Biology subjects

Khan, M. W.

Publications and source records attributed to Khan, M. W..

7 recordsLinked to original sources

bioRxiv2026

A high fermentable fiber Western diet reduces indole levels

Changes in gut microbiota composition due to diet impact health. Fiber-rich diets promote beneficial microbiota and reduce the risk of metabolic diseases, while low-fiber, calorie-dense diets are linked to dysbiosis and increased disease risk. This study examines the effects of a Western diet (WD) and explores dietary fiber supplements as potential modifiers of those effects. 10-week-old C57Bl/6J male mice were fed control (low-fat) or WD (high-fat, high-sucrose) containing 0% fermentable fiber (FF) or WD supplemented with 20% FF (fructooligosaccharides, FOS; guar gum, GG, or pectin, Pec). After 19 weeks, analysis of the cecal metagenome using whole-genome shotgun sequencing, metabolome by untargeted and targeted LC-MS/MS, and tissue RNA and protein expression by RT-PCR and immunoblotting was undertaken. WD-FF reduced metabolic derangements from WD while also improving GM diversity and altering cecal metabolites, particularly tryptophan metabolism. A profound increase in cecal indole levels (targeted metabolomics) was noted in WD vs WD-FF groups. As the primary indole-oxidizing enzyme, CYP2E1 generates indoxyl sulfate, which contributes to oxidative stress and a leaky gut. Mice on WD displayed higher expression of Cyp2e1 mRNA in the gut. In the liver, the levels of both CYP2E1 protein and mRNA were higher in the WD group compared to the WD-FOS group, with protein levels also higher than in the WD-Pec group and mRNA levels higher than in the WD-GG group. mRNA expression of markers of oxidative stress, inflammation, and leaky barrier was significantly higher in the liver and intestine of the WD vs the WD-FF groups. FFs reduced high plasma indoxyl sulfate levels (except in WD-GG), and boosted short-chain fatty acids and indole acetic acid. Our data suggest that WD disrupts GM tryptophan metabolism, possibly by altering the balance between indole-producing and utilizing gut bacteria. Dietary fiber supplementation exerts protective effects, in part, by mitigating this imbalance.

physiology↗

bioRxiv2025

Integrative analysis of taste genetics and the dental plaque microbiome in early childhood caries

Early childhood caries (ECC) is a multifactorial disease mainly caused by the oral microbiome; however, it is also influenced by host genetics and environmental factors. The combinatorial analysis of these multiple factors influencing ECC susceptibility requires further research. This study investigated the interplay between genetic variants in taste-related genes and the microbiome in ECC, targeting taste genes because of their role in taste preference and potential interactions with oral fungi and bacteria. Using a case-control design involving 538 children, we obtained dental plaque microbiome profiles and genetic variants across 55 candidate genes through next-generation sequencing. Our association analysis for taste genetics and ECC outcome used the socioeconomic factor index (SEFI) and rural-urban status as confounders. We observed a few taste gene variants associated with ECC and microbial diversity. However, no specific association was observed between the variants and cariogenic species. Furthermore, our analysis indicated that Streptococcus mutans is a partial mediator between these genetic variants and ECC outcomes. Machine learning models integrating microbiome, genetics, and covariates achieved robust ECC vs. caries-free classification (AUROC = 0.96), with Streptococcus mutans, rural-urban status, a bitter taste receptor variant, Candida dubliniensis, and SEFI as the top ECC-associated factors. Our findings highlight the association between host genetics and the oral microbiome, underscoring the need for multiomics approaches in ECC risk assessment. HighlightsO_LIS. mutans, C. dubliniensis, and taste genetic variants are associated with ECC. C_LIO_LIRural-urban status and SEFI score are among the top social markers for ECC prediction. C_LIO_LITaste-related genetic factors modulate the composition of dental plaque microbiome. C_LI

genomics↗

bioRxiv2024

Hepatic HKDC1 Deletion Alleviates Western Diet-Induced MASH in Mice

The global prevalence of Metabolic dysfunction-associated steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury. This selective upregulation suggests HKDC1s potential specialization in hepatic glucose and lipid dysregulation, linking it closely to the progression of MASLD and MASH. This study aims to clarify the role of HKDC1 in Western diet-induced MASH in female mice by examining its impact on hepatic glucose and lipid metabolism, offering insights into its potential as a therapeutic target and addressing the need for sex-specific research in liver disease. This study reveals that HKDC1 expression is elevated in obese women with MASH and correlates with liver pathology. In a mouse model, liver-specific HKDC1 knockout (HKDC1LKO) protected against Western diet-induced obesity, glucose intolerance, and MASH features, including steatosis, inflammation, and fibrosis. Transcriptomic analysis showed that HKDC1 deletion reduced pro-inflammatory and pro-fibrotic gene expression, while gut microbiome analysis indicated a shift toward MASH-protective bacteria. These findings suggest that HKDC1 may exacerbate MASH progression through its role in metabolic and inflammatory pathways, making it a potential therapeutic target.

biochemistry↗

bioRxiv2024

Role of socioeconomic factors and interkingdom crosstalk in the dental plaque microbiome in early childhood caries

Early childhood caries (ECC) is influenced by microbial and host factors, including social, behavioral, and oral health. In this cross-sectional study, we analyzed interkingdom dynamics in the dental plaque microbiome and its association with host variables. The samples collected from the preschool children underwent 16S rRNA and ITS1 rRNA gene sequencing. The questionnaire data were analyzed for social determinants of oral health. The results indicated a significant enrichment of Streptococcus mutans and Candida dubliniensis in ECC samples, in contrast to Neisseria oralis in caries-free children. Our interkingdom correlation analysis revealed that Candida dubliniensis was strongly correlated with both Neisseria bacilliformis and Prevotella veroralis in ECC. Additionally, ECC showed significant associations with host variables, including oral health status, age, place of residence, and mode of childbirth. This study provides empirical evidence associating the oral microbiome with socioeconomic and behavioral factors in relation to ECC, offering insights for developing targeted prevention strategies. HIGHLIGHTSO_LICharacterized interkingdom association between cariogenic species of genus Neisseria and Candida C_LIO_LIBoth bacterial and fungal species are important for caries status prediction using artificial intelligence C_LIO_LISocioeconomic index is associated with caries status and caries-associated microbial markers C_LI

microbiology↗

bioRxiv2023

Discovering Disease Genes in PPI Networks: A Bridge from Centrality to Communities

Targeted therapies have become pivotal in modern clinical oncology, driven by a molecularlevel understanding of cancers intricacies, its progression, and innovative research and technology. Personalized and targeted treatments hinge on identifying key genes, hub genes, or biomarkers. Protein-protein interaction (PPI) networks are instrumental in understanding the molecular basis of diseases. While existing literature has identified significant genes based on network centrality, investigations based on community-aware centrality have been notably absent. This omission matters because disease networks frequently display modular structures, necessitating a new perspective. This study bridges the gap between network centrality and community-based investigations. Indeed, in modular networks, node influence can be categorized into two types: local impact within its community, determined by intra-community connections, and global effect on nodes in other communities, established through inter-community links. This concept extends conventional centrality measures to networks with a community structure. Initially, we performed a comparative analysis of seven PPI networks related to cancer and noncancerous conditions. We explore the correlation between classical network centralities and their equivalents at the global (inter-community) and local (intra-community) levels. Notably, we consistently observed a high correlation between network degree and local degree centrality in all PPIs, leading us to select local degree centrality for further investigation. Pronounced modularity characterizes prostate and cervical disease networks. Consequently, we investigate these networks to identify key genes at the local community level and validate them by examining their expression levels. Variations in gene expression between cancerous and non-cancerous tissues bolster our findings. We identify a novel set of genes as potential key players in prostate and cervical cancer. Specifically, in cervical cancer, the top genes at the mesoscopic level include AKT1, CDK2, BRCA1, VEGFA, SRC, PSMD14, MRPL3, TP53, and NUP37. Meanwhile, the top genes identified in prostate cancer are FOS, TP53, UBA52, HLA-B, TSPO, and CD19. Although we focus on cancer data, our methodologys versatility makes it applicable to other disease networks, opening avenues to identify key genes as potential drug targets.

cancer biology↗

bioRxiv2021

The hexokinase ''HKDC1'' interaction with the mitochondria is essential for hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is a leading cause of death from cancer malignancies. Recently, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in HCC compared to healthy tissue. Using in vitro and in vivo tools, we examined the role of HKDC1 in HCC progression. Importantly, HKDC1 ablation stops HCC progression by promoting metabolic reprogramming by shifting glucose flux away from the TCA cycle. Next, HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy which cannot be compensated by enhanced glucose uptake. And finally, we show that the interaction of HKDC1 with the mitochondria is essential for its role in HCC progression, and without this mitochondrial interaction mitochondrial dysfunction occurs. In sum, HKDC1 is highly expressed in HCC cells compared to normal hepatocytes, therefore targeting HKDC1, specifically its interaction with the mitochondria, reveals a highly selective approach to target cancer cells in HCC.

cancer biology↗

bioRxiv2021

Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis

Background and aimsNormal gestation involves reprogramming of maternal gut microbiome (GM) that may contribute to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM - maternal metabolism interaction. MethodsThe GM and plasma metabolome of CD1, NIH-Swiss and C57BL/6J mice were analyzed using 16S rRNA sequencing and untargeted LC-MS throughout gestation and postpartum. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM in the process was studied using fecal microbial transplants (FMT). ResultsSignificant variation in gut microbial alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time-point specific, with species enriched at gestation day 15/19 (G15/19), a point of heightened IR, distinct from those enriched pre- or post- pregnancy. Untargeted and targeted metabolomics revealed elevated plasma kynurenine at G15/19 in all three mouse strains. IDO1, the rate limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine levels effects on IR derive from the GM in both mouse and human pregnancy. ConclusionsGM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.

physiology↗