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Mining the microbiota for microbial and metabolite-based immunotherapies

Nature Reviews Immunology (2019) | Download Citation


Trillions of microorganisms transit through and reside in the mammalian gastrointestinal tract each day, collectively producing thousands of small molecules and metabolites with local and systemic effects on host physiology. Identifying effector microorganisms that causally affect host phenotype and deciphering the underlying mechanisms have become foci of microbiome research and have begun to enable the development of microbiota-based therapeutics. Two complementary, reductionist approaches have commonly been used: the first starts with an immune phenotype and narrows down the microbiota to identify responsible effector bacteria, while the second starts with bacteria-derived molecules and metabolites and seeks to understand their effects on the host immune system. Together, these strategies provide the basis for the rational design of microbial and metabolite-based therapeutics that target and ameliorate immune deficits in patients.

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This work was supported by the Japan Agency for Medical Research and Development (AMED) LEAP under grant number JP18gm0010003, the Takeda Science Foundation, the Mitsukoshi Health and Welfare Foundation (K.H.) and Grant-in-Aid for Japan Society for the Promotion of Science (JSPS) Fellows (18F18104) (S.K.).

Reviewer information

Nature Reviews Immunology thanks N. Cerf-Bensussan, L. O’Neill and P. Turnbaugh for their contribution to the peer review of this work.

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  1. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    • Ashwin N. Skelly
    • , Yuko Sato
    • , Sean Kearney
    •  & Kenya Honda
  2. RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan

    • Yuko Sato
    •  & Kenya Honda


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All authors were involved in discussing the content and writing this article. A.N.S., Y.S. and S.K. were involved in researching data for the article. K.H. and A.N.S. contributed to the review and editing of the article before submission.

Competing interests

K.H. is co-founder of and scientific adviser to Vedanta Biosciences since 11 August 2011. The other authors declare no competing interests.

Corresponding author

Correspondence to Kenya Honda.

Supplementary information



The perturbation of the homeostatic microbiota composition; associated with a slew of diseases. The ambiguity of this term can encompass increases in pathobionts, decreases in commensals or changes that do not clearly distinguish healthy from unhealthy guts.


Referring to mice that are only colonized by a known, defined set of microorganisms.

Colonization resistance

The mechanism by which certain microorganisms are prevented from colonizing an ecosystem (for example, the gut) by the indigenous microorganisms.

Germ-free (GF) mice

Mice living in sterile conditions, uncolonized by any microorganism.

Muricholic acids

A class of 6-hydroxy bile acids present in mice but not humans.


The ecological diversity between environments (for example, gut microbial diversity between different individuals).

M cells

Microfold cells found in Peyer’s patches that transcytose material (including antigen and IgA) across the intestinal epithelium.

Metabolic oligosaccharide engineering

The process of co-opting endogenous bacterial biosynthetic machinery to introduce a synthetic non-natural sugar containing an inert chemical ‘handle’ into surface macromolecules.

Bioorthogonal click chemistry

Any chemical reaction that can occur rapidly and specifically in the complex cellular milieu. Often used in conjunction with metabolic oligosaccharide engineering to functionalize a tagged macromolecule.

Outer membrane vesicles

(OMVs). Vesicles containing periplasm; released into the extracellular space by Gram-negative bacteria.

Aryl hydrocarbon receptor

(AhR). A cytosolic ligand-activated transcription factor that controls the expression of many genes.


Relating to auxotrophy; the inability to produce a substance required for growth. Using an auxotrophic bacterial strain enables reversible colonization under experimental conditions.

M2 macrophage phenotype

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when classically activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when alternatively activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.


A therapeutic consisting of probiotics (bacteria) together with prebiotics (nutrients).


The ability to sense population density and respond accordingly at the gene expression level.

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