Biology subjects

O'Connell, T. M.

Publications and source records attributed to O'Connell, T. M..

4 recordsLinked to original sources

bioRxiv2025

Prebiotic xylo-oligosaccharides for alleviation of hepatic steatosis: Results from a four-month dietary intervention and determinants of response

A common complexity from increasing rates of overweight is metabolic dysfunction associated steatotic liver disease (MASLD) which can develop into more severe conditions such as fibrosis or hepatocellular carcinoma. The gut and its microbial flora interact with the liver through the gut-liver axis and supporting healthy composition and metabolism of the microbiota can benefit metabolic health. We have previously shown in animals that a xylo-oligosaccharide (XOS) prebiotic can drive beneficial gut flora and ameliorate hepatic steatosis- our current objective is to validate these results in humans. Forty-two adults (mean age 53.7, mean BMI 33.5) ingested a prebiotic dose of XOS daily for four months. Liver fat was quantified with MRI and body composition was measured. Standard clinical measurements and untargeted metabolomes were analyzed from serum. Microbiota composition, metagenome and metabolites were analyzed from fecal samples. A subgroup analysis was conducted between non-steatotic individuals, non-responders, and responders. The XOS supplementation caused decreases in detrimental amino acid degradation products (AADPs) isovalerate, isobutyrate, and phenylacetate in the gut while serum metabolome remained stable. A decrease in liver fat during the prebiotic was accompanied by a decrease in visceral fat. In a prediction analysis, this response was driven by higher initial ratio of Bacteroides to Faecalibacterium, higher fecal AADPs, and higher serum amino acids. Non-responders had metabolomic signatures of advanced steatosis, possibly impeding effects from XOS. In overweight individuals with early hepatic steatosis, XOS may correct fermentation imbalances in the gut and decrease production of harmful metabolites, which may benefit hepatic health. IMPORTANCEPre- and probiotics are emerging, yet unknown, avenues of treatment for metabolism-associated steatotic liver disease. In overweight humans, a xylo-oligosaccharide (XOS) prebiotic induced shifts in gut bacteria and their metabolites. High proteolytic activity in the gut was predictive of hepatic response to XOS, which may serve the development of personalized treatment of fatty liver.

systems biology↗

bioRxiv2024

Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training

Investigating repeated resistance training separated by a training break enables exploration of the potential for a proteomic memory of resistance training (RT)-induced skeletal muscle growth. Our aim was to examine skeletal muscle proteome response to 10-week RT (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Thirty healthy, untrained participants conducted either periodic RT (RT1-DT-RT2, n=17) or a 10-week no-training control period (n=13) followed by 20 weeks of RT (n=11). RT included twice-weekly supervised whole-body RT sessions, and resting vastus lateralis biopsies were obtained every ten weeks for proteomics analysis using high-end DIA-PASEFs mass spectrometry. The first RT period altered 150 proteins (93% increased) involved in e.g. energy metabolism and protein processing compared with minor changes during the no-training control period. The proteome adaptations were similar after the second RT compared to baseline demonstrating reproducibility in proteome adaptations to RT. Many of the proteins induced by RT1 were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Interestingly, several proteins increased after RT1 remain elevated after detraining, including carbonyl reductase 1 (CBR1) and proteins involved in muscle contraction, cytoskeleton and calcium-binding. Amongst the latter, calcium-activated protease calpain-2 (CAPN2) has been recently identified as an epigenetic muscle memory gene. We show that resistance training evokes retained protein levels even after 2.5 months of no training. This is the first study to demonstrate a potential proteomic memory of resistance training-induced muscle growth in human skeletal muscle. Key pointsO_LIRepeated resistance training in humans separated by a training break (i.e. detraining) enables the identification of temporal protein signatures over the training, detraining, and retraining periods as well as studying reproducibility of protein changes to resistance training. C_LIO_LIMuscle proteome adaptations were similar after a second period of resistance training when compared to baseline, demonstrating reproducibility in proteome adaptations to earlier resistance training. C_LIO_LIMany of the proteins induced by resistance training were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. C_LIO_LISeveral proteins increased after resistance training remain elevated after detraining, including carbonyl reductase 1 (CBR1) and calcium-binding proteins such as calpain-2 (CAPN2), a recently identified epigenetic muscle memory gene. C_LIO_LIHuman skeletal muscle experiences retained protein changes following resistance training persisting over two months demonstrating a potential proteomic memory of resistance training-induced muscle growth. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/624068v3_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1f0ae2corg.highwire.dtl.DTLVardef@3af3b4org.highwire.dtl.DTLVardef@55d064org.highwire.dtl.DTLVardef@1e46bf9_HPS_FORMAT_FIGEXP M_FIG Human skeletal muscle proteome response was investigated after 10-week resistance training (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Many of the proteins were reversed towards baseline after DT and increased again after RT2. These reversible proteins were especially involved in aerobic energy metabolism. However, several RT-induced proteins remain elevated after DT, including carbonyl reductase 1 (CBR1) and many proteins involved in muscle contraction or cytoskeleton and calcium-binding. Amongst the latter, calcium-activated protease calpain-2 (CAPN2) is a recently identified epigenetic muscle memory gene. This study shows that resistance training evokes retained protein levels even after 2.5 months of no training and demonstrates a potential proteomic memory of RT-induced muscle growth in human skeletal muscle. Created in BioRender.com. C_FIG

physiology↗

bioRxiv2024

Interlaboratory comparison of standardised metabolomics and lipidomics analyses in human and rodent blood using the MxP(R) Quant 500 kit

Metabolomics and lipidomics are pivotal in understanding phenotypic variations beyond genomics. However, quantification and comparability of mass spectrometry (MS)-derived data are challenging. Standardised assays can enhance data comparability, enabling applications in multi-center epidemiological and clinical studies. Here we evaluated the performance and reproducibility of the MxP(R) Quant 500 kit across 14 laboratories. The kit allows quantification of 634 different metabolites from 26 compound classes using triple quadrupole MS. Each laboratory analysed twelve samples, including human plasma and serum, lipaemic plasma, NIST SRM 1950, and mouse and rat plasma, in triplicates. 505 out of the 634 metabolites were measurable above the limit of detection in all laboratories, while eight metabolites were undetectable in our study. Out of the 505 metabolites, 412 were observed in both human and rodent samples. Overall, the kit exhibited high reproducibility with a median coefficient of variation (CV) of 14.3 %. CVs in NIST SRM 1950 reference plasma were below 25 % and 10 % for 494 and 138 metabolites, respectively. To facilitate further inspection of reproducibility for any compound, we provide detailed results from the in-depth evaluation of reproducibility across concentration ranges using Deming regression. Interlaboratory reproducibility was similar across sample types, with some species-, matrix-, and phenotype-specific differences due to variations in concentration ranges. Comparisons with previous studies on the performance of MS-based kits (including the AbsoluteIDQ p180 and the Lipidyzer) revealed good concordance of reproducibility results and measured absolute concentrations in NIST SRM 1950 for most metabolites, making the MxP(R) Quant 500 kit a relevant tool to apply metabolomics and lipidomics in multi-center studies.

biochemistry↗

bioRxiv2020

IL-6 Trans-Signaling and Tumor-Muscle-Adipose Crosstalk Mediate Pancreatic Cancer Cachexia

Most patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia. SignificancePDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.

cancer biology↗