Original ResearchFull Report: Gut MicrobiotaHistone Deacetylase Inhibition by Gut Microbe-Generated Short-Chain Fatty Acids Entrains Intestinal Epithelial Circadian Rhythms
Graphical abstract
Section snippets
ASF Strain Information
All strains used in this study originate from the ASF, a defined mouse gut microbiota. ASF strains were a gift to the Papin laboratory from Drs Michael Wannemuehler and Gregory Phillips. The members used in this study are: Clostridium species ASF356, Lactobacillus intestinalis ASF360, Ligilactobacillus murinus ASF361, Eubacterium plexicaudatum ASF492, Pseudoflavonifractor species ASF500, Clostridium species ASF502, and Parabacteroides goldsteinii ASF519. Mucispirillum schaedleri ASF457 was
Metabolites From ASF Species Differentially Modulate the Intestinal Epithelial Clock
Incubating PER2::LUC enteroids with bacterial supernatants from ASF356, ASF492, ASF500, and ASF519 significantly altered the circadian phase (Figure 1B), whereas supernatants from ASF360, ASF361, and ASF502 did not (Figure 1A). Mann-Whitney U test indicated significant phase delays in hours with ASF356 (10% median, 7.09 hours; P < .05; 25% median, 10.89 hours; P < .05), ASF492 (25% median, 3.37 hours; P < .05), ASF500 (10% median, 2.2 hours; P < .05; 25% median, 7.67 hours; P < .05), and ASF519
Discussion
In these ex vivo intestinal organoid studies of microbial metabolites and intestinal epithelial circadian timekeeping, we used a combination of tissue culture experiments and systems metabolomics to elucidate gut microbial influences on host circadian rhythms. Recently, Kuang et al21 demonstrated cross-talk between intestinal microbiota and the intestinal circadian clock and role of SCFA and HDAC epigenetic pathways in mice. Our present results complement their findings by revealing: (1) SCFAs
CRediT Authorship Contributions
Jibraan A. Fawad, MBBS (Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Validation: Lead; Visualization: Lead; Writing – original draft: Lead).
Deborah H. Luzader, PhD (Conceptualization: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Software: Lead; Validation: Lead; Writing – original draft: Lead).
Gabriel F. Hanson, BS (Data curation: Supporting; Formal analysis: Supporting; Investigation:
References (75)
- et al.
A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock
Cell
(1999) - et al.
Clock genes, intestinal transport and plasma lipid homeostasis
Trends Endocrinol Metab
(2009) Biological clocks and the digestive system
Gastroenterology
(2000)- et al.
Sleep and circadian hygiene and inflammatory bowel disease
Gastroenterol Clin North Am
(2017) - et al.
Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism
Cell Host Microbe
(2015) - et al.
Diet diurnally regulates small intestinal microbiome-epithelial-immune homeostasis and enteritis
Cell
(2020) - et al.
Microbiota diurnal rhythmicity programs host transcriptome oscillations
Cell
(2016) - et al.
Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs
Cell
(2013) - et al.
Intercellular coupling of the cell cycle and circadian clock in adult stem cell culture
Mol Cell
(2016) - et al.
Inferring metabolic mechanisms of interaction within a defined gut microbiota
Cell Syst
(2018)
A serum shock induces circadian gene expression in mammalian tissue culture cells
Cell
Clocks, metabolism, and the epigenome
Mol Cell
Circadian regulator CLOCK is a histone acetyltransferase
Cell
Post-translational modifications in circadian rhythms
Trends Biochem Sci
Advances and challenges of HDAC inhibitors in cancer therapeutics
Adv Cancer Res
Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)
Bioorg Med Chem Lett
Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias
Blood
Disruption of epithelial HDAC3 in intestine prevents diet-induced obesity in mice
Gastroenterology
Diversion procto-colitis: response to treatment with short-chain fatty acids
J Pediatr Surg
Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway
Biochem Pharmacol
Interplay between circadian clock and cancer: new frontiers for cancer treatment
Trends Cancer Res
A double-blind trial of melatonin as a treatment for jet lag in international cabin crew
Biol Psychiatry
The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome
Cell Metab
Controlling epithelial polarity: a human enteroid model for host-pathogen interactions
Cell Rep
A gut commensal-produced metabolite mediates colonization resistance to salmonella infection
Cell Host Microbe
Rhythm and bugs: circadian clocks, gut microbiota, and enteric infections
Curr Opin Gastroenterol
Circadian rhythms, sleep, and metabolism
J Clin Invest
Understanding systems-level properties: timely stories from the study of clocks
Nat Rev Genet
Stopping time: the genetics of fly and mouse circadian clocks
Annu Rev Neurosci
Molecular components of the mammalian circadian clock
Hum Mol Genet
Circadian oscillation of a mammalian homologue of the Drosophila period gene
Nature
A new mammalian period gene predominantly expressed in the suprachiasmatic nucleus
Genes Cells
Circadian gastric acidity in Helicobacter pylori positive ulcer patients with and without gastric metaplasia in the duodenum
Gut
Is diurnal temperature range a risk factor for childhood diarrhea?
PLoS One
Role of biological rhythms in gastrointestinal health and disease
Rev Endocr Metab Disord
A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism
Science
A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use
Nature
Cited by (27)
Anti-obesity effect of butyrate links to modulation of gut microbiome and epigenetic regulation of muscular circadian clock
2024, Journal of Nutritional BiochemistryDistribution and roles of Ligilactobacillus murinus in hosts
2024, Microbiological ResearchEpigenetic control of circadian clocks by environmental signals
2024, Trends in Cell BiologyGut-derived short-chain fatty acids bridge cardiac and systemic metabolism and immunity in heart failure
2023, Journal of Nutritional BiochemistryTargeting gut microbiota and metabolism as the major probiotic mechanism - An evidence-based review
2023, Trends in Food Science and Technology
Conflicts of interest S.R.M. is a consultant for Takeda (short bowel syndrome). D.T.B. is now a full-time employee of Lumen Biosciences. G.L.M. is now a full-time employee of Vedanta Biosciences. A.E.R. is now a full-time employee at Procter & Gamble. The contributions of D.T.B., G.L.M., and A.E.R. to the paper predated their transition to industry and they declare no conflict of interest with its contents. The remaining authors disclose no conflicts.
Funding This work was supported by National Institutes of Health grants R01 DK117005 (C.I.H., S.R.M.), U19 AI116491 (S.R.M., C.I.H.), R01AT010253 (J.A.P.), Pendleton Laboratory Endowment (S.R.M.), and R01DK114123 (T.A), the University of Virginia Trans-University Microbiome Initiative, and the National Research Foundation of Korea 2020R1A6A3A03038405 (M.P.).
- ∗
Authors share co-first authorship.