Biology subjects

Gurung, M.

Publications and source records attributed to Gurung, M..

3 recordsLinked to original sources

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↗

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↗

bioRxiv2018

Laboratory and Molecular Surveillance of Paediatric Typhoidal Salmonella in Nepal: Antimicrobial Resistance and Implications for Vaccine Policy

BackgroundChildren are substantially affected by enteric fever in most settings with a high burden of the disease, which could be due to immune naivety, or enhanced risk of exposure to the pathogen. Although Nepal is a high burden setting for enteric fever, the bacterial population structure and transmission dynamics are poorly delineated in young children, the proposed target group for immunization programs.\n\nMethodsBlood culture surveillance amongst children aged 2 months to 15 years of age was conducted at Patan Hospital between 2008 and 2016. A total of 198 S. Typhi and 66 S. Paratyphi A isolated from children treated in both inpatient and outpatient settings were subjected to whole genome sequencing and antimicrobial susceptibility testing. Demographic and clinical data were also collected from the inpatients. The resulting data were used to place these paediatric Nepali isolates into a worldwide context, based on their phylogeny and carriage of molecular determinants of antimicrobial resistance (AMR).\n\nResultsChildren aged [≤]4 years made up >40% of the inpatient population. The majority of isolates (78 %) were S. Typhi, comprising several distinct genotypes but dominated by 4.3.1 (H58). Several distinct S. Typhi genotypes were identified, but the globally disseminated S. Typhi clade 4.3.1 (H58) dominated. The majority of isolates (86%) were insusceptible to fluoroquinolones. This was mainly associated with S. Typhi H58 Lineage II and S. Paratyphi A; non-susceptible strains from these two genotypes accounted for 50% and 25% of all enteric fever cases. Multi-drug resistance (MDR) was rare (3.5% of S. Typhi, 0 S. Paratyphi A) and restricted to chromosomal insertions of AMR genes in H58 lineage I strains. Comparison to global data sets showed the local S. Typhi and S. Paratyphi A strains had close genetic relatives in other South Asian countries, indicating regional strain circulation.\n\nConclusionsThese data indicate that enteric fever in Nepal continues to be a major public health issue with ongoing inter- and intra-country transmission, and highlights the need for regional coordination of intervention strategies. The absence of a S. Paratyphi A vaccine is cause for concern, given its prevalence as an enteric fever agent in this setting, and the large proportion of isolates displaying fluoroquinolone resistance. This study also highlights an urgent need for routine laboratory and molecular surveillance to monitor the epidemiology of enteric fever and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions in prevention and control of this febrile illness.

molecular biology↗