Hierarchical contribution of individual lifestyle factors and their interactions on adenomatous and serrated polyp risk.

BACKGROUND Individual colorectal polyp risk factors are well characterized; however, insights into their pathway-specific interactions are scarce. We aimed to identify the impact of individual risk factors and their joint effects on adenomatous (AP) and serrated polyp (SP) risk. METHODS We collected information on 363 lifestyle and metabolic parameters from 1597 colonoscopy participants, resulting in over 521,000 data points. We used multivariate statistics and machine-learning approaches to assess associations of single variables and their interactions with AP and SP risk. RESULTS Individual factors and their interactions showed common and polyp subtype-specific effects. Abdominal obesity, high body mass index (BMI), metabolic syndrome, and red meat consumption globally increased polyp risk. Age, gender, and western diet associated with AP risk, while smoking was associated with SP risk. CRC family history was associated with advanced adenomas and diabetes with sessile serrated lesions. Regarding lifestyle factor interactions, no lifestyle or dietary adjustments mitigated the adverse smoking effect on SP risk, whereas its negative effect was exacerbated by alcohol in the conventional pathway. The adverse effect of red meat on SP risk was not ameliorated by any factor, but was further exacerbated by western diet along the conventional pathway. No modification of any factor reduced the negative impact of metabolic syndrome on AP risk, whereas increased fatless fish or meat substitutes' intake mitigated its effect on SP risk. CONCLUSIONS Individual risk factors and their interactions for polyp formation along the adenomatous and serrated pathways are strongly heterogeneous. Our findings may facilitate tailored lifestyle recommendations and contribute to a better understanding of how risk factor combinations impact colorectal carcinogenesis

Serotonin Reduction in Post-acute Sequelae of Viral Infection

Post-acute sequelae of COVID-19 (PASC, Long COVID ) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes

Supplementary files associated with the DRiDO microbiome manuscript

The Dietary Restriction in Diversity Outbred mice (DRiDO) study assessed how caloric restriction and fasting affect lifespan and health in a large population of genetically diverse mice. The DRiDO microbiome manuscript specifically focused on the microbiome data generated as part of this study. The microbiome dataset consists of 2997 metagenomic profiles from 913 Diversity Outbred mice. Here, we provide large supplementary files required for reproducing analyses performed in the manuscript.Main DRiDO manuscript: https://www.biorxiv.org/content/10.1101/2023.11.28.568901Microbiome DRiDO manuscript: https://www.biorxiv.org/content/10.1101/2023.11.28.568137</p

Proteomic profiling dataset of chemical perturbations in multiple biological backgrounds

While gene expression profling has traditionally been the method of choice for large-scale perturbational profling studies, proteomics has emerged as an efective tool in this context for directly monitoring cellular responses to perturbations. We previously reported a pilot library containing 3400 profles of multiple perturbations across diverse cellular backgrounds in the reduced-representation phosphoproteome (P100) and chromatin space (Global Chromatin Profling, GCP). Here, we expand our original dataset to include profles from a new set of cardiotoxic compounds and from astrocytes, an additional neural cell model, totaling 5300 proteomic signatures. We describe fltering criteria and quality control metrics used to assess and validate the technical quality and reproducibility of our data. To demonstrate the power of the library, we present two case studies where data is queried using the concept of “connectivity” to obtain biological insight. All data presented in this study have been deposited to the ProteomeXchange Consortium with identifers PXD017458 (P100) and PXD017459 (GCP) and can be queried at https://clue.io/proteomics

A microbiome-dependent gut-brain pathway regulates motivation for exercise.

Exercise exerts a wide range of beneficial effects for healthy physiology. However, the mechanisms regulating an individual’s motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut–brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the “connectivity” framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics. A large compendium of cellular responses to drugs as profiled through proteomic assays of phosphosignaling and histone modifications reveals cellular responses that transcend lineage, discovers unexpected associations between drugs, and recognizes therapeutic hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. Keywords: mass spectrometry; proteomics; drug discovery; signaling; epigenetics; mechanism of action; LINCS project; GCP; P100; L1000NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program (Grant U54HG008097)NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program (Grant U54HG008699