Biology subjects

Heddes, M.

Publications and source records attributed to Heddes, M..

5 recordsLinked to original sources

bioRxiv2023

Diurnal rhythmicity of fecal microbiota and metabolite profiles in the first year of life: a randomized controlled interventional trial with infant formula

Microbiota assembly in the infant gut is influenced by time and duration of dietary exposure to breast-milk, infant formula and solid foods. In this randomized controlled intervention study, longitudinal sampling of infant stool (n=998) showed similar development of fecal bacterial communities (16S rRNA/shallow metagenomics sequencing) between formula- and breast-fed infants during the first year of life (N=210). Infant formula supplemented with galacto-oligosaccharides (GOS) was most efficient to sustain high levels of bifidobacteria compared to formula containing B. longum and B. breve or placebo. In addition to primary endpoints, metabolite and bacterial profiling revealed 24-hour oscillations and data integration identified circadian networks. Rhythmicity in bacterial diversity, specific taxa and functional pathways increased with age and was strongest following breast-feeding and GOS-supplementation. Circadian rhythms in dominant taxa were discovered ex-vivo in a chemostat model. Hence, microbiota rhythmicity develops early in life, likely via bacterial intrinsic clock mechanism and is affected by diet.

microbiology↗

bioRxiv2023

The Intestinal Clock Regulates Host Metabolism through the Fiber-Dependent Microbiome and Macronutrient Transcriptome.

Circadian disruption, e.g. through shift work, causes microbial dysbiosis and increases the risk of metabolic diseases. Microbial rhythmicity in mice depends on a functional intestinal clock and frequent jetlag as well as high-caloric energy intake induces loss of these oscillations. Similarly, arrhythmic microbiota was found in obese and T2D populations. However, the interplay between the intestinal circadian clock, the microbiome, diet and host metabolism is poorly understood. In intestinal-specific Bmal1 knockout mice (Bmal1IEC-/-) we demonstrate the relevance of the intestinal clock in microbiome oscillations and host and microbial nutrient metabolism. Microbiota transfer from Bmal1IEC-/- mice into germ-free recipients led to obesity, reflected by increased bodyweight and fat mass. Western diet-fed Bmal1IEC-/- mice increased bodyweight likely through mechanisms involving the intestinal clock-control of lipid and hexose transporters. Additionally, we identified dietary fiber as novel link between circadian microbial rhythmicity, intestinal clock functioning and host physiology. Thus, revealing the potential of fiber-rich diet intervention as a non-invasive strategy targeting microbial oscillations in metabolic disease prevention.

molecular biology↗

bioRxiv2023

Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation

ObjectiveImpaired clock genes expression has been observed in biopsy samples from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The intestinal clock balances gastrointestinal homeostasis by regulating the microbiome. Here we characterize intestinal immune functions in mice lacking the intestinal clock and IBD-relevant mouse model under different feeding conditions to describe the functional impact of the intestinal clock in the development of gastrointestinal inflammation. DesignTissues and fecal samples from intestinal clock-deficient mice (Bmal1IEC-/-) and mouse models for colitis (IL-10-/-, Bmal1IEC-/-xIL-10-/-, dextran sulfate sodium (DSS) administration) under ad libitum and restricted feeding (RF) conditions were used to determine the causal role of the intestinal clock for colitis. ResultsIn IL-10-/- mice, inflammation correlated with disrupted colon clock genes expression. Genetic loss of intestinal clock functions promoted DSS and IBD inflammatory phenotypes and dramatically reduces survival, and colonization with disease-associated microbiota in germ- free Bmal1IEC-/- hosts increased their inflammatory responses, demonstrating the causal role of colonic clock disruption and the severity of IBD. RF in IL-10-/- mice restored the colon clock and related immune functions, improved the inflammatory responses and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC-/- xIL-10-/- demonstrating the significance of the colonic clock to gate the effect of RF. ConclusionWe provide evidence that inflammation-associated intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate the symptoms in IBD patients.

physiology↗

bioRxiv2022

Genetic and environmental circadian disruption induce metabolic impairment through changes in the gut microbiome

ObjectiveInternal 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. MethodsCore 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 hosts physiology. ResultsBoth 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. ConclusionsCollectively, 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.

physiology↗

bioRxiv2021

The intestinal circadian clock drives microbial rhythmicity to maintain gastrointestinal homeostasis

Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the hosts circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for circadian microbiota composition and function, which is required to balance the hosts gastrointestinal homeostasis.

physiology↗