Biology subjects

Shen, X.

Publications and source records attributed to Shen, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

haCCA: Multi-module Integrating of spatial transcriptomes and metabolomes.

Spatial techniques such as spatial transcriptomes and MALDI-MSI, offering insights into both transcripts and metabolite of tissue sections. However, integrating them with high accuracy is challenge due to no shared spots or features. We present haCCA, a workflow designed to integrate spatial transcriptomes and metabolomes data using high-correlated feature pairs and modified spatial morphological alignment. This approach ensures high-resolution and accurate spot-to-spot data integration across neighbor tissue section. We applied haCCA to both publicly available 10X Visium and MALDI-MSI datasets from mouse brain tissue and a custom spatial transcriptome and MALDI-MSI dataset from an intrahepatic cholangiocarcinoma (ICC) model, exploring the metabolic alteration of NETs(neutrophil extracellular traps) on ICC, and finding a potential mechanism that NETs upregulated Scd1 to activate fatty acid metabolism. Providing new insights into the dynamic crosstalk between genes and metabolites that regulates the tumor biological behavior and drives the response to treatment. We developed and published an easy-to-use Python package to facilitate its use.

bioinformatics↗

bioRxiv2024

Melanocortin system activates carotid body arterial chemoreceptors in hypertension

BackgroundThe bodys internal milieu is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. MethodsGuided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signalling pathways involved in arterial chemosensory function. ResultsHere, we report the presence of the Melanocortin 4 receptor (MC4R) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence both resting and chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (Ascl1) regulatory network in driving elevated Mc4r expression. ConclusionsCollectively, our data indicate a primarily pathophysiological role of melanocortin signalling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.

neuroscience↗

bioRxiv2024

Acupuncture triggers earlier recovery from ischemic stroke than sham needling in a rat model

Summary paragraphAcupuncture, a traditional Chinese medical treatment that has been practiced for over 2,000 years, is widely used around the world [1]. However, its efficacy and distinction from random stimulation are still being questioned [2, 3]. Over the years, many studies have reported either favorable, neutral or even skeptical outcomes regarding the treatment effect of acupuncture on diverse ailments [4-7]. The major question behind this controversy is whether acupuncture is different from random needle insertion and whether its efficacy can be attributed to the placebo effect [8, 9]. Here, we use micro-positron emission tomography (microPET) imaging in a randomized controlled animal study to show that acupuncture facilitates faster recuperation in comparison to sham acupuncture and blank control. Based on the microPET imaging of subjects undergoing daily acupuncture over two weeks duration, we dynamically monitored the metabolic activity levels in different brain regions and found that both acupoint and non-acupoint stimulation could improve ischemic stroke recovery. This finding is consistent with previous reports that both acupuncture and sham needling show a positive effect in the treatment of diseases [4, 5, 8]. More importantly, we further found that rats receiving acupuncture at Baihui (GV20) and Shuigou (GV26), two commonly used acupoints for stroke rehabilitation based on the concept of the meridian system, showed earlier recovery effects than rats receiving sham needling treatment. This difference mainly appeared in regions involved in motor control and was validated by a balance beam walking test. Our findings, in conjunction with a recent electroacupuncture study that revealed a neuroanatomical pathway to mediate the vagal-adrenal anti-inflammatory axis [10], provide quantitative evidence supporting the specificity of acupoints in acupuncture therapy.

neuroscience↗

bioRxiv2024

Mutation of phosphatidate phosphohydrolase genes confers broad-spectrum disease resistance in plants

Phosphatidic acid (PA) is considered as a second messenger that interacts with protein kinases, phosphatases and NADPH oxidases, amplifying the signal to initiate plant defense signaling responses (Li and Wang, 2019). In rice, mutation of RBL1 causes the accumulation of PA, enhancing multipathogen resistance (Sha et al., 2023). In our previous study, we attempted to rescue rbl1 mutant by overexpressing phosphatidate phosphohydrolase (PAH) genes. However, overexpression of PAH2 reduced the PA level but did not affect the disease resistance, which made us to reconsider the importance of PA and PAH in rice immunity. Here, we identified that mutation of PAHs caused PA accumulation and enhanced multipathogen resistance in rice and Arabidopsis.

plant biology↗

bioRxiv2024

A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS

The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort. Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g., SLC7A11) or drive (e.g., SLC1A5) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations. Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such as DHODH, GCH1, and AIFM2 in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/600340v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1607205org.highwire.dtl.DTLVardef@ddab12org.highwire.dtl.DTLVardef@10a3885org.highwire.dtl.DTLVardef@4cc4d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Novel sex-biased outcomes in neuroblastoma are associated with distinct gene expression and chromosomal loss patterns.

The worst patient outcomes in neuroblastoma are driven by high-risk disease1,2, which is divided into similarly sized MYCN amplified and MYCN non-amplified patient subgroups3. Male patients have been reported to have slightly worse outcomes than females in all-patient analyses of multiple studies3,4. However, we show here that in MYCN non- amplified high-risk and stage 4s low-risk disease, female patients have significantly worse overall survival than males. Female MYCN non-amplified high-risk patients highly express H19 and DLK1, both of which drive cell growth in vitro and are associated with worse outcomes in females but not males. Further, chromosome-specific expression analysis of these patients reveals broad sex disparities in chromosomal patterning, including female-specific retention of chromosome 11q, a pattern typically reserved for MYCN-amplified disease5,6. Finally, we show that H19, a known let-7 microRNA target7, sequesters let-7 in females, providing a rationale for worse female survival and reconciling retention of chromosome 11q. We propose that this novel sex-based outcome disparity is driven by let-7 inhibition, expanding on a model of neuroblastoma development where let-7 mitigation is central to disease pathology8.

cancer biology↗

bioRxiv2024

Genome-wide mapping of native co-localized G4s and R-loops in living cells

The non-B DNA structures can act as dynamic functional genomic elements regulating gene expression. Among them, G4s and R-loops are two of the best studied. The interplay between R-loops and G4s are emerging in regulating DNA repair, replication and transcription. A comprehensive picture of native co-localized G4s and R-loops in living cells is currently lacking. Here, we describe the development of HepG4-seq and an optimized HBD-seq methods, which robustly capture native G4s and R-loops, respectively, in living cells. We successfully employed these methods to establish comprehensive maps of native co-localized G4s and R-loops in human HEK293 cells and mouse embryonic stem cells (mESCs). We discovered that co-localized G4s and R-loops are dynamically altered in a cell type-dependent manner and are largely localized at active promoters and enhancers of transcriptional active genes. We further demonstrated the helicase Dhx9 as a direct and major regulator that modulates the formation and resolution of co-localized G4s and R-loops. Depletion of Dhx9 impaired the self-renewal and differentiation capacities of mESCs by altering the transcription of co-localized G4s and R-loops - associated genes. Taken together, our work established that the endogenous co-localized G4s and R-loops are prevalently persisted in the regulatory regions of active genes and are involved in the transcriptional regulation of their linked genes, opening the door for exploring broader roles of co-localized G4s and R-loops in development and disease.

genomics↗

bioRxiv2024

Repetitive mild closed-head injury induced synapse loss and increased local BOLD-fMRI signal homogeneity

Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries, requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild closed-head injury (rmTBI) and chronic variable stress (CVS) mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [18F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an increase in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.

neuroscience↗

bioRxiv2024

Multimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome-based identification to be successful and explored various features of these data.

neuroscience↗

bioRxiv2024

PAMPHLET: A Robust Toolkit for Precise PAM Prediction and Unveiling PAM Consistency in Highly Co-occurrence CRISPR-Cas Systems

The CRISPR-Cas technology has sparked a new technological revolution, significantly enhancing our ability to understand and engineer organisms. The nuclease that underpins this technology is evolving from the "One Cas9 for all" model to a diverse CRISPR toolbox. Identifying PAM sequences is a critical bottleneck in developing novel Cas proteins. Given the limitations of experimental methods, bioinformatics approaches are essential for predicting PAM sequences of Cas proteins in advance. To date, there are only a few PAM sequence prediction programs, and their accuracy is relatively low due to the limited number of spacers in CRISPR-Cas systems. To overcome this challenge, we have developed a pipeline named PAMPHLET, which innovatively utilizes homology searches of Cas proteins to identify additional spacers. PAMPHLET was tested on 20 CRISPR-Cas systems with known PAMs, increasing the number of spacers by up to 18-fold compared to the original datasets and successfully predicting 18 PAM sequences for protospacers. For rigorous and high-quality wet-lab validation of the predictions made by PAMPHLET, we employed the published DocMF platform. This platform leverages next-generation sequencing chips to profile protein-DNA interactions and can simultaneously screen both 5 and 3 PAMs with high throughput. The PAMPHLET predictions showed high consistency with the DocMF results for four novel Cas proteins. We expect that PAMPHLET will overcome the current limitations in PAM sequence prediction, expedite the discovery of PAM sequences, and help to shorten the development cycle for CRISPR tools. Remarkably, PAMPHLET has revealed an intriguing genomic phenomenon: the C2c9 and C2c10 systems, which lack the canonical adaptation module, possess identical PAM sequences to those found in co-occurring type I systems, suggesting potential shared spacer acquisition mechanisms. This finding highlights the complex evolutionary relationships of CRISPR-Cas systems and propels us toward a deeper understanding of their mechanistic diversity and adaptability.

bioinformatics↗

bioRxiv2024

Whole-brain functional connectivity predicts groupwise and sex-specific tau PET in preclincal Alzheimer's disease

Preclinical Alzheimers disease (AD), characterized by the abnormal accumulation of amyloid prior to cognitive symptoms, presents a critical opportunity for early intervention. Past work has described functional connectivity changes in preclinical disease, yet the interplay between AD pathology and the functional connectome during this window remains unexplored. We applied connectome-based predictive modeling to investigate the ability of resting-state whole-brain functional connectivity to predict tau (18F-flortaucipir) and amyloid (18F-florbetapir) PET binding in a preclinical AD cohort (A4, n=342, age 65-85). Separate predictive models were developed for each of 14 regions, and model performance was assessed using a Spearmans correlation between predicted and observed PET binding standard uptake value ratios. We assessed the validity of significant models by applying them to an external dataset, and visualized the underlying connectivity that was positively and negatively correlated to posterior cingulate tau binding, the most successful model. We found that whole brain functional connectivity predicts regional tau PET, outperforming amyloid PET models. The best performing tau models were for regions affected in Braak stage IV-V regions (posterior cingulate, precuneus, lateral occipital cortex, middle temporal, inferior temporal, and Bank STS), while models for regions of earlier tau pathology (entorhinal, parahippocampal, fusiform, and amygdala) performed poorly. Importantly, tau models generalized to a symptomatic AD cohort (ADNI; amyloid positive, n = 211, age 55-90), in tau-elevated but not tau-negative individuals. For the posterior cingulate A4 tau model, the most successful model, the predictive edges positively correlated with posterior cingulate tau predominantly came from nodes within temporal, limbic, and cerebellar regions. The most predictive edges negatively associated to tau were from nodes of heteromodal association areas, particularly within the prefrontal and parietal cortices. These findings reveal that whole-brain functional connectivity predicts tau PET in preclinical AD and generalizes to a clinical dataset specifically in individuals with abnormal tau PET, highlighting the relevance of the functional connectome for the early detection and monitoring of AD pathology.

neuroscience↗

bioRxiv2024

Unveiling Frequency-Specific Microstate Correlates of Anxiety and Depression Symptoms

Electroencephalography (EEG) microstates are canonical voltage topographies that reflect the temporal dynamics of resting-state brain networks on a millisecond time scale. Changes in microstate parameters have been described in patients with psychiatric disorders, indicating their potential as clinical biomarkers with broadband EEG signals (e.g., 1-30 Hz). Considering the distinct information provided by specific frequency bands, we hypothesized that microstates in decomposed frequency band could provide a more detailed depiction of the underlying psychological mechanism. In this study, with a large open access resting-state dataset (n = 203), we examined the properties of frequency-specific microstates and their relationship with emotional disorders. We conducted clustering on EEG topographies in decomposed frequency band (delta, theta, alpha and beta), and determined the number of clusters with a meta-criterion. Microstate parameters, including global explained variance (GEV), duration, coverage, occurrence and transition probability, were calculated for eyes-open and eyes-closed states, respectively. Their predictive power for the scores of depression and anxiety symptoms were identified by correlation and regression analysis. Distinct microstate patterns were observed across different frequency bands. Microstate parameters in the alpha band held the best predictive power for emotional symptoms. Microstates B (GEV, coverage) and parieto-central maximum microstate C (coverage, occurrence, transitions from B to C) in the alpha band exhibited significant correlations with depression and anxiety, respectively. Microstate parameters of the alpha band achieved predictive R-square of 0.100 for anxiety scores, which is much higher than those of broadband (R-square = -0.026, p < .01). These results suggested the value of frequency-specific microstates in predicting emotional symptoms.

neuroscience↗

bioRxiv2024

Global variation in prior exposure shapes antibody neutralization profiles of SARS-CoV-2 variants up to BA.2.86

The highly mutated SARS-CoV-2 variant, BA.2.86, and its descendants are now the most frequently sequenced variants of SARS-CoV-2. We analyze antibody neutralization data from eight laboratories from the UK, USA, Denmark, and China, including two datasets assessing the effect of XBB.1.5 vaccines, to determine the effect of infection and vaccination history on neutralization of variants up to and including BA.2.86, and produce antibody landscapes to describe these neutralization profiles. We find evidence for lower levels of immune imprinting on pre-Omicron variants in sera collected from Denmark and China, which may be explained by lower levels of circulation of the ancestral variant in these countries, and the use of an inactivated virus vaccine in China.

immunology↗

bioRxiv2024

Rejuvenation of aged oocyte through exposure to young follicular microenvironment

Reproductive aging is a major cause of fertility decline, attributed to decreased oocyte quantity and competence. Follicular somatic cells play crucial roles in the growth and development of the oocyte by providing nutrients and regulatory factors. Here we investigated how oocyte quality is affected by its somatic cell environment by creating chimeric follicles, whereby an oocyte from one follicle was transplanted into and cultured within another follicle whose native oocyte was removed. Somatic cells within the chimeric follicle re-establish connections with the oocyte and support oocyte growth and maturation in a three-dimensional (3D) culture system. We show that young oocytes transplanted into aged follicles exhibited reduced meiotic maturation and developmental potential, whereas the young follicular environment significantly improved the rates of maturation, blastocyst formation and live birth of aged oocytes. Aged oocytes cultured within young follicles exhibited enhanced interaction with somatic cells, more youth-like transcriptome, remodelled metabolome, improved mitochondrial function, and enhanced fidelity of meiotic chromosome segregation. These findings provide the basis for a future follicular somatic cell-based therapy to treat age-associated female infertility.

developmental biology↗

bioRxiv2024

Unraveling the Role of Urea Hydrolysis in Salt Stress Response during Seed Germination and Seedling Growth in Arabidopsis thaliana

Urea is intensively utilized as a nitrogen fertilizer in agriculture, originating either from root uptake or from catabolism of arginine by arginase. Despite its extensive use, the underlying physiological mechanisms of urea, particularly its adverse effects on seed germination and seedling growth under salt stress remains unclear. In this study, we demonstrate that salt stress induces excessive hydrolysis of arginine-derived urea, leading to an increase in cytoplasmic pH within seed radical cells, which, in turn, triggers salt-induced inhibition of seed germination (SISG) and hampers seedling growth. Our findings challenge the long-held belief that ammonium accumulation and toxicity are the primary causes of SISG, offering a novel perspective on the mechanism underlying these processes. This study provides significant insights into the physiological impact of urea hydrolysis under salt stress, contributing to a better understanding of SISG.

plant biology↗

bioRxiv2024

Multi-site Ultrashort Echo Time 3D Phosphorous MRSI repeatability using novel Rosette Trajectory (PETALUTE)

PurposeThis study aims 1) to implement an operator-independent acquisition, reconstruction, and processing pipeline using a novel rosette k-space pattern for UTE 31P 3D MRSI and 2) to evaluate the clinical applicability and replicability at different experimental setups. MethodsA multicenter repeatability study was conducted for the novel UTE 31P 3D Rosette MRSI at three institutions with different experimental setups. Non-localized 31P MRSI data of 5 healthy subjects at each site were acquired with an acquisition delay of 65 s and a final resolution of 10 x 10 x 10 mm3 in 9 min. Spectra were quantified using the LCModel package. The potential acceleration was achieved using compressed sensing on retrospectively undersampled data. Reproducibility at each site was evaluated using the inter-subject coefficient of variance. ResultsThis novel acquisition and advanced processing techniques yielded high-quality spectra and enabled the detection of the critical brain metabolites at three different sites with different hardware specifications. In vivo, feasibility with an acceleration factor of 4 in 6.75 min resulted in a mean Cramer-Rao lower bounds below 20% for PCr, ATPs, PME, and the mean CoV of ATP/PCr resulted in below %20. ConclusionWe demonstrated that UTE 31P 3D Rosette MRSI acquisition, combined with compressed sensing and LCModel analysis, allows patient-friendly, operator-independent, high-resolution 31P MRSI to be acquired at clinical setups.

neuroscience↗

bioRxiv2024

Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer

ObjectiveOverweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential abilities of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. MethodsLkb1fl/flp53fl/fl mice were fed high-fat diet (HFD) or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on HFD or switched to LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial tumor, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. ResultsHFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. ConclusionIn Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as a EC prevention strategy in women with overweight/obesity.

cancer biology↗

bioRxiv2024

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease. Study HighlightsO_LIThe stability of the human microbiome varies among individuals and body sites. C_LIO_LIHighly individualized microbial genera are more stable over time. C_LIO_LIAt each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected. C_LIO_LIIndividuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions. C_LI

microbiology↗