scholarly journals Gut Microbial Trimethylamine is Elevated in Alcohol-Associated Hepatitis and Contributes to Ethanol-Induced Liver Injury in Mice

2022 ◽  
Author(s):  
Robert N Helsley ◽  
Tatsunori Miyata ◽  
Anagha Kadam ◽  
Varadharajan Venkateshwari ◽  
Naseer Sangwan ◽  
...  
Keyword(s):  
Liver Injury ◽  
Gut Microbiome ◽  
Ethanol Administration ◽  
Microbial Metabolite ◽  
Gut Microbes ◽  
Hepatic Expression ◽  
Small Molecule Inhibition ◽  
Liver Transcriptome ◽  
Liquid Chromatography Tandem Mass ◽  
The Impact

Background:There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. Methods: We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbedependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. Results: We show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. Conclusions: The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.

scholarly journals Impact of Dietary Resistant Starch on the Human Gut Microbiome, Metaproteome, and Metabolome

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Tanja V. Maier ◽  
Marianna Lucio ◽  
Lang Ho Lee ◽  
Nathan C. VerBerkmoes ◽  
Colin J. Brislawn ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Gut Microbiome ◽  
Resistant Starch ◽  
Metabolic Pathways ◽  
Bacterial Species ◽  
Human Microbiome ◽  
Rrna Gene ◽  
Gut Microbes ◽  
Mechanistic Understanding ◽  
The Impact

ABSTRACT Diet can influence the composition of the human microbiome, and yet relatively few dietary ingredients have been systematically investigated with respect to their impact on the functional potential of the microbiome. Dietary resistant starch (RS) has been shown to have health benefits, but we lack a mechanistic understanding of the metabolic processes that occur in the gut during digestion of RS. Here, we collected samples during a dietary crossover study with diets containing large or small amounts of RS. We determined the impact of RS on the gut microbiome and metabolic pathways in the gut, using a combination of “omics” approaches, including 16S rRNA gene sequencing, metaproteomics, and metabolomics. This multiomics approach captured changes in the abundance of specific bacterial species, proteins, and metabolites after a diet high in resistant starch (HRS), providing key insights into the influence of dietary interventions on the gut microbiome. The combined data showed that a high-RS diet caused an increase in the ratio of Firmicutes to Bacteroidetes , including increases in relative abundances of some specific members of the Firmicutes and concurrent increases in enzymatic pathways and metabolites involved in lipid metabolism in the gut. IMPORTANCE This work was undertaken to obtain a mechanistic understanding of the complex interplay between diet and the microorganisms residing in the intestine. Although it is known that gut microbes play a key role in digestion of the food that we consume, the specific contributions of different microorganisms are not well understood. In addition, the metabolic pathways and resultant products of metabolism during digestion are highly complex. To address these knowledge gaps, we used a combination of molecular approaches to determine the identities of the microorganisms in the gut during digestion of dietary starch as well as the metabolic pathways that they carry out. Together, these data provide a more complete picture of the function of the gut microbiome in digestion, including links between an RS diet and lipid metabolism and novel linkages between specific gut microbes and their metabolites and proteins produced in the gut.

scholarly journals Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome

mSystems ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Anupriya Tripathi ◽  
Alexey V. Melnik ◽  
Jin Xue ◽  
Orit Poulsen ◽  
Michael J. Meehan ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Gut Microbiome ◽  
Intermittent Hypoxia ◽  
Joint Analysis ◽  
Gut Microbes ◽  
Causal Pathways ◽  
Obstructive Sleep ◽  
Cardiometabolic Disorders ◽  
The Impact

ABSTRACTObstructive sleep apnea (OSA) is a common disorder characterized by episodic obstruction to breathing due to upper airway collapse during sleep. Because of the episodic airway obstruction, intermittently low O2(hypoxia) and high CO2(hypercapnia) ensue. OSA has been associated with adverse cardiovascular and metabolic outcomes, although data regarding potential causal pathways are still evolving. As changes in inspired O2and CO2can affect the ecology of the gut microbiota and the microbiota has been shown to contribute to various cardiometabolic disorders, we hypothesized that OSA alters the gut ecosystem, which, in turn, exacerbates the downstream physiological consequences. Here, we model human OSA and its cardiovascular consequence usingLdlr−/−mice fed a high-fat diet and exposed to intermittent hypoxia and hypercapnia (IHH). The gut microbiome and metabolome were characterized longitudinally (using 16S rRNA amplicon sequencing and untargeted liquid chromatography-tandem mass spectrometry [LC-MS/MS]) and seen to covary during IHH. Joint analysis of microbiome and metabolome data revealed marked compositional changes in both microbial (>10%, most remarkably inClostridia) and molecular (>22%) species in the gut. Moreover, molecules that altered in abundance included microbe-dependent bile acids, enterolignans, and fatty acids, highlighting the impact of IHH on host-commensal organism cometabolism in the gut. Thus, we present the first evidence that IHH perturbs the gut microbiome functionally, setting the stage for understanding its involvement in cardiometabolic disorders.IMPORTANCEIntestinal dysbiosis mediates various cardiovascular diseases comorbid with OSA. To understand the role of dysbiosis in cardiovascular and metabolic disease caused by OSA, we systematically study the effect of intermittent hypoxic/hypercapnic stress (IHH, mimicking OSA) on gut microbes in an animal model. We take advantage of a longitudinal study design and paired omics to investigate the microbial and molecular dynamics in the gut to ascertain the contribution of microbes on intestinal metabolism in IHH. We observe microbe-dependent changes in the gut metabolome that will guide future research on unrecognized mechanistic links between gut microbes and comorbidities of OSA. Additionally, we highlight novel and noninvasive biomarkers for OSA-linked cardiovascular and metabolic disorders.

scholarly journals Species Deletions from Microbiome Consortia Reveal Key Metabolic Interactions between Gut Microbes

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Natalia Gutiérrez ◽  
Daniel Garrido
Keyword(s):  
Gut Microbiome ◽  
Keystone Species ◽  
Microbial Interactions ◽  
Microbial Consortia ◽  
Microbial Composition ◽  
Bifidobacterium Adolescentis ◽  
Fermentation Products ◽  
Content Type ◽  
Gut Microbes ◽  
The Impact

ABSTRACT The gut microbiome is a complex microbial community that plays a key role in human health. Diet is an important factor dictating gut microbiome composition. This is mediated by multiple microbe-microbe interactions that result in the fermentation of nondigestible carbohydrates and the production of short-chain fatty acids. Certain species play key metabolic roles in the microbiome, and their disappearance could result in dysbiosis. In this work, a synthetic consortium of 14 gut microbes was studied during the utilization of prebiotic inulin in batch bioreactors. Fermentations were repeated leaving one species out every time, in order to evaluate the impact of their elimination on the system. Substrate consumption, microbial composition, and metabolite production were determined. Single deletions never resulted in a complete loss of bacterial growth or inulin consumption, suggesting functional redundancy. Deletions of Bacteroides dorei and Lachnoclostridium clostridioforme resulted in lower biomass and higher residual inulin. The absence of B. dorei impacted the abundance of the other 10 species negatively. Lachnoclostridium symbiosum, a butyrate producer, appeared to be the most sensitive species to deletions, being stimulated by the presence of Escherichia coli, Bifidobacterium adolescentis, B. dorei, and Lactobacillus plantarum. Conversely, bioreactors without these species did not show butyrate production. L. clostridioforme was observed to be essential for propionate production, and B. dorei for lactate production. Our analysis identified specific members that were essential for the function of the consortium. In conclusion, species deletions from microbial consortia could be a useful approach to identify relevant interactions between microorganisms and defining metabolic roles in the gut microbiome. IMPORTANCE Gut microbes associate, compete for, and specialize in specific metabolic tasks. These interactions are dictated by the cross-feeding of degradation or fermentation products. However, the individual contribution of microbes to the function of the gut microbiome is difficult to evaluate. It is essential to understand the complexity of microbial interactions and how the presence or absence of specific microorganisms affects the stability and functioning of the gut microbiome. The experimental approach of this study could be used for identifying keystone species, in addition to redundant functions and conditions that contribute to community stability. Redundancy is an important feature of the microbiome, and its reduction could be useful for the design of microbial consortia with desired metabolic properties enhancing the tasks of the keystone species.

Effect of chronic ethanol administration on hepatic eNOS activity and its association with caveolin-1 and calmodulin in female rats

2005 ◽  
Vol 289 (3) ◽  
pp. G579-G585 ◽  
Author(s):  
Xu Wang ◽  
Abdel A. Abdel-Rahman
Keyword(s):  
Nitric Oxide ◽  
Liver Injury ◽  
Female Rats ◽  
Ethanol Administration ◽  
Inhibitory Protein ◽  
Dynamic Interactions ◽  
Excessive Alcohol Consumption ◽  
Caveolin 1 ◽  
Hepatic Expression ◽  
Enos Activity

Although chronic and excessive alcohol consumption is associated with liver disease, the mechanism of alcoholic liver injury is still not clear. Whether reduced hepatic production of nitric oxide, which is evident in models of liver injury, is associated with alcohol-induced liver injury has not been investigated. We measured nitric oxide synthase (NOS) activity in the liver of pair-fed rats receiving liquid diet with or without alcohol [3% (vol/vol)] for 12 wk. Compared with control rats, hepatic NOS activity was significantly reduced in alcohol-treated rats along with the evidence of liver injury. Interestingly, there was no difference in the hepatic expression of endothelial NOS (eNOS) between ethanol-fed and pair-fed rats. We then tested the hypothesis that an imbalance between the binding of eNOS with inhibitory and stimulatory proteins may underlie the reduced activity of eNOS because eNOS catalytic activity is regulated partly through dynamic interactions with the inhibitory protein caveolin-1 and the stimulatory protein calmodulin. We found that hepatic caveolin-1 was markedly increased in alcohol-treated rats compared with control rats, whereas calmodulin remained unaltered. The binding of caveolin-1 and calmodulin with eNOS was increased and decreased, respectively, in alcohol-treated rats. Our results suggest that chronic alcohol intake attenuates hepatic eNOS activity by increasing the expression of the inhibitory protein caveolin-1 and enhancing its binding with eNOS.

scholarly journals Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeffrey Warner ◽  
Josiah Hardesty ◽  
Ying Song ◽  
Rui Sun ◽  
Zhongbin Deng ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Liver Disease ◽  
Liver Injury ◽  
Polyunsaturated Fatty Acids ◽  
Dietary Fatty Acids ◽  
Ethanol Administration ◽  
Protective Effects ◽  
Hepatic Expression ◽  
N3 Polyunsaturated Fatty Acids ◽  
Pai 1

Alcohol-associated liver disease (ALD) is the leading cause of liver disease worldwide, and alcohol-associated hepatitis (AH), a severe form of ALD, is a major contributor to the mortality and morbidity due to ALD. Many factors modulate susceptibility to ALD development and progression, including nutritional factors such as dietary fatty acids. Recent work from our group and others showed that modulation of dietary or endogenous levels of n6-and n3-polyunsaturated fatty acids (PUFAs) can exacerbate or attenuate experimental ALD, respectively. In the current study, we interrogated the effects of endogenous n3-PUFA enrichment in a mouse model which recapitulates features of early human AH using transgenic fat-1 mice which endogenously convert n6-PUFAs to n3-PUFAs. Male wild type (WT) and fat-1 littermates were provided an ethanol (EtOH, 5% v/v)-containing liquid diet for 10 days, then administered a binge of EtOH (5 g/kg) by oral gavage on the 11th day, 9 h prior to sacrifice. In WT mice, EtOH treatment resulted in liver injury as determined by significantly elevated plasma ALT levels, whereas in fat-1 mice, EtOH caused no increase in this biomarker. Compared to their pair-fed controls, a significant EtOH-mediated increase in liver neutrophil infiltration was observed also in WT, but not fat-1 mice. The hepatic expression of several cytokines and chemokines, including Pai-1, was significantly lower in fat-1 vs WT EtOH-challenged mice. Cultured bone marrow-derived macrophages isolated from fat-1 mice expressed less Pai-1 and Cxcl2 (a canonical neutrophil chemoattractant) mRNA compared to WT when stimulated with lipopolysaccharide. Further, we observed decreased pro-inflammatory M1 liver tissue-resident macrophages (Kupffer cells, KCs), as well as increased liver T regulatory cells in fat-1 vs WT EtOH-fed mice. Taken together, our data demonstrated protective effects of endogenous n3-PUFA enrichment on liver injury caused by an acute-on-chronic EtOH exposure, a paradigm which recapitulates human AH, suggesting that n3-PUFAs may be a viable nutritional adjuvant therapy for this disease.

scholarly journals Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Peter Dornbos ◽  
Amanda Jurgelewicz ◽  
Kelly A. Fader ◽  
Kurt Williams ◽  
Timothy R. Zacharewski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Cholesterol Homeostasis ◽  
Hepatic Glycogen ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Aryl Hydrocarbon ◽  
The Impact

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.

scholarly journals Comparative proteomic profiling of newly acquired, virulent and attenuated Neoparamoeba perurans proteins associated with amoebic gill disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kerrie Ní Dhufaigh ◽  
Eugene Dillon ◽  
Natasha Botwright ◽  
Anita Talbot ◽  
Ian O’Connor ◽  
...  
Keyword(s):  
Bacterial Community Composition ◽  
Illumina Miseq ◽  
Proteomic Profiling ◽  
Farmed Fish ◽  
Liquid Chromatography Tandem Mass ◽  
Proteome Database ◽  
Gill Disease ◽  
The Impact ◽  
In Vitro Maintenance

AbstractThe causative agent of amoebic gill disease, Neoparamoeba perurans is reported to lose virulence during prolonged in vitro maintenance. In this study, the impact of prolonged culture on N. perurans virulence and its proteome was investigated. Two isolates, attenuated and virulent, had their virulence assessed in an experimental trial using Atlantic salmon smolts and their bacterial community composition was evaluated by 16S rRNA Illumina MiSeq sequencing. Soluble proteins were isolated from three isolates: a newly acquired, virulent and attenuated N. perurans culture. Proteins were analysed using two-dimensional electrophoresis coupled with liquid chromatography tandem mass spectrometry (LC–MS/MS). The challenge trial using naïve smolts confirmed a loss in virulence in the attenuated N. perurans culture. A greater diversity of bacterial communities was found in the microbiome of the virulent isolate in contrast to a reduction in microbial community richness in the attenuated microbiome. A collated proteome database of N. perurans, Amoebozoa and four bacterial genera resulted in 24 proteins differentially expressed between the three cultures. The present LC–MS/MS results indicate protein synthesis, oxidative stress and immunomodulation are upregulated in a newly acquired N. perurans culture and future studies may exploit these protein identifications for therapeutic purposes in infected farmed fish.

scholarly journals Consideration of Gut Microbiome in Murine Models of Diseases

2021 ◽  
Vol 9 (5) ◽  
pp. 1062
Author(s):  
Chunye Zhang ◽  
Craig L. Franklin ◽  
Aaron C. Ericsson
Keyword(s):  
Animal Models ◽  
Mouse Models ◽  
Biomedical Research ◽  
Gut Microbiome ◽  
Close Association ◽  
Disease Model ◽  
Potential Contributor ◽  
Potential Factors ◽  
Models Of Disease ◽  
The Impact

The gut microbiome (GM), a complex community of bacteria, viruses, protozoa, and fungi located in the gut of humans and animals, plays significant roles in host health and disease. Animal models are widely used to investigate human diseases in biomedical research and the GM within animal models can change due to the impact of many factors, such as the vendor, husbandry, and environment. Notably, variations in GM can contribute to differences in disease model phenotypes, which can result in poor reproducibility in biomedical research. Variation in the gut microbiome can also impact the translatability of animal models. For example, standard lab mice have different pathogen exposure experiences when compared to wild or pet store mice. As humans have antigen experiences that are more similar to the latter, the use of lab mice with more simplified microbiomes may not yield optimally translatable data. Additionally, the literature describes many methods to manipulate the GM and differences between these methods can also result in differing interpretations of outcomes measures. In this review, we focus on the GM as a potential contributor to the poor reproducibility and translatability of mouse models of disease. First, we summarize the important role of GM in host disease and health through different gut–organ axes and the close association between GM and disease susceptibility through colonization resistance, immune response, and metabolic pathways. Then, we focus on the variation in the microbiome in mouse models of disease and address how this variation can potentially impact disease phenotypes and subsequently influence research reproducibility and translatability. We also discuss the variations between genetic substrains as potential factors that cause poor reproducibility via their effects on the microbiome. In addition, we discuss the utility of complex microbiomes in prospective studies and how manipulation of the GM through differing transfer methods can impact model phenotypes. Lastly, we emphasize the need to explore appropriate methods of GM characterization and manipulation.

scholarly journals A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Christophe Lay ◽  
Collins Wenhan Chu ◽  
Rikky Wenang Purbojati ◽  
Enzo Acerbi ◽  
Daniela I. Drautz-Moses ◽  
...  
Keyword(s):  
Risk Factor ◽  
Gut Microbiome ◽  
Reference Group ◽  
Mode Of Delivery ◽  
Controlled Study ◽  
Double Blind ◽  
Lipopolysaccharide Biosynthesis ◽  
Infant Gut Microbiome ◽  
Stool Samples ◽  
The Impact

Abstract Background The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). In a double-blind randomized controlled study, 153 infants born by elective C-section received an infant formula supplemented with either synbiotic, prebiotics, or unsupplemented from birth until 4 months old. Vaginally born infants were included as a reference group. Stool samples were collected from day 3 till week 22. Multi-omics were deployed to investigate the impact of mode of delivery and nutrition on the development of the infant gut microbiome, and uncover putative biological mechanisms underlying the role of a compromised microbiome as a risk factor for NCD. Results As early as day 3, infants born vaginally presented a hypoxic and acidic gut environment characterized by an enrichment of strict anaerobes (Bifidobacteriaceae). Infants born by C-section presented the hallmark of a compromised microbiome driven by an enrichment of Enterobacteriaceae. This was associated with meta-omics signatures characteristic of a microbiome adapted to a more oxygen-rich gut environment, enriched with genes associated with reactive oxygen species metabolism and lipopolysaccharide biosynthesis, and depleted in genes involved in the metabolism of milk carbohydrates. The synbiotic formula modulated expression of microbial genes involved in (oligo)saccharide metabolism, which emulates the eco-physiological gut environment observed in vaginally born infants. The resulting hypoxic and acidic milieu prevented the establishment of a compromised microbiome. Conclusions This study deciphers the putative functional hallmarks of a compromised microbiome acquired during C-section birth, and the impact of nutrition that may counteract disturbed microbiome development. Trial registration The study was registered in the Dutch Trial Register (Number: 2838) on 4th April 2011.

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