Biology subjects

Layden, B. T.

Publications and source records attributed to Layden, B. T..

8 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↗

bioRxiv2023

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process. HighlightsO_LIEstrogen restores beige adipocyte failure along with improved energy metabolism in old mice. C_LIO_LIEstrogen enhances the thermogenic gene program by mitigating age-induced ER stress. C_LIO_LIEstrogen enhances the beige adipogenesis derived from SMA+ APCs. C_LIO_LIInhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis. C_LI

physiology↗

bioRxiv2023

The Notch-Pdgfr beta axis suppresses brown adipocyte progenitor differentiation in early postnatal mice

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here through in vivo lineage tracing, we observed that PDGFR{beta}+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFR{beta}+ pericytes promotes brown adipogenesis through the downregulation of PDGFR{beta}. Furthermore, inhibition of Notch signaling in PDGFR{beta}+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFR{beta} axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health. HighlightsO_LIPDGFR{beta}+ pericytes act as an essential developmental brown APC. C_LIO_LITBX18+ pericytes contribute to brown adipogenesis in a depot-specific manner. C_LIO_LIInhibiting Notch-Pdgfr{beta} axis promotes brown APC adipogenesis. C_LIO_LIEnhanced postnatal brown adipogenesis improves metabolic health in adult stage. C_LI

developmental biology↗

bioRxiv2023

Gut microbiota and fecal short chain fatty acids differ with adiposity and country of origin: The METS-Microbiome Study

The relationship between the gut microbiota, short chain fatty acid (SCFA) metabolism, and obesity remains unclear due to conflicting reports from studies with limited statistical power. Additionally, this association has rarely been explored in large scale diverse populations. Here, we investigated associations between fecal microbial composition, predicted metabolic potential, SCFA concentrations, and obesity in a large (N = 1,934) adult cohort of African-origin spanning the epidemiologic transition, from Ghana, South Africa, Jamaica, Seychelles, and the United States (US). The greatest gut microbiota diversity and total fecal SCFA concentration was found in the Ghanaian population, while the lowest levels were found in the US population, respectively representing the lowest and the highest end of the epidemiologic transition spectrum. Country-specific bacterial taxa and predicted-functional pathways were observed, including an increased prevalence of Prevotella, Butyrivibrio, Weisella and Romboutsia in Ghana and South Africa, while Bacteroides and Parabacteroides were enriched in Jamaican and the US populations. Importantly, VANISH taxa, including Butyricicoccus and Succinivibrio, were significantly enriched in the Ghanaian cohort, reflecting the participants traditional lifestyles. Obesity was significantly associated with lower SCFA concentrations, a decrease in microbial richness, and dissimilarities in community composition, and reduction in the proportion of SCFA synthesizing bacteria including Oscillospira, Christensenella, Eubacterium, Alistipes, Clostridium and Odoribacter. Further, the predicted proportions of genes in the lipopolysaccharide (LPS) synthesis pathway were enriched in obese individuals, while genes associated with butyrate synthesis via the dominant pyruvate pathway were significantly reduced in obese individuals. Using machine learning, we identified features predictive of metabolic state and country of origin. Country of origin could accurately be predicted by the fecal microbiota (AUC = 0.97), whereas obesity could not be predicted as accurately (AUC = 0.65). Participant sex (AUC = 0.75), diabetes status (AUC = 0.63), hypertensive status (AUC = 0.65), and glucose status (AUC = 0.66) could all be predicted with different success. Interestingly, within country, the predictive accuracy of the microbiota for obesity was inversely correlated to the epidemiological transition, being greatest in Ghana (AUC = 0.57). Collectively, our findings reveal profound variation in the gut microbiota, inferred functional pathways, and SCFA synthesis as a function of country of origin. While obesity could be predicted accurately from the microbiota, the variation in accuracy in parallel with the epidemiological transition suggests that differences in the microbiota between obesity and non-obesity may be larger in low-to-middle countries compared to high-income countries. Further examination of independent study populations using multi-omic approaches will be necessary to determine the factors that drive this association.

microbiology↗

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↗

bioRxiv2020

MiMeNet: Exploring Microbiome-Metabolome Relationships using Neural Networks

The advance in microbiome and metabolome studies has generated rich omics data revealing the involvement of the microbial community in host disease pathogenesis through interactions with their host at a metabolic level. However, the computational tools to uncover these relationships are just emerging. Here, we present MiMeNet, a neural network framework for modeling microbe-metabolite relationships. Using ten iterations of 10-fold cross-validation on three paired microbiome-metabolome datasets, we show that MiMeNet more accurately predicts metabolite abundances (mean Spearman correlation coefficients increase from 0.108 to 0.309, 0.276 to 0.457, and -0.272 to 0.264) and identifies more well-predicted metabolites (increase in the number of well-predicted metabolites from 198 to 366, 104 to 143, and 4 to 29) compared to state-of-art linear models for individual metabolite predictions. Additionally, we demonstrate that MiMeNet can group microbes and metabolites with similar interaction patterns and functions to illuminate the underlying structure of the microbe-metabolite interaction network, which could potentially shed light on uncharacterized metabolites through "Guilt by Association". Our results demonstrated that MiMeNet is a powerful tool to provide insights into the causes of metabolic dysregulation in disease, facilitating future hypothesis generation at the interface of the microbiome and metabolomics.

bioinformatics↗

bioRxiv2018

Gut microbial features can predict host phenotype response to protein deficiency

Malnutrition remains a major health problem in low and middle income countries. During low protein intake, < 0.67 g/kg/day, there is a loss of nitrogen (N2) balance, due to the unavailability of amino acid for metabolism and unbalanced protein catabolism results. However, there are individuals, who consume the same low protein intake, and preserve N2 balance for unknown reasons. A novel factor, the gut microbiota, may account for these N2 balance differences. To investigate this, we correlated gut microbial profiles with the growth of four murine strains (C57Bl6/J, CD-1, FVB, and NIH-Swiss) on protein deficient (PD) diet. Results show that a PD diet exerts a strain-dependent impact on growth and N2 balance as determined through analysis of urinary urea, ammonia and creatinine excretion. Bacterial alpha diversity was significantly (p < 0.05, FDR) lower across all strains on a PD diet compared to normal chow (NC). Multi-group analyses of the composition of microbiomes (ANCOM) revealed significantly differential microbial signatures between the four strains independent of diet. However, mice on a PD diet demonstrated differential enrichment of bacterial genera including, Allobaculum (C57Bl6/J), Parabacteroides (CD-1), Turicibacter (FVB), and Mucispirillum (NIH-Swiss) relative to NC. Additionally, statistical model fitting revealed that the relative abundance of genera such as Bifidobacterium, Ruminococcus, and Lactobacillus were significantly positively correlated with body weight, while Anaerofustis, Roseburia, and Bilophila were significantly positively correlated with ammonia excretion. Taken together, these results suggest a potential relationship between the specific gut microbiota, N2 balance and animal response to malnutrition.

physiology↗