Biology subjects

Shulzhenko, N.

Publications and source records attributed to Shulzhenko, N..

6 recordsLinked to original sources

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

Reversing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S sequences and systemic metabolic phenotypic data using a transkingdom network analysis. By incorporating cell type information from single cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reversed levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes from diet-induced obesity and metabolic syndrome. It primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in adipose tissue.

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↗

bioRxiv2021

GATA4 regionalizes intestinal metabolism and barrier function to prevent immunopathology

Different regions of the gastrointestinal tract have distinct digestive and absorptive functions, which may be locally disrupted by infection or autoimmune disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. Here, we used mouse models, transcriptomics, and immune profiling to show that regional epithelial expression of the transcription factor GATA4 prevented adherent bacterial colonization and inflammation in the proximal small intestine by regulating retinol metabolism and luminal IgA. Loss of epithelial GATA4 expression increased mortality in mice infected with Citrobacter rodentium. In active celiac patients with villous atrophy, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. This study reveals broad impacts of GATA4-regulated intestinal regionalization and highlights an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease. One-sentence summaryEpithelial GATA4 regulates intestinal regionalization of bacterial colonization, metabolic pathways, and tissue immunity.

immunology↗

bioRxiv2021

Dietary palmitic acid induces trained immunity that controls inflammation and infection

Trained immunity is an innate immune memory response that is induced by primary microbial or sterile stimuli that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Nutritional components, such as dietary fatty acids, can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli in the context of innate immune memory. Here we find mice fed diets enriched in saturated fatty acids (SFAs) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and glycemic modulation. Ex vivo, we show monocytes and splenocytes from mice fed enriched SFAs do not have altered baseline inflammation, but enhanced responses to a secondary inflammatory challenge. Lipidomics identified enhanced free palmitic acid (PA) and PA-associated lipids in SFA-fed mice serum. We found pre-treatment with physiologically relevant concentrations of PA alone reprograms macrophages to induce a hyper-inflammatory response to secondary challenge with LPS. This response was found to be dependent on the synthesis of ceramide, and reversible when treated with oleic acid, a mono-unsaturated FA that depletes intracellular ceramide. In vivo, we found systemic PA confers enhanced inflammation and mortality during an acute septic response to systemic LPS, which was not reversible for up to 7 days post-PA-exposure. While PA-treatment is harmful for acute septic shock outcome, we find PA exposure enhanced clearance of Candida albicans in RAG-/- mice. These are the first data to implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory that is detrimental during an acute septic response, but beneficial for clearance of pathogens.

immunology↗

bioRxiv2020

Host response to cholestyramine can be mediated by the gut microbiota

The gut microbiome has been implicated as a major factor contributing to metabolic diseases as well as being contributors to the response to drugs used for the treatment of such diseases. In this study, using a diet-induced obesity mouse model, we tested the effect of cholestyramine, a bile acid sequestrant, on the murine gut microbiome and mammalian metabolism. We also explored the hypothesis that some beneficial effects of this drug on systemic metabolism can be attributed to alterations in gut microbiota. First, we demonstrated that cholestyramine can decrease glucose and epidydimal fat levels. Next, while investigating gut microbiota we found increased alpha diversity of the gut microbiome of cholestyramine-treated mice, with fourteen taxa showing restoration of abundance to levels resembling those in mice fed with a control diet. Analyzing expression of genes known to be regulated by cholestyramine (including Cyp7a1), we confirmed the expected effect of this drug in the liver and ileum. Finally, using a transkingdom network analysis we inferred Acetatifactor muris and Muribaculum intestinale as potential mediators/modifiers of cholestyramine effects on the mammalian host. In addition, A. muris correlated positively with glucagon (Gcg) expression in the ileum and negatively correlated with small heterodimer partner (Shp) expression in the liver. Interestingly, A. muris also correlated negatively with glucose levels, further indicating the potential probiotic role for A. muris. In conclusion, our results indicate the gut microbiome has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations.

pharmacology and toxicology↗