Biology subjects

Peng, J.

Publications and source records attributed to Peng, J..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

Avirulent ME49Δgra5 Protecting Hosts Against Toxoplasma gondii Infection and Breast Tumors

Toxoplasma gondii is the causative agent of toxoplasmosis, a zoonotic disease that poses a threat to human health and a considerable loss to livestock farming. At present, clinical therapeutic drugs mainly target T. gondii tachyzoites and fail to eradicate bradyzoites. Developing a safe and effective vaccine against toxoplasmosis is urgent and important. T. gondii possesses dense granule organelles that secrete immunogenic dense granule proteins (GRAs). GRA5 localizes to the parasitophorous vacuole membrane (PVM) in the tachyzoite stage and to the cyst wall in the bradyzoite stage. Here we report that gra5 knockout T. gondii strain is avirulent and fails to form cysts, but stimulates sero-conversion in mice. We next investigated the protective efficacy of ME49{Delta}gra5 vaccination against T. gondii infection. All the immunized mice survived the challenge infection with either wild-type RH, ME49, VEG tachyzoites or ME49 cysts. Remarkably, ME49{Delta}gra5 tachyzoites inoculation in situ attenuated the growth of murine breast tumor (4T1) in mice and prevented 4T1s lung metastasis. ME49{Delta}gra5 inoculation might upregulate the levels of Th1 cytokines and tumor-infiltrating T cells in tumor microenvironment (TME) and trigger anti-tumor responses by increasing the number of NK, B, T cells, macrophages, and dendritic cells (DCs) in spleen. Collectively, the results support the potential of ME49{Delta}gra5 as attenuated live vaccine against T. gondii infection and breast cancer. Author summaryThe zoonotic toxoplasmosis poses a great disease burden to humans and big loss to livestock farming. At present, clinical therapeutic drugs mainly target T. gondii tachyzoites but have no effect on bradyzoites. A safe and effective vaccine against toxoplasmosis is urgent and important. Dense granule proteins (GRAs) are a group of immunoactive proteins secreted by T. gondii dense granule organelles. GRA5 is located on the parasitophorous vacuole membrane (PVM) at the tachyzoite stage and on the cyst wall at the bradyzoite stage. We discovered that the gra5 knockout T. gondii strain became avirulent and failed to form cysts in mice. ME49{Delta}gra5 immunized mice survived the challenge infection of wild-type RH, ME49, and VEG tachyzoites, and ME49 cysts. Meanwhile, ME49{Delta}gra5 tachyzoites inoculation in situ remarkably attenuated the growth of murine breast tumor (4T1) in mice including the injected and distant tumors, as well as prevented 4T1s lung metastasis. This results support the potential of ME49{Delta}gra5 as attenuated live vaccine against T. gondii infection and breast cancer.

microbiology↗

bioRxiv2023

Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse

Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 (RRM2) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B. Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.

cancer biology↗

bioRxiv2023

Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways in B-cell acute lymphoblastic leukemia

Glucocorticoids (GCs; i.e., steroids) are important chemotherapeutic agents in the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL) and de novo GC resistance predicts relapse and poor clinical outcome in patients. Glucocorticoids induce B-ALL cell apoptosis through activation of glucocorticoid receptor (GR), a ligand-induced nuclear receptor transcription factor (TF). We previously identified disruptions to glucocorticoid receptor (GR)-bound cis-regulatory elements controlling TLE1 expression in GC-resistant primary B-ALL cells from patients. TLE1 is a GC-response gene up-regulated by steroids and functions as a canonical Wnt signaling repressor. To better understand the mechanistic relationship between GC signaling and canonical Wnt signaling, we performed diverse functional analyses that identified extensive crosstalk and mutual antagonism between these two signaling pathways in B-ALL. We determined that crosstalk and antagonism was driven by the binding of GR and the canonical Wnt signaling TFs LEF1 and TCF7L2 to overlapping sets of cis-regulatory elements associated with genes impacting cell death and cell proliferation, and was further accompanied by overlapping and opposing transcriptional programs. Our data additionally suggest that cis-regulatory disruptions at TLE1 are linked to GC resistance through a dampening of the GC response and GC-mediated apoptosis via enhanced canonical Wnt signaling. As a result of the extensive genomic and gene regulatory connectivity between these two signaling pathways, our data supports the importance of canonical Wnt signaling in mediating GC resistance in B-ALL.

cancer biology↗

bioRxiv2023

Adaptations to water stress and pastoralism in the Turkana of northwest Kenya

The Turkana people inhabit arid regions of east Africa--where temperatures are high and water is scarce--and they practice subsistence pastoralism, such that their diet is primarily composed of animal products. Working with Turkana communities, we sequenced 367 genomes and identified 8 regions putatively involved in adaptation to water stress and pastoralism. One of these regions includes a putative enhancer for STC1--a kidney-expressed gene involved in the response to dehydration and the metabolism of purine-rich foods such as red meat. We show that STC1 is induced by antidiuretic hormone in humans, is associated with urea levels in the Turkana themselves, and is under strong selection in this population (s[~]0.041). This work highlights that partnerships with subsistence-level groups can lead to new models of human physiology with biomedical relevance.

evolutionary biology↗

bioRxiv2022

Integrated proteomics reveals the landscape of autophagy degradation in human neurons and autophagy receptors regulating neuronal activity

Autophagy is a catabolic and self-degradative process crucial for maintaining cellular homeostasis. Malfunctional autophagy is implicated in neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we reported a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and LC3-interactome uncovers a role of neuronal autophagy in targeting primarily endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) proteins, and cAMP-PKA pathway, for degradation. Tubular ER and specific SV proteins are significant autophagy cargos in the axons. Functional validation identified calumenin as an ER resident autophagy receptor and illuminated a role of autophagy in regulating PKA and neuronal activity through AKAP11-mediated degradation. Our study thus reveals the landscape of autophagy degradation in human neurons and offers molecular insight into mechanisms of neurological disorders linked to autophagy deficiency. HighlightO_LIIntegrated proteomics reveals the landscape of autophagy degradation in human neurons C_LIO_LIAutophagy clears tubular ER and selective ER and synaptic vesicle proteins in neurons C_LIO_LICalumenin is an ER resident autophagy receptor C_LIO_LIAutophagy controls PKA pathway and neuronal activity through autophagy receptor AKAP11 C_LI

neuroscience↗

bioRxiv2022

Learning predictive models of tissue cellular neighborhoods from cell phenotypes with graph pooling

It remains poorly understood how different cell types organize and coordinate with each other to support tissue functions. We describe CytoCommunity for identification of tissue cellular neighborhoods (TCNs) based on cell phenotypes and their spatial distributions. CytoCommunity learns a mapping directly from cell phenotype space to TCN space by a graph neural network model without using additional gene or protein expression features and is thus applicable to tissue imaging data with a small number of measured features. By leveraging graph pooling, CytoCommunity enables de novo identification of condition-specific TCNs under the supervision of image labels. Using various types of single-cell-resolution spatial proteomics and transcriptomics images, we demonstrate that CytoCommunity can identify TCNs of variable sizes with substantial improvement over existing methods. To further evaluate the ability of CytoCommunity for discovering condition-specific TCNs by supervised learning, we apply it to colorectal and breast cancer tissue images with clinical outcome information. Our analysis reveals novel granulocyte- and cancer associated fibroblast-enriched TCNs specific to high-risk tumors as well as altered tumor-immune and tumor-stromal interactions within and between TCNs compared to low-risk tumors. CytoCommunity represents the first computational tool for end-to-end unsupervised and supervised analyses of single-cell spatial maps and enables direct discovery of conditional-specific cell-cell communication patterns across variable spatial scales.

bioinformatics↗

bioRxiv2022

QCR7 affects the virulence of Candida albicans and the uptake of multiple carbon sources present in different host niches

BackgroundCandida albicans is a commensal yeast that may cause life-threatening infections. Studies have shown that the cytochrome b-c1 complex subunit 7 gene (QCR7) of C. albicans encodes a protein that forms a component of the mitochondrial electron transport chain complex III, making it an important target for studying the virulence of this yeast. However, to the best of our knowledge, the functions of QCR7 have not yet been characterized. MethodsA QCR7 knockout strain was constructed using SN152, and BALb/c mice were used as model animals to determine the role of QCR7 in the virulence of C. albicans. Subsequently, the effects of QCR7 on mitochondrial functions and use of carbon sources were investigated. Next, its mutant biofilm formation and hyphal growth maintenance were compared with those of the wild type. Furthermore, the transcriptome of the qcr7{Delta}/{Delta} mutant was compared with that of the WT strain to explore pathogenic mechanisms. ResultsDefective QCR7 attenuated the virulence of C. albicans infection in vivo. Furthermore, the mutant influenced the use of multiple alternative carbon sources that exist in several host niches. Moreover, it led to mitochondrial dysfunction. Furthermore, the QCR7 knockout strain showed defects in biofilm formation or the maintenance of filamentous growth. The overexpression of cell-surface-associated genes (HWP1, YWP1, XOG1, and SAP6) can restore defective virulence phenotypes and the carbon-source utilization of qcr7{Delta}/{Delta}. ConclusionThis study provides new insights into the mitochondria-based metabolism of C. albicans, accounting for its virulence and the use of variable carbon sources that promote C. albicans to colonize host niches.

microbiology↗

bioRxiv2022

Chromosome territory reorganization through artificial chromosome fusion is negligible to cell fate determination and mouse development.

SummaryChromosomes occupy discrete spaces in the interphase cell nucleus, called chromosome territory. The structural and functional relevance of chromosome territory remains elusive. We fused chromosome 15 and 17 in mouse haploid embryonic stem cells (haESCs), resulting in distinct changes of territories in the corresponding native chromosomes, but affecting little on gene expression, pluripotency and gamete functions of haESCs. The karyotype engineered haESCs were successfully implemented in cultivating heterozygous (2n=39) and homozygous (2n=38) mouse models. The mice containing fusion-chromosome are fertile, and their representative tissues and organs display no phenotypic abnormalities, suggesting mouse development unscathed. These results indicate that the mammalian chromosome architectures are highly resilient, and reorganization of chromosome territories can be readily tolerated during cell differentiation and mouse development.

molecular biology↗

bioRxiv2022

Microglia are involved in regulating histamine dependent and non-dependent itch transmissions with distinguished signal pathways

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ central microglia and peripheral macrophages together (whole depletion), or selectively deplete central microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that central microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

neuroscience↗

bioRxiv2022

Inferring Single-Molecule Chromatin Interactions via Online Convex Network Dictionary Learning

MotivationGenomes of multicellular systems are compartmentalized and dynamically folded within the three-dimensional (3D) confines of the nucleus in order to facilitate gene regulation. Among the 3D-genome mapping technologies currently in use, droplet-based, barcode-linked sequencing (ChIA-Drop) has the unique capability to capture complex multi-way chromatin interactions at the single-molecule level. ChIA-Drop data gives rise to higher-order interaction networks in which nodes represent genomic fragments while (hyper)edges capture observed physical contacts. The problem of interest is to use this data to create a "dictionary" of interaction patterns (subnetworks) that accurately describe all global chromatin structures and associate dictionary elements with cellular functions. ResultsTo construct interpretable chromatin dictionaries, we introduce a new algorithm termed online convex network dictionary learning (online cvxNDL). Unlike classical dictionary learning for image or text processing, online cvxNDL uses special subgraph sampling methods and produces interpretable subnetwork representatives corresponding to "convex mixtures" of patterns observed in real data. To demonstrate the utility of the method, we perform an in-depth study of RNAPII-enriched ChIA-Drop data from Drosophila Melanogaster S2 cell lines. Our results are two-fold: First, we show that online cvxNDL allows for accurate reconstruction of the original interaction network data using only a collection of roughly 25 dictionary elements and their "representatives" directly observed in the data. Second, we identify collections of interaction patterns of chromatin elements shared by related processes on different chromosomes and those unique to certain chromosomes. This is accomplished through Gene Ontology (GO) enrichment analysis that allows us to associate dictionary element representatives with functional properties of their corresponding chromatin region and in the process, determine what we call the "span" and "density" of chromatin interaction patterns. Availability and ImplementationThe code and dataset are available at: https://github.com/jianhao2016/online_cvxNDL/ Contactmilenkov@illinois.edu

bioinformatics↗

bioRxiv2022

A molecular mechanism for membrane chaperoning by a late embryogenesis abundant protein

Environmental stress can result in substantial damage to proteins, membranes, and genetic material, impacting organismal survival1-3. Stress tolerance can be conferred by intrinsically disordered proteins (IDPs)4 that lack stable tertiary structure. IDPs from the large family of late embryogenesis abundant (LEA) proteins confer a fitness advantage when heterologously expressed5,6. Such protection suggests a general molecular function leading to stress tolerance, although the mechanisms remain unclear. Here, we report that a tardigrade LEA protein that confers stress tolerance in yeast acts as a molecular chaperone for the mitochondrial membrane. This protein, named HeLEA1, localizes to the mitochondrial matrix, and harbors conserved LEA sequence motifs that undergo dynamic disorder-to-helical transition upon binding to negatively charged membranes. Yeast expressing HeLEA1 show increased mitochondrial membrane fluidity, increased membrane potential, and enhanced tolerance to hyperosmotic stress under non-fermentative growth without significantly altering mitochondrial lipid composition or triggering a generic stress response. We demonstrate that membrane binding ameliorates excess surface tension, possibly by stabilizing lipid packing defects. Evolutionary analysis suggests that HeLEA1 homologs localize to different membrane-bound organelles and share similar sequence and biophysical features. We suggest that membrane chaperoning by LEA proteins represents a general biophysical solution that can operate across the domains of life.

biophysics↗

bioRxiv2022

Metabolic activity organizes olfactory representations

Hearing and vision sensory systems are tuned to the natural statistics of acoustic and electromagnetic energy on earth, and are evolved to be sensitive in ethologically relevant ranges. But what are the natural statistics of odors, and how do olfactory systems exploit them? Dissecting an accurate machine learning model1 for human odor perception, we find a computable representation for odor at the molecular level that can predict the odor-evoked receptor, neural, and behavioral responses of nearly all terrestrial organisms studied in olfactory neuroscience. Using this olfactory representation (Principal Odor Map, POM), we find that odorous compounds with similar POM representations are more likely to co-occur within a substance and be metabolically closely related; metabolic reaction sequences2 also follow smooth paths in POM despite large jumps in molecular structure. Just as the brains visual representations have evolved around the natural statistics of light and shapes, the natural statistics of metabolism appear to shape the brains representation of the olfactory world.

neuroscience↗

bioRxiv2022

High-resolution de novo structure prediction from primary sequence

Recent breakthroughs have used deep learning to exploit evolutionary information in multiple sequence alignments (MSAs) to accurately predict protein structures. However, MSAs of homologous proteins are not always available, such as with orphan proteins or fast-evolving proteins like antibodies, and a protein typically folds in a natural setting from its primary amino acid sequence into its three-dimensional structure, suggesting that evolutionary information and MSAs should not be necessary to predict a proteins folded form. Here, we introduce OmegaFold, the first computational method to successfully predict high-resolution protein structure from a single primary sequence alone. Using a new combination of a protein language model that allows us to make predictions from single sequences and a geometry-inspired transformer model trained on protein structures, OmegaFold outperforms RoseTTAFold and achieves similar prediction accuracy to AlphaFold2 on recently released structures. OmegaFold enables accurate predictions on orphan proteins that do not belong to any functionally characterized protein family and antibodies that tend to have noisy MSAs due to fast evolution. Our study fills a much-encountered gap in structure prediction and brings us a step closer to understanding protein folding in nature.

bioinformatics↗

bioRxiv2022

Dissecting the genetic basis of the heterosis of Y900, an elite super-hybrid rice

Y900 is one of the top hybrid rice varieties with a yield exceeding 15 t/hm2. To dissect the mechanism of heterosis, the male parent line R900 and female parent line Y58S were sequenced using long-read and Hi-C technology. High-quality reference genomes of sizes of 396.41 Mb and 398.24 Mb were obtained for R900 and Y58S, respectively. Genome-wide variations between the parents were systematically identified, including 1,367,758 SNPs and 299,149 Indels. No megabase level structural variations exist. >75% of genes exhibited variation between the two parents. Compared with other two-line hybrids sharing the same female parent, the Geng/japonica-type genetic components from different male parents showed an increasing trend from phase 2-4 super-hybrid rice; Transcriptome analysis revealed that additive and dominance effects are the main genetic effects that constitute the heterosis of Y900. Allele-specific expression patterns and expression regulation patterns are quite dynamic in different tissues. For young panicle tissues, cis-regulation is dominant, while trans-regulation is more popular in leaf issues. Overdominance is more likely regulated by the trans-regulation mechanism. The differential gene expression and regulation pattern are closely related to Geng/japonica introgression. Additionally, R900 contained several excellent japonica haplotypes, such as NAL1, OsSPL13, Ghd8, OsBRI1, and DTH2, which make a good complement to Y58S. The fine tune mechanism through dynamic expression or regulation pattern change, especially on some key functional genes, is the base for heterosis.

plant biology↗

bioRxiv2022

Human iPSC-derived neuron of 16p11.2 deletion reveals haplotype-specific expression of MAPK3 and its contribution to variable NDD phenotypes

Recurrent proximal 16p11.2 deletion (16p11.2del) is risk factor of diverse neurodevelopmental disorders (NDDs) with variable penetrance. Although previous human induced pluripotent stem cell (hiPSC) models of 16p11.2del confirmed disrupted neuron development, it is not known which gene(s) at this interval are mainly responsible for the abnormal cellular phenotypes and how the NDD penetrance is regulated. After haplotype phasing of 16p11.2 region, we generated hiPSCs for two 16p11.2del families with distinct residual haplotypes and variable NDD phenotypes. We also differentiated the hiPSCs to cortical neural cells and demonstrated MAPK3 as a driver signal of 16p11.2 region contributing to the dysfunctions in multiple pathways related to neuron development, which leads to altered morphological or electrophysiological properties in neuron cells. Furthermore, residual haplotype-specific MAPK3 expression was identified in 16p11.2del neuron cells, associating MAPK3 down-expression with the minor allele of the residual haplotype. Ten SNPs of the residual haplotype are mapped as enhancer SNPs (enSNPs) of MAPK3, eight enSNPs were functionally validated by luciferase assays, implying enSNPs contribute to residual haplotype-specific MAPK3 expression via cis-regulation. Finally, the analyses of three different patient cohorts showed that the residual haplotype of 16p11.2del is associated with variable NDD phenotypes.

genetics↗

bioRxiv2022

Antigen-Specific Antibody Design and Optimization with Diffusion-Based Generative Models

Antibodies are immune system proteins that protect the host by binding to specific antigens such as viruses and bacteria. The binding between antibodies and antigens is mainly determined by the complementarity-determining regions (CDR) of the antibodies. In this work, we develop a deep generative model that jointly models sequences and structures of CDRs based on diffusion probabilistic models and equivariant neural networks. Our method is the first deep learning-based method that generates antibodies explicitly targeting specific antigen structures and is one of the earliest diffusion probabilistic models for protein structures. The model is a "Swiss Army Knife" capable of sequence-structure co-design, sequence design for given backbone structures, and antibody optimization. We conduct extensive experiments to evaluate the quality of both sequences and structures of designed antibodies. We find that our model could yield competitive results in binding affinity measured by biophysical energy functions and other protein design metrics.

bioinformatics↗

bioRxiv2022

PPIX-binding Proteins Reveal Porphyrin Synthesis and Ferroptosis Link

All aerobic organisms require the cofactor heme to survive, but its synthesis requires formation of a potentially toxic intermediate protoporphyrin IX (PPIX). Little is known about the extent of PPIXs cellular interactions. Here, we report the development of PPB, a biotin-conjugated, PPIX-probe that captures proteins capable of interacting with PPIX. Quantitative proteomics with PPB identified common proteins among a diverse panel of mammalian cell lineages. Pathway and quantitative difference analysis revealed PPB-bound proteins related to iron and heme metabolism and suggested that these processes might be altered by heme/porphyrin synthesis. We show that increased heme/porphyrin synthesis in cells promotes ferroptosis that is pharmacologically distinct from canonical ferroptosis driven by erastin, an inhibitor of the cystine/glutamate antiporter. Proteomic data derived from PPB revealed an interactor, PRDX3, a mitochondrial peroxidase, that modulated heme/porphyrin biosynthesis driven ferroptosis. Consistent with a role in porphyrin-induced ferroptotic death targeted gene knockdown of PRDX3, but not peroxidases, PRDX1 or 2, enhanced porphyrin-induced ferroptotic death. The relationship between increased heme/porphyrin synthesis and ferroptosis was also found in a ferrochelatase-deficient T-lymphoblastoid leukemia cell line, suggesting potential strategy for treating certain cancers. We demonstrate that when the PPB probe is coupled with unbiased proteomics a previously unreported relationship between heme/porphyrin synthesis, and ferroptosis was discovered.

biochemistry↗

bioRxiv2022

Chemotherapy drugs induce different gut microbiota disorder pattern and NODs/RIP2/NF-κB signaling pathway activation that lead to different degrees of intestinal injury

5-Fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (L-OHP) and calcium folinate (CF) are the widely used chemotherapy drugs to treat colorectal cancer. However, the use of chemotherapy is often accompanied by intestinal inflammation and gut microbiota disorder. Moreover, the change of gut microbiota may lead to destruction of the intestinal barrier, which contributes to the severity of intestinal injury. There was no detailed comparison of intestinal injury and gut microbiota disorder among 5-FU, CPT-11, L-OHP and CF, which is not benefit for the development of targeted detoxification therapy after chemotherapy. In this project, a model of chemotherapy-induced intestinal injury in tumor-bearing mice was established by intraperitoneal injection of chemotherapy drugs at a clinically equivalent dose. 16S rDNA sequencing was used to detect gut microbiota. We found that 5-FU, CPT-11 and L-OHP caused intestinal injury, inflammatory cytokine (IFN-{gamma}, TNF-, IL-1{beta}, and IL-6) secretion, and gut microbiota disorder. Importantly, we established a complex but clear network between the gut microbiota change pattern and intestinal damage degree induced by different chemotherapy drugs. L-OHP caused the most severe damage in intestine and disorder of gut microbiota, and showed considerable overlap of the microbiota change pattern with 5-FU and CPT-11. The phylogenetic investigation of communities by reconstruction of unobserved states, V1.0 (PICRUSt) analysis showed that the microbiota disorder pattern induced by 5-FU, CPT-11 and L-OHP was related to the NOD like signaling pathway. Therefore, we detected the protein expression of the NODs/RIP2/NF-{kappa}B signaling pathway and found that L-OHP activated that pathway highest. Furthermore, by RDA/CCA analysis, we found that Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, Streptococcus and Candidatus Saccharimonas were highly correlated with the NODs/RIP2/NF-{kappa}B signaling pathway, and influenced by chemotherapy drugs. IMPORTANCEThe chemotherapy-induced intestinal injury limit drugs clinical use. Intestinal injury involves multiple signaling pathways and the disruption of microbiota. Our results suggest that the degree of intestinal injury caused by different drugs of the first-line colorectal chemotherapy regimen is related to the change pattern of microbiota. Moreover, the NODs/RIP2/NF-{kappa}B signaling pathway was activated in different degrees is also related to the change pattern of microbiota. We found L-OHP caused the most severe change of gut microbiota, and showed considerable overlap of the microbiota changes pattern with 5-FU and CPT-11. Here, we have established a network of different chemotherapy drugs, gut microbiota and NODs/RIP2/NF-{kappa}B signaling pathway, which may provide a new basis for further elucidating the mechanism and clinical treatment of intestinal injury caused by chemotherapy.

molecular biology↗