Biology subjects

Dzutsev, A. K.

Publications and source records attributed to Dzutsev, A. K..

3 recordsLinked to original sources

bioRxiv2024

The Gut Microbiome Controls Liver Tumors via the Vagus Nerve

Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. Liver denervation via hepatic vagotomy (HV) significantly reduced liver tumor burden, while pharmacological enhancement of parasympathetic tone promoted tumor growth. Cholinergic disruption in Rag1KO mice revealed that cholinergic regulation requires adaptive immunity. Further scRNA-seq and in vitro studies indicated that vagal ACh dampens CD8+ T cell activity via muscarinic ACh receptor (AChR) CHRM3. Depletion of CD8+ T cells abrogated HV outcomes and selective deletion of Chrm3 on CD8+ T cells inhibited liver tumor growth. Beyond tumor-specific outcomes, vagotomy improved cancer-associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we investigated putative microbiota-neuroimmune crosstalk. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, increasing Desulfovibrionales and Clostridial taxa. Strikingly, in tumor-free mice, vagotomy permitted HCC-associated microbiota to activate hepatic CD8+ T cells. These findings reveal that gut bacteria influence behavior and liver anti-tumor immunity via a dynamic and pharmaceutically targetable, vagus-liver axis.

cancer biology↗

bioRxiv2023

Transkingdom Network Analysis (TkNA): a systems approach inferring causal factors underlying host-microbiota interactions.

Technological advances have generated tremendous amounts of high-throughput omics data. Integrating data from multiple cohorts and diverse omics types from new and previously published studies can offer a holistic view of a biological system and aid in deciphering its critical players and key mechanisms. In this protocol, we describe how to use Transkingdom Network Analysis (TkNA), a unique causal-inference analytical framework that can perform meta-analysis of cohorts and detect master regulators among measured parameters that govern pathological or physiological responses of host-microbiota (or any multi-omic data) interactions in a particular condition or disease. TkNA first reconstructs the network that represents a statistical model capturing the complex relationships between the different omics of the biological system. Here, it selects differential features and their per-group correlations by identifying robust and reproducible patterns of fold change direction and sign of correlation across several cohorts. Next, a causality-sensitive metric, statistical thresholds, and a set of topological criteria are used to select the final edges that form the transkingdom network. The second part of the analysis involves interrogating the network. Using the networks local and global topology metrics, it detects nodes that are responsible for control of given subnetwork or control of communication between kingdoms and/or subnetworks. The underlying basis of the TkNA approach involves fundamental principles including laws of causality, graph theory and information theory. Hence, TkNA can be used for causal inference via network analysis of any host and/or microbiota multi-omics data. This quick and easy-to-run protocol requires very basic familiarity with the Unix command-line environment.

systems biology↗

bioRxiv2022

Suppression of Betacellulin expression is a key mechanism for omega-3 fatty acid mediated attenuation of nonalcoholic steatohepatitis

Clinical and preclinical studies have established that supplementing diets with {omega}3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH). Herein, we used multi-omic network analysis to unveil novel mechanistic targets of {omega}3 PUFA effects in a preclinical mouse model of western diet induced NASH. After identifying critical molecular processes responsible for the effects of {omega}3 PUFA, we next performed meta-analysis of human liver cancer transcriptomes and uncovered betacellulin as a key EGFR-binding protein that was induced in liver cancer and downregulated by {omega}3 PUFAs in animals with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, stimulating transforming growth factor-{beta}2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti-inflammatory and antifibrotic effects of {omega}3 PUFA during NASH. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/510635v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@b8ebe7org.highwire.dtl.DTLVardef@879e8dorg.highwire.dtl.DTLVardef@1ba56f3org.highwire.dtl.DTLVardef@a26c67_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIMulti-omic network analysis points to mitochondrial cardiolipin precursors as candidate key lipids whereby {omega}3 fatty acids restore mitochondrial functioning. C_LIO_LIMulti-omic network analysis suggests betacellulin (BTC) as one of the key mediators of NASH suppressed by {omega}3 polyunsaturated fatty acids. C_LIO_LIReduction of liver fibrosis by omega-3 fatty acids (especially by docosahexaenoic acid, DHA) is accomplished by simultaneous inhibition of betacellulin and TLR agonists. C_LIO_LIBTC promotes collagen production and induces TGFB2 in hepatic stellate cells. C_LIO_LIBTC together with TLR2/4 agonists stimulate expression of integrins in macrophages. C_LIO_LIDHA suppresses BTC-EGFR pathway in NASH animal model potentially preventing progression to hepatocellular carcinoma. C_LI

systems biology↗