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Human metagenome

ABSTRACT: Circadian Misalignment as a disease risk factor in Inflammatory Bowel Disease

PROVIDER: PRJNA576887 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10279200_1.fastq.gz	Fastqsanger.gz
	SRR10279200_2.fastq.gz	Fastqsanger.gz
	SRR10279201_1.fastq.gz	Fastqsanger.gz
	SRR10279201_2.fastq.gz	Fastqsanger.gz
	SRR10279202_1.fastq.gz	Fastqsanger.gz

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Circadian misalignment induces fatty acid metabolism gene profiles and induces insulin resistance in human skeletal muscle.

Project description:Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes, however, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and muscle molecular circadian clock have never been investigated in humans. Here we investigated insulin sensitivity and muscle metabolism in fourteen healthy young lean men (age 22.4 ± 2.8 years; BMI 22.3 ± 2.1 kg/m2 [mean ± SD]) after a 3-day control protocol and a 3.5-day misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that circadian misalignment results in a significant decrease in peripheral insulin sensitivity due to a reduced skeletal muscle non-oxidative glucose disposal (Rate of disappearance: 23.7 ± 2.4 vs. 18.4 ± 1.4 mg/kg/min; control vs. misalignment; p=0.024). Fasting glucose and FFA levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the new behavourial rhythm, and microarray analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misallignement. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers.

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Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice

Project description:Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1+CD44high CD4 T cells as well as CD95+GL7+ germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.

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Project description:Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation nor elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes, where misaligned mice undergo an 8-hour phase advance every week for 15 weeks. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected against the cardiometabolic impact of circadian disruption seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice. In the UK biobank, female shiftworkers showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males. Thus we show that female mice are resilient to chronic circadian misalignment, and that these differences are conserved in humans.

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