Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Dec 25;7(1):78-87.
doi: 10.1093/jcag/gwad044. eCollection 2024 Feb.

Crosstalk Between Microbiota, Microbial Metabolites, and Interferons in the Inflammatory Bowel Disease Gut

Vi To Diep Vu  1   2   3   4 , Ramsha Mahmood  1   2   3   4 , Heather K Armstrong  1   2   3   4   5   6 , Deanna M Santer  1   2   3
Affiliations
Review

Crosstalk Between Microbiota, Microbial Metabolites, and Interferons in the Inflammatory Bowel Disease Gut

Vi To Diep Vu et al. J Can Assoc Gastroenterol. .

Abstract

With the prevalence of inflammatory bowel diseases (IBD) continuing to rise in Canada and globally, developing improved therapeutics that successfully treat greater percentages of patients with reduced complications is paramount. A better understanding of pertinent immune pathways in IBD will improve our ability to both successfully dampen inflammation and promote gut healing, beyond just inhibiting specific immune proteins; success of combination therapies supports this approach. Interferons (IFNs) are key cytokines that protect mucosal barrier surfaces, and their roles in regulating gut homeostasis and inflammation differ between the three IFN families (type I, II, and III). Interestingly, the gut microbiota and microbial metabolites impact IFN-signaling, yet how this system is impacted in IBD remains unclear. In this review, we discuss the current knowledge of how gut microbiota directly or indirectly impact IFN levels/responses, and what is known about IFNs differentially regulating gut homeostasis and inflammation in animal models or patients with IBD.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Overview of the three IFN receptor signaling pathways. In the human intestine, the majority of all IFN receptors are located basolaterally. Signaling downstream of each heterodimeric receptor involves the activation of janus kinases (JAKs; JAK1, JAK2, TYK2) and phosphorylation of signal transducer and activator of transcription-1 or -2 (STAT1/2). The ? by TYK2 in the type III IFN pathway reflects recent studies demonstrating TYK2 independent signaling is also possible in certain cell types. In type I and III IFN signaling, activated STAT1/2 binds to interferon regulatory factor 9 (IRF9), forming the IFN-stimulated gene factor 3 (ISGF3) transcriptional complex that translocates to the nucleus to promote expression of hundreds of IFN-stimulated genes (ISGs) through binding IFN-stimulated response elements (ISREs). The alternative JAK/STAT pathway shown involves the formation of phosphorylated STAT1 homodimers that translocate to the nucleus to bind gamma interferon-activated sites (GAS) to induce the expression of a distinct set of ISGs, some of which are pro-inflammatory in IBD. This is a simplified figure as there are also other STATs and other signaling cascades activated downstream of each IFN family receptor including for example mitogen‑activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and nuclear factor-κB (NFκB). TYK2, tyrosine kinase 2; P, phosphate. Created with BioRender.com.
Figure 2.
Figure 2.
Comparison of gut microbiota and downstream metabolites in the regulation of interferons in healthy versus inflammatory bowel disease tissue. Summary of what is known and discussed in this review related to steady state induction of interferons (IFNs) by microbiota and metabolites, and how this is potentially altered in inflammatory bowel disease (IBD) patients. Trp, tryptophan; AhR, aryl hydrocarbon receptor; SCFA, short-chain fatty acids; BAR, bile acid receptor. Created with BioRender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Windsor, Joseph W., Kuenzig M. Ellen, Murthy Sanjay K., Bitton Alain, Bernstein Charles N., Jones Jennifer L., Lee Kate,. et al. “The 2023 Impact of Inflammatory Bowel Disease in Canada: Executive Summary.” Journal of the Canadian Association of Gastroenterology 6, no. Supplement_2 (2023): S1–8. 10.1093/jcag/gwad003 - DOI - PMC - PubMed
    1. Moreau, Jacques, and Mas Emmanuel.. “Drug Resistance in Inflammatory Bowel Diseases.” Current Opinion in Pharmacology 25 (2015): 56–61. 10.1016/j.coph.2015.11.003 - DOI - PubMed
    1. Isaacs Alick, and Lindenmann Jean.. “Virus Interference. I. The Interferon.” Proceedings of the Royal Society of London. Series B, Biological sciences 147, no. 927 (1957): 258–67. 10.1098/rspb.1957.0048 - DOI - PubMed
    1. Kotenko, Sergei V., Gallagher Grant, Baurin Vitaliy V., Lewis-Antes Anita, Shen Meiling, Shah Nital K., Langer Jerome A., Sheikh Faruk, Dickensheets Harold, and Donnelly Raymond P... “IFN-lambdas Mediate Antiviral Protection through a Distinct Class II Cytokine Receptor Complex.” Nature Immunology 4, no. 1 (2003): 69–77. 10.1038/ni875 - DOI - PubMed
    1. Prokunina-Olsson, Ludmila, Muchmore Brian, Tang Wei, Pfeiffer Ruth M., Park Heiyoung, Dickensheets Harold, Hergott Dianna,. et al. “A Variant Upstream of IFNL3 (IL28B) Creating a New Interferon Gene IFNL4 is Associated with Impaired Clearance of Hepatitis C Virus.” Nature Genetics 45, no. 2 (2013): 164–71. 10.1038/ng.2521 - DOI - PMC - PubMed

LinkOut - more resources