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Histone deacetylase inhibition by gut microbe-generated short chain fatty acids entrains intestinal epithelial circadian rhythms


Footnotes

Author names in bold designate shared co-first authorship

Grant Support: This work was supported by NIH grants R01 DK117005 (CIH, SRM), U19 AI116491 (SRM, CIH), R01AT010253 (JAP), the UVA Trans-University Microbiome Initiative, and National Research Foundation of Korea 2020R1A6A3A03038405 (MP).

Disclosures:

S.R.M. is a consultant for Takeda (short bowel syndrome).

David Bolick is now a full-time employee of Lumen Biosciences.

Greg Medlock is now a full-time employee of Vedanta Biosciences.

Both David and Greg’s contributions to the paper predated their transition to industry and declare no COI with its contents.

The remaining authors have no conflict of interests to declare

AUTHOR CONTRIBUTIONS (using CRediT Taxonomy):

J.A.F.: Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft and revision;

D.H.L.: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Writing – original draft;

G.F.H.: Investigation, Methodology, Writing – revision;

T.J.M.: Formal analysis, Methodology, Software, Visualization, Writing – original draft

C.A.M.: Investigation

P.G.M.: Investigation, Visualization, Writing – original draft

K.B.S.: Investigation, Methodology

A.K.: Investigation, Methodology

M.P.: Investigation, Methodology

S.L.: Investigation, Methodology

D.T.B: Investigation, Methodology

G.L.M.: Methodology, Visualization, Writing – revision

J.Y.Z.: Software

A.E.R.: Investigation, Methodology, Writing – original draft;

C.I.H.: Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Writing – review & editing

C.J.C.: Methodology, Resources

E.E.: Methodology, Resources

T.A.: Methodology, Resources

J.A.P.: Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Writing – review & editing;

S.R.M.: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – review & editing

BACKGROUND AND CONTEXT: Gastrointestinal circadian rhythms drive diurnal fluctuations in the makeup and function of gut microbiota. Microbial metabolites, in turn, influence gut circadian physiology via epigenetic mechanisms.

NEW FINDINGS: Bacterial short chain fatty acids (SCFA) entrain intestinal epithelial circadian rhythms in mouse and human intestinal epithelial organoids by HDAC inhibition (HDACi).

LIMITATIONS: Static intestinal epithelial organoids lack non-epithelial cells. Circadian timescale co-cultures with immunocytes and live microbiota would better mimic circadian dynamics at the gut epithelial-microbial interface.

RELEVANCE: Use of bioluminescent organoids and machine learning to identify microbial mechanisms of host circadian entrainment provides new tools for discovery in gastrointestinal disorders where circadian disruption modifies risk and severity.

LAY SUMMARY

Circadian timekeeping in intestinal organoids is reset by gut microbe-generated short chain fatty acids through an epigenetic mechanism of HDAC inhibition.



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