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Host–microbiota interactions in immune-mediated diseases

This article has been updated


Host–microbiota interactions are fundamental for the development of the immune system. Drastic changes in modern environments and lifestyles have led to an imbalance of this evolutionarily ancient process, coinciding with a steep rise in immune-mediated diseases such as autoimmune, allergic and chronic inflammatory disorders. There is an urgent need to better understand these diseases in the context of mucosal and skin microbiota. This Review discusses the mechanisms of how the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases in the context of a genetically prone host. It is timely owing to the wealth of new studies that recently contributed to this field, ranging from metagenomic studies in humans and mechanistic studies of host–microorganism interactions in gnotobiotic models and in vitro systems, to molecular mechanisms with broader implications across immune-mediated diseases. We focus on the general principles, such as breaches in immune tolerance and barriers, leading to the promotion of immune-mediated diseases by gut, oral and skin microbiota. Lastly, the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis will be explored.

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Fig. 1: Enterococcus gallinarum translocation drives organ-specific and systemic autoimmunity through various mechanisms.
Fig. 2: Multistep pathogenesis of systemic lupus erythematosus and type 1 diabetes as a paradigm for microbiota involvement as initiators and propagators.
Fig. 3: Pathobiont–host immune interactions in the pathogenesis of immune-mediated diseases.

Change history

  • 01 June 2020

    Fig. 2 file initially published online was corrupted and was replaced on 1/6/20.


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The M.A.K. laboratory received funding from the National Institutes of Health (NIH) (K08AI095318, R01AI118855, T32AI07019, T32DK007017-39), the O’Brien Center at Yale (NIH P30DK079310), the Yale Rheumatic Diseases Research Core (NIH P30 AR053495), the Yale Liver Center (NIH P30 DK34989), the Women’s Health Research at Yale, the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute.

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W.E.R, T.M.G. and M.A.K. equally conceived, wrote and edited the article. M.A.K. drafted the figures with input from W.E.R and T.M.G., and all authors contributed substantially to all aspects of the article and revised versions.

Corresponding author

Correspondence to Martin A. Kriegel.

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Competing interests

M.A.K. received salary, consulting fees, honoraria or research funds from Roche, Bristol–Meyers Squibb, AbbVie and Cell Applications, and is an employee of Roche. M.A.K. holds a patent on the use of antibiotics and commensal vaccination to treat autoimmunity and received royalties. T.M.G. received research funds from Eli Lilly and Company and Janssen Scientific Affairs. W.E.R. declares no competing interests.

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Nature Reviews Microbiology thanks C. Nagler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Pattern recognition receptors

Critical detection system of innate immunity, with different classes capable of recognizing a variety of evolutionarily conserved microorganism-associated molecular patterns.

Toll-like receptors

(TLRs). Evolutionarily conserved pattern recognition receptors recognizing surface and endosomal ligands.

Innate immunity

First line of defence that involves physical, chemical and various epithelial and innate immune responses that are rapid (within hours) and focused on detecting evolutionarily conserved patterns.

Adaptive immunity

Second line of defence by lymphocytes using somatically rearranged receptors that can recognize any antigen and are initially slow (within days) before immunological memory is formed.

Peyer’s patches

Anatomical structures in the small intestine composed of aggregated lymphoid follicles that act as immune sensors within the gut-associated lymphoid tissue.

Secretory IgA

Main subclass of immunoglobulin found in mucus secretions, typically in dimeric form.

Mesenteric lymph nodes

(MLNs). Organized secondary lymphoid organs within the mesentery that contain all immune components of peripheral lymph nodes but are receiving the draining lymph from the gut.

Antimicrobial peptides

Secreted small molecules at barrier surfaces that have antimicrobial activity to contain the microbiota and pathogens.

Nucleotide-binding oligomerization domain (NOD)-like receptors

Evolutionarily conserved pattern recognition receptors sensing intracellular ligands such as bacterial peptidoglycan.

Inflammatory bowel disease

(IBD). A disease spectrum of ulcerative colitis and Crohn’s disease affecting the large or small bowels due to excessive immune responses towards the gut microbiota, gut epithelium and surrounding tissue.

Type 1 diabetes

(T1D). Organ-specific autoimmune disease characterized by destruction of the endocrine pancreas, specifically the insulin-producing β-islet cells required for glucose homeostasis.

Autoimmune pancreatitis

Chronic, organ-specific autoimmune disease due to autoimmune attack of the exocrine tissue of the pancreas and associated with elevated serum IgG4.

Systemic lupus erythematosus

(SLE). Chronic, systemic autoimmune syndrome affecting the kidneys, skin, joints, brain and other organs but rarely involving the gut.

Autoimmune hepatitis

Chronic organ-specific autoimmune disease of the liver that leads to immune cell-mediated hepatocyte damage and is associated with circulating autoantibodies.


An environment for rearing or culturing organisms in which all microorganisms are either known or excluded (germ free).

Primary sclerosing cholangitis

(PSC). Chronic autoimmune disease destroying the bile ducts outside and within the liver, frequently associated with inflammatory bowel disease.


All potentially pathogenic microorganisms in a microbiota that are harmless under homeostasis but can provoke non-infectious diseases in a predisposed host; to be differentiated from opportunistic pathogens that cause infectious diseases in a predisposed host.

Graft-versus-host disease

Acute or chronic alloimmune attack of host tissues by immune cells from the donor (graft). Graft-versus-host disease occurs after allogeneic bone marrow or stem cell transplantation.

Rheumatoid arthritis

Systemic, rheumatic autoimmune disease causing primarily widespread inflammation of the joint linings (synovium) that leads to cartilage and bone destruction of small and large joints. It can also affect internal organs, such as the lung, leading to interstitial lung disease.

Atopic dermatitis

Cutaneous inflammatory disease characterized by chronic relapsing pruritic skin rashes mediated by cutaneous barrier dysfunction and T helper 2 cell-skewed immune dysregulation.

Sjögren’s syndrome

Chronic autoimmune disease targeting the salivary and lacrimal glands that leads to dryness of the eyes and mouth as well as systemic organ involvement and increased risk of lymphoma.

Glomerular immune complex deposition

Deposition of autoantibody–autoantigen complexes in the glomeruli of the kidney that can lead to kidney damage and functional impairment.

Lupus nephritis

Inflammation of the kidney in systemic lupus erythematosus that results from glomerular immune complex deposition and inflammation in the interstitium.

Subacute cutaneous lupus erythematosus

A subtype of lupus that affects the skin, which can be associated with systemic lupus and is mediated by lymphocyte infiltration and immune complexes deposited in the skin.


A T cell-mediated skin autoimmune disease that manifests after loss of cutaneous melanocytes owing to T cell-mediated destruction with subsequent depigmentation of the skin.

Multiple sclerosis

Chronic progressive or relapsing autoimmune neurologic disease due to immune-mediated destruction of myelin sheaths causing central nervous system dysfunction of varying severity.


Peptide sequences that mimic the structure of an epitope of a protein, carbohydrate or lipid antigen; a mimotope of a protein autoantigen can mimic a linear or conformational stretch of amino acids.


A spectrum of rheumatic diseases that include ankylosing spondylitis and primarily affect the spine, leading to fusion or ankylosis. Spondyloarthritis can also involve peripheral joints, skin, gut and eyes.

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Ruff, W.E., Greiling, T.M. & Kriegel, M.A. Host–microbiota interactions in immune-mediated diseases. Nat Rev Microbiol 18, 521–538 (2020).

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