross talk between commensal bacteria and their host during homeostasis and dysbiosis may hold the key to understanding many idiopathic diseases. While most attention has focused on the innate recognition of immune-stimulatory bacterial molecules, such as cell wall components and nucleic acids, we emphasize here the impact of diet-dependent microbial metabolites on the development and function of the immune system.

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

References (114)

  • T. Inagaki

    Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor

    Proc Natl Acad Sci U S A

    (2006)
  • S. Yoshimoto

    Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome

    Nature

    (2013)
  • P. Vavassori

    The bile acid receptor FXR is a modulator of intestinal innate immunity

    J Immunol

    (2009)
  • S.K. Mazmanian et al.

    A microbial symbiosis factor prevents intestinal inflammatory disease

    Nature

    (2008)
  • J. Ochoa-Reparaz

    Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression

    J Immunol

    (2010)
  • R.J. Harvey et al.

    Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain

    Nat Rev Drug Discov

    (2013)
  • J.S. Lee

    AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch

    Nat Immunol

    (2012)
  • J. Qiu

    The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells

    Immunity

    (2012)
  • A. Barbul

    Arginine and immune function

    Nutrition

    (1990)
  • R.A. Koeth

    Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis

    Nat Med

    (2013)
  • J.R. Roth et al.

    Cobalamin (coenzyme B12): synthesis and biological significance

    Annu Rev Microbiol

    (1996)
  • A. Pompei

    Folate production by bifidobacteria as a potential probiotic property

    Appl Environ Microbiol

    (2007)
  • M. Kleerebezem et al.

    Probiotic and gut lactobacilli and bifidobacteria: molecular approaches to study diversity and activity

    Annu Rev Microbiol

    (2009)
  • J.A. Hall

    The role of retinoic acid in tolerance and immunity

    Immunity

    (2011)
  • W. Rojanapo et al.

    The prevalence, metabolism and migration of goblet cells in rat intestine following the induction of rapid, synchronous vitamin A deficiency

    J Nutr

    (1980)
  • S.G. Kang et al.

    metabolites induce gut-homing FoxP3+ regulatory T cells

    J Immunol

    (2007)
  • K. Pino-Lagos

    A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity

    J Exp Med

    (2011)
  • F. Sommer et al.

    The gut microbiota—masters of host development and physiology

    Nat Rev Microbiol

    (2013)
  • L.V. Hooper et al.

    Interactions between the microbiota and the immune system

    Science

    (2012)
  • L.A. David

    Diet rapidly and reproducibly alters the human gut microbiome

    Nature

    (2014)
  • K.M. Maslowski

    Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

    Nature

    (2009)
  • P.M. Smith

    The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis

    Science

    (2013)
  • N. Arpaia

    Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation

    Nature

    (2013)
  • P.V. Chang

    The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition

    Proc Natl Acad Sci U S A

    (2014)
  • N. Singh

    Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis

    Immunity

    (2014)
  • E. Elinav

    NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis

    Cell

    (2011)
  • I.C. Allen

    The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer

    J Exp Med

    (2010)
  • D.R. Donohoe

    The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon

    Cell Metab

    (2011)
  • A. Trompette

    Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

    Nat Med

    (2014)
  • L. Gorissen

    Production of conjugated linoleic acid and conjugated linolenic acid isomers by Bifidobacterium species

    Appl Microbiol Biotechnol

    (2010)
  • F.M. McIntosh

    Mechanism of conjugated linoleic acid and vaccenic acid formation in human faecal suspensions and pure cultures of intestinal bacteria

    Microbiology

    (2009)
  • R. Wall

    Metabolic activity of the enteric microbiota influences the fatty acid composition of murine and porcine liver and adipose tissues

    Am J Clin Nutr

    (2009)
  • S. Kishino

    Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition

    Proc Natl Acad Sci U S A

    (2013)
  • O.A. Gudbrandsen

    Trans-10,cis-12-conjugated linoleic acid reduces the hepatic triacylglycerol content and the leptin mRNA level in adipose tissue in obese Zucker fa/fa rats

    Br J Nutr

    (2009)
  • T. Itoh

    Structural basis for the activation of PPARgamma by oxidized fatty acids

    Nat Struct Mol Biol

    (2008)
  • S.Y. Moya-Camarena

    Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha

    J Lipid Res

    (1999)
  • A. Are

    Enterococcus faecalis from newborn babies regulate endogenous PPARgamma activity and IL-10 levels in colonic epithelial cells

    Proc Natl Acad Sci U S A

    (2008)
  • D. Kelly

    Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA

    Nat Immunol

    (2004)
  • C. Thomas

    Targeting bile-acid signalling for metabolic diseases

    Nat Rev Drug Discov

    (2008)
  • T. Midtvedt

    Microbial bile acid transformation

    Am J Clin Nutr

    (1974)
  • Cited by (137)

    • Insufficient or excessive dietary carbohydrates affect gut health through change in gut microbiota and regulation of gene expression of gut epithelial cells in grass carp (Ctenopharyngodon idella)

      2023, Fish and Shellfish Immunology
      Citation Excerpt :

      Unfortunately, the above studies seem to rely too much on tapping into changes in the structure of gut microbiota composition and its possible effects on the gut, while neglecting the immune response of the gut in direct response to stress caused by dietary excessive or insufficient carbohydrate, and the interactions between the microbiota and the gut of host. An increasing number of findings have shown that host physiological processes are jointly determined by an active crosstalk between the gut microbiota and host gene expression [23,24]. Big data analysis can often find that the interaction between certain strains and host genes is particularly significant, and plays a key role in the occurrence of a certain physiological process [23–25].

    • Impact of indigenous microbiota in gut inflammatory disorders

      2022, Human-Gut Microbiome: Establishment and Interactions
    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text