Genetic and environmental circadian disruption induce metabolic impairment through changes in the gut microbiome
biorxiv(2022)
摘要
Objective Internal clocks time behavior and physiology, including the gut microbiome in a circadian (∼24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown.
Methods Core and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus ( Bmal1SCNfl/- ), and wild-type mice exposed to simulated shift work (SSW). Body composition and energy balance were evaluated by nuclear magnetic resonance (NMR), bomb calorimetry, food intake and running-wheel activity. Intestinal permeability was measured in an Ussing chamber. Microbiota composition and functionality were evaluated by 16S rRNA gene amplicon sequencing, PICRUST2.0 analysis and targeted metabolomics. Finally, microbiota transfer was conducted to evaluate the functional impact of SSW-associated microbiota on the host’s physiology.
Results Both chronodisruption models show desynchronization within and between peripheral clocks in GI tissues and reduced microbial rhythmicity, in particular in taxa involved in short-chain fatty acid (SCFA) fermentation and lipid metabolism. In Bmal1SCNfl/- mice, loss of rhythmicity in microbial functioning associates with previously shown increased body weight, dysfunctional glucose homeostasis and adiposity. Similarly, we observe an increase in body weight in SSW mice. Germ-free colonization experiments with SSW- associated microbiota mechanistically link body weight gain to microbial changes. Moreover, alterations in expression of peripheral clock genes as well as clock-controlled genes (CCGs) relevant for metabolic functioning of the host were observed in recipients, indicating a bidirectional relationship between microbiota rhythmicity and peripheral clock regulation.
Conclusions Collectively, our data suggest that loss of rhythmicity in bacteria taxa and their products, which likely originates in desynchronization of intestinal clocks, promotes metabolic abnormalities during shift work.
### Competing Interest Statement
The authors have declared no competing interest.
* BA
: bile acid
Bmal1
: Brain and Muscle ARNT-Like 1
CCGs
: clock-controlled genes
Cry1
: cryptochrome circadian regulator 1
CT
: circadian time
Dbp
: D Site of Albumin Promoter (Albumin D-Box) Binding Protein
DD
: constant darkness
EC
: Enzyme Commission
Ef1a
: Elongation factor 1-alpha
Fabp2
: Fatty Acid Binding Protein 2
GF
: Germ-free
GI
: gastrointestinal
GUniFrac
: Generalized UniFrac
Glut2
: Glucose transporter 2
Hdac3
: Histone Deacetylase 3
Ifabp
: Intestinal-type fatty acid-binding protein
LD
: 12 hours light and 12 hours darkness schedule
LEFSE
: LDA effective score
NMR
: Nuclear magnetic resonance
Per2
: Period 2
PICRUST
: Phylogenetic Investigation of Communities by Reconstruction of Unobserved States
Pparγ
: Peroxisome Proliferator Activated Receptor Gamma
qRT-PCR
: Quantitative real-time PCR
Rev-erbα
: Nuclear receptor subfamily 1 group D member 1
SCFA
: short-chain fatty acid
SCN
: suprachiasmatic nucleus
SPF
: specific-pathogen free
SSW
: simulated shift work
T2D
: type 2 diabetes
UPL
: Universal Probe Library system
zOTUs
: Zero-radius operational taxonomic units
ZT
: Zeitgeber time
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关键词
environmental circadian disruption,metabolic impairment
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