Author response: Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice
Year: 2022
Type: peer-review
Abstract: Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Methods Data availability References Author response Article and author information Metrics Abstract There is mounting evidence that microbes residing 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. 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 microbe-dependent 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. We show the gut microbial choline metabolite 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. 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. Editor's evaluation This paper aims to understand the mechanisms by which gut microbes synergize with excessive alcohol intake to cause liver injury, and whether drugs that selectively target gut microbial metabolism can improve alcohol-associated liver disease (ALD). The authors used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in controls and patients with alcohol-associated hepatitis (AH). They also treated mice with bacterial choline trimethylamine (TMA) lyase inhibitors to reduce gut microbe-dependent TMA production, followed by measurement of Indices of liver injury. They showed that gut microbial choline metabolite TMA is increased in AH patients, which correlates with reduced liver expression of the TMA oxygenase Flavin-containing monooxygenase 3 (FMO3). They also show that inhibition of gut microbial CutC/D activity protects from ethanol-induced liver injury in mouse models, which was associated with reorganization of the gut microbiome and host liver transcriptome. The authors conclude that microbial TMA is elevated in patients with AH, and inhibition of TMA production by gut microbes protects against ethanol-induced liver injury. https://doi.org/10.7554/eLife.76554.sa0 eLife's review process Introduction Alcohol-associated liver disease (ALD) includes a spectrum of liver pathologies including steatosis, fibrosis, cirrhosis, and the most severe manifestation known as alcohol-associated hepatitis (AH). Shortly after diagnosis AH patients die at a staggering rate of 40–50% (Masarone et al., 2016; Kochanek et al., 2017). Despite many attempts, an effective therapy for this deadly disease has been elusive. Similar to other components of the spectrum of ALD, AH has consistently been linked to reorganization of the gut microbiome and dysregulation of microbe-host interactions (Chen et al., 2011; Yan et al., 2011; Mutlu et al., 2009; Mutlu et al., 2012; Tripathi et al., 2018; Ciocan et al., 2018; Llopis et al., 2016; Duan et al., 2019; Smirnova et al., 2020; Gao et al., 2019; Puri et al., 2018; Lang and Schnabl, 2020). It is well appreciated that chronic alcohol use can elicit structural alterations in the gut barrier, allowing either live bacteria themselves or microbe-associated molecule patterns (MAMPs), such as lipopolysaccharide (LPS), to enter the portal circulation where they can directly engage pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or NOD-like receptors (NLRP3, NLRP6, etc.) to promote hepatic inflammation and tissue injury (Wilkinson et al., 1974; Tarao et al., 1979; Uesugi et al., 2001; Paik et al., 2003; DeSantis et al., 2013; Knorr et al., 2020). In addition to MAMP-PRR interactions, gut microbes can act as a collective endocrine organ, producing a vast array of small molecules, proteins, and lipid metabolites that can engage dedicated host receptor systems to also impact liver disease progression (Brown and Hazen, 2015). Collectively, these MAMP-PRR and microbial metabolite-host receptor interactions converge to promote ALD and many other diseases of uncontrolled inflammation (Brown and Hazen, 2015; Gilbert et al., 2018). Although there is now clear evidence that microbe-host interactions play a key role in liver disease progression (Chen et al., 2011; Yan et al., 2011; Mutlu et al., 2009; Mutlu et al., 2012; Tripathi et al., 2018; Ciocan et al., 2018; Llopis et al., 2016; Duan et al., 2019; Smirnova et al., 2020; Gao et al., 2019; Puri et al., 2018; Lang and Schnabl, 2020; Wilkinson et al., 1974; Tarao et al., 1979; Uesugi et al., 2001; Paik et al., 2003; DeSantis et al., 2013; Knorr et al., 2020; Brown and Hazen, 2015; Gilbert et al., 2018), ALD drug discovery to this point has focused primarily on targets encoded by the human genome. Our knowledge is rapidly expanding as to how microbes intersect with ALD progression, including cataloging microbial genomes. We also now understand the repertoire of MAMPs gut microbes harbor as well as the vast array of metabolites that they produce in both patients with ALD and animal models of ethanol-induced liver injury (Chen et al., 2011; Yan et al., 2011; Mutlu et al., 2009; Mutlu et al., 2012; Tripathi et al., 2018; Ciocan et al., 2018; Llopis et al., 2016; Duan et al., 2019; Smirnova et al., 2020; Gao et al., 2019; Puri et al., 2018; Lang and Schnabl, 2020; Wilkinson et al., 1974; Tarao et al., 1979; Uesugi et al., 2001; Paik et al., 2003; DeSantis et al., 2013; Knorr et al., 2020; Brown and Hazen, 2015; Gilbert et al., 2018). However, there are very few examples of where this information has been leveraged into safe and effective therapeutic strategies. In general, the microbiome-targeted therapeutic field has primarily focused on either anti-, pre-, or pro-biotic approaches, yet these microbial community-restructuring approaches have resulted in very modest or non-significant effects in clinical studies of liver disease (Kwak et al., 2014; Asgharian et al., 2020; Reijnders et al., 2016; Madjd et al., 2016). As an alternative microbiome-targeted approach, we and others have begun developing non-lethal selective small molecule inhibitors of bacterial enzymes with the intention of reducing levels of disease-associated microbial metabolites with mechanistic rationale for contribution to disease pathogenesis (Roberts et al., 2018; Wang et al., 2015; Gupta et al., 2020; Organ et al., 2020; Orman et al., 2019). In fact, we have recently shown that small molecule inhibition of the gut microbial transformation of choline into trimethylamine (TMA), the initial and rate-limiting step in the generation of the cardiovascular disease (CVD)-associated metabolite trimethylamine N-oxide (TMAO), can significantly reduce disease burden in animal models of atherosclerosis, thrombosis, heart failure, and chronic kidney disease (Roberts et al., 2018; Wang et al., 2015; Gupta et al., 2020; Organ et al., 2020). Although the gut microbial TMAO pathway has been studied mostly in the context of CVD (Wang et al., 2011; Koeth et al., 2013; Zhu et al., 2016; Zhu et al., 2017; Tang et al., 2013; Wang et al., 2014b; Trøseid et al., 2015; Tang and Hazen, 2014), recent studies found that breath levels of the primary metabolite TMA and other related co-metabolites are elevated in patients with ALD (Hanouneh et al., 2014; Ascha et al., 2016). These data showed promise, but whether the gut microbial TMAO pathway is causally related to ALD has never been explored. Hence, here we set out to understand how the gut microbial TMA/TMAO pathway may play a contributory role in ALD susceptibility and progression, and to test whether selective drugs that lower gut microbial production of TMA can be an effective therapeutic strategy. In an era when host genetics/genomics approaches dominate, this work reminds us that genes and metabolic products produced by gut bacteria play equally important roles in modulating disease susceptibility. Whereas pathways encoded by the host genome have long been pursued as drug targets, this work provides proof of concept that rationally designed drugs that target bacterial metabolism likely have untapped therapeutic potential in ALD and beyond. Results Circulating levels of the gut microbial metabolite TMA are elevated in AH In a previous collaborative study, we reported that the highly volatile microbial metabolite TMA is elevated in exhaled breath of patients with AH (Hanouneh et al., 2014), and related co-metabolites, such as trimethyllysine and carnitine, can serve as prognostic indicators of mortality in AH (Ascha et al., 2016). Given the extremely volatile nature of TMA, it is readily detectable in breath, but is challenging to accurately quantitate levels in the circulation because TMA rapidly dissipates during collection and storage. To reduce the volatility of TMA and enable its analysis in the circulation, we coordinated patient blood collection utilizing rapid acidification of separated plasma (protonated TMA has a lower vapor pressure) across a large multi-center AH consortium (Defeat Alcoholic Steatohepatitis [DASH] consortium) (Crabb et al., 2016; Vatsalya et al., 2020; Saha et al., 2019). This provided us the unique opportunity to accurately quantify circulating TMA levels in human subjects, including those with moderate or severe AH for the first time. Patient demographics and clinical characteristics for the cohort examined are summarized in Figure 1—source data 1; Figure 1—source data 2. Importantly, MELD score, Maddrey’s discriminant function score, Child-Pugh score, aspartate aminotransferase (AST), total bilirubin, creatinine, and international normalized ratio were higher in patients with severe AH compared to moderate AH patients, while serum albumin was lower in severe AH compared to moderate AH patients. In agreement with previous breath metabolomics studies (Hanouneh et al., 2014; Ascha et al., 2016), plasma TMA levels were significantly elevated in moderate and severe AH patients compared to healthy controls (Figure 1A). However, the CVD-related co-metabolite TMAO was reciprocally decreased in AH patients (Figure 1B). Given the reciprocal alterations in plasma TMA and TMAO levels, we next examined the expression of the host liver enzyme flavin-containing monooxygenase 3 (FMO3) which is the predominant TMA to TMAO converting enzyme in the adult liver (Cashman, 2002). Interestingly, mRNA levels for FMO3 are uniquely repressed in patients with more severe AH (AH with liver failure [MELD 22–28] and AH with emergency liver transplant [MELD 18–21]), but not in other liver disease etiologies such as non-alcoholic fatty liver disease (NAFLD) or viral hepatitis (Figure 1C). In agreement with reduced mRNA levels (Figure 1C), patients with severe AH undergoing emergency liver transplant have marked reduction in FMO3 protein (Figure 1D), which likely contributes to elevations in plasma TMA (Figure 1A). Although ethanol feeding in mice does not consistently result in reduced hepatic Fmo3 expression (data not shown), a single injection of lipopolysaccharide (LPS) to induce acute hepatic inflammation is associated with both a reduction in the expression of Fmo3 and a significant increase in the TMA receptor trace amine-associated receptor 5 (Taar5) (Figure 1E). It is important to note that circulating choline levels was not significantly altered in patients with AH compared to healthy controls (Figure 1—figure supplement 1). However, plasma levels of one of the gut microbial substrates for TMA production (carnitine) and other TMA pathway co-metabolites (e.g. betaine and γ-butyrobetaine) were elevated in patients with AH compared to healthy controls (Figure 1—figure supplement 1). These findings, in addition to previous breath metabolomic studies (Hanouneh et al., 2014; Ascha et al., 2016), provide evidence that TMA and related co-metabolites may allow for discrimination of AH from other liver diseases. Figure 1 with 1 supplement see all Download asset Open asset The gut microbial volatile metabolite trimethylamine (TMA) is elevated in alcohol-associated hepatitis (AH). Plasma TMA (A) and trimethylamine N-oxide (TMAO) (B) levels in patients considered healthy (n = 13 for TMA and 20 for TMAO), or who have moderate (MELD < 20) (n = 52 for TMA and 111 for TMAO) or severe (MELD > 20) (n = 83 for TMA and 152 for TMAO) AH. (C) RNA sequencing results from liver tissues of patients with different pathologies, including: healthy controls (HC, n = 10), early AH (EAH, n = 12; MELD 7–8), AH with liver failure (AHL, n = 18; MELD 22–28), explant tissue from patients with severe AH with emergency liver transplants (ExAH, n = 10; MELD 18–21), non-alcohol-associated fatty liver disease (NAFLD; n = 8), hepatitis C virus (HCV; n = 9), and hepatitis C virus with cirrhosis (HCV_Cirr, n = 9). Gene expression was measured by transcripts per million (TPM). Boxplots of average expression for Fmo3 in different disease groups; error bars indicate SD (q < 0.05 in comparison to healthy controls). (D) Liver FMO3 protein expression measured by Western blot from healthy patients and patients with severe AH undergoing emergency liver transplant (Maddrey’s discriminant function 45–187). (E) Liver Tnfa, Il1b, Fmo3, and Taar5 transcript levels were measured by qPCR from female WT mice injected with either saline or lipopolysaccharide (LPS) for 6 hr. N = 6; unpaired Student’s t-test. *p ≤ 0.05; ***p ≤ 0.001. Figure 1—source data 1 Demographic and clinical parameters for entire cohort of healthy controls and patients with AH. https://cdn.elifesciences.org/articles/76554/elife-76554-fig1-data1-v3.docx Download elife-76554-fig1-data1-v3.docx Figure 1—source data 2 Demographic and clinical parameters for subset of healthy controls and patients with AH included in TMA assay. https://cdn.elifesciences.org/articles/76554/elife-76554-fig1-data2-v3.docx Download elife-76554-fig1-data2-v3.docx Figure 1—source data 3 Liver flavin-containing monooxygenase 3 (FMO3) protein expression measured by Western blot from healthy patients (HC) and patients with severe alcohol-associated hepatitis (AH) undergoing emergency liver transplant (Maddrey’s discriminant function 45–187). These data are showing the entire blot. https://cdn.elifesciences.org/articles/76554/elife-76554-fig1-data3-v3.zip Download elife-76554-fig1-data3-v3.zip Figure 1—source data 4 Liver flavin-containing monooxygenase 3 (FMO3) protein expression measured by Western blot from healthy patients (HC) and patients with severe alcohol-associated hepatitis (AH) undergoing emergency liver transplant (Maddrey’s discriminant function 45–187). These data are showing the cropped version of the blot. https://cdn.elifesciences.org/articles/76554/elife-76554-fig1-data4-v3.zip Download elife-76554-fig1-data4-v3.zip Figure 1—source data 5 Liver HSC70 protein expression measured by Western blot from healthy patients (HC) and patients with severe alcohol-associated hepatitis (AH) undergoing emergency liver transplant (Maddrey’s discriminant function 45–187). These data are showing the entire blot. https://cdn.elifesciences.org/articles/76554/elife-76554-fig1-data5-v3.zip Download elife-76554-fig1-data5-v3.zip Figure 1—source data 6 Liver HSC70 protein expression measured by Western Blot from healthy patients (HC) and patients with severe alcohol-associated hepatitis (AH) undergoing emergency liver transplant (Maddrey’s discriminant function 45–187). These data are showing the cropped version of the blot. https://cdn.elifesciences.org/articles/76554/elife-76554-fig1-data6-v3.zip Download elife-76554-fig1-data6-v3.zip Microbial choline TMA lyase inhibition protects mice from ethanol-induced liver injury We next sought to establish whether a causal relationship between gut microbial TMA production and ALD progression exists, and to test the hypothesis that selectively drugging microbial choline transformation can serve as a mechanism for improving host liver disease and attenuating ethanol-induced liver injury in mice. Mice were individually treated with two recently reported non-lethal bacterial choline TMA lyase inhibitors, iodomethylcholine (IMC) and fluoromethylcholine (FMC) (Roberts et al., 2018). These small molecule inhibitors exhibit potent in vivo inhibition of the gut microbial choline TMA lyase enzyme CutC (Craciun and Balskus, 2012), and have been shown to effectively block bacterial choline to TMA conversion in vivo (Roberts et al., 2018). Designed as suicide substrate mechanism-based inhibitors, past studies reveal that the vast majority of IMC and FMC is retained in the gut within luminal bacteria and excreted in the feces with limited systemic exposure of the polar drug in the host (Roberts et al., 2018; Gupta et al., 2020; Organ et al., 2020). IMC treatment effectively blunted ethanol-induced increases in plasma TMA and TMAO (Figure 2A and B). IMC also produced modest increases in plasma choline and betaine, while reducing plasma carnitine, particularly in pair-fed mice (Figure 2C–E). IMC also prevented ethanol-induced increases in alanine aminotransferase (ALT) and hepatic steatosis (Figure 2F, G, and K). Interestingly, IMC treatment prevented ethanol-induced increases in hepatic triglycerides (Figure 2G), and reduced hepatic total and cholesterol esters, but not free cholesterol, in both pair- and ethanol-fed conditions (Figure 2H–I). IMC treatment also reduced the expression levels of the pro-inflammatory cytokine tumor necrosis factor α (Tnfα) (Figure 2L). Although IMC was well tolerated in several previous mouse studies in the setting of standard rodent chow-feeding (Roberts et al., 2018; Gupta et al., 2020; Organ et al., 2020), here we found an unexpected reduction in food intake and body weights in mice receiving both IMC and ethanol (Figure 2—figure supplement 1A, B). Although IMC was clearly protective against ethanol-induced liver injury, this potential drug-ethanol interaction prompted us to test another structurally distinct gut microbe-targeted choline TMA lyase inhibitor FMC (Roberts et al., 2018; Figure 3 and Figure 3—figure supplement 1). Figure 2 with 1 supplement see all Download asset Open asset Small molecule choline trimethylamine (TMA) lyase inhibition with iodomethylcholine (IMC) protects mice against ethanol-induced liver injury. Nine- to eleven-week-old female C57BL6/J mice were fed either ethanol-fed or pair-fed in the presence and absence of IMC as described in the methods. Plasma levels of TMA (A), trimethylamine N-oxide (TMAO) (B), choline (C), carnitine (D), and betaine (E) were measured by mass spectrometry (n = 4–5). Plasma alanine aminotransferase (ALT) (F) was measured enzymatically (n = 4–5). Liver triglycerides (G), total cholesterol (H), cholesterol esters (I), and free cholesterol (J) were measured enzymatically (n = 4–5). (K) Representative H&E staining of livers from pair and EtOH-fed mice in the presence and absence of IMC. (L) Hepatic messenger RNA levels of tumor necrosis factor alpha (Tnfα). Statistics were completed by a two-way analysis of variance (ANOVA) followed by a Tukey’s multiple comparison test. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001. All data are presented as mean ± SEM, unless otherwise noted. Figure 3 with 2 supplements see all Download asset Open asset Small molecule choline trimethylamine (TMA) lyase inhibition with fluoromethylcholine (FMC) protects mice against ethanol-induced liver injury. Nine- to eleven-week-old female C57BL6/J mice were fed either ethanol-fed or pair-fed in the presence and absence of FMC as described in the methods. Plasma levels of TMA (A), trimethylamine N-oxide (TMAO) (B), choline (C), carnitine (D), and betaine (E) were measured by mass spectrometry (n = 3–5). Plasma alanine aminotransferase (ALT) (F) were measured at necropsy (n = 4–5). Liver triglycerides (G), total cholesterol (H), cholesterol esters (I), and free cholesterol (J) were measured enzymatically (n = 4–5). (K) Representative H&E staining of livers from pair and EtOH-fed mice in the presence and absence of FMC. (L) Hepatic messenger RNA levels of tumor necrosis factor alpha (Tnfα). Statistics were completed by a two-way analysis of variance (ANOVA) followed by a Tukey’s multiple comparison test. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001. All data are presented as mean ± SEM, unless otherwise noted. Importantly, FMC was well tolerated and did not significantly alter liquid diet intake or body weights throughout the 25-day chronic ethanol feeding study (Figure 2—figure supplement 1C, D). FMC treatment trended toward reducing plasma TMA (Figure 3A), and more dramatically suppressed plasma TMAO levels (Figure 3B). Unlike IMC, which also altered other co-metabolites such as choline, betaine, and carnitine (Figure 2B-E), FMC did not significantly alter these TMA co-metabolites (Figure 3C-E). More importantly, as with IMC (Figure 2F–K), FMC treatment significantly protected against ethanol-induced ALT elevations (Figure 3F), hepatic steatosis (Figure 3G and K), and reduced total and esterified cholesterol levels without altering free cholesterol (Figure 3H–J). However, FMC trended to reduce but did not significantly alter Tnfα expression (Figure 3L). To determine whether these effects were generalizable in other models of ethanol-induced liver injury, we exposed control and FMC-treated mice to a 10-day chronic model in which mice were allowed free access to a 5% vol/vol (27% kcal) for 10 days (Figure 3—figure supplement 1). In this 5%–10-day ethanol feeding model FMC treatment did not significantly alter food intake, body weight, or blood ethanol levels, but was able to selectively suppress TMA and TMAO levels (Figure 3—figure supplement 1). FMC treatment in the 5%–10-day model significantly reduced plasma AST and ALT levels, and trended toward lowering liver triglycerides (Figure 3—figure supplement 1). However, in this short-term model there were no apparent differences in hepatic cytokine/chemokine gene expression with either ethanol exposure or FMC treatment (Figure 3—figure supplement 1 and data not shown). Collectively, these data demonstrate that gut microbe-targeted choline TMA lyase inhibition with two structurally distinct inhibitors (IMC or FMC) can generally protect mice against ethanol-induced liver injury. Microbial choline TMA lyase inhibitors promote remodeling of the gut microbiome and host liver transcriptome in an ethanol-dependent manner One theoretical advantage of the selective microbe-targeted choline TMA lyase inhibitors, compared to antibiotic or MAMP-PRR-targeted therapies, is that they are anticipated to exert less selective pressure for development of drug resistance given their non-lethal nature. However, microbes that preferentially utilize choline as a carbon or nitrogen source might be anticipated to have reduced competitive advantage in the presence of the inhibitor. We therefore next examined whether IMC or FMC treatment was associated with alterations in choline utilizers and other members of the murine gut microbiome community that are known to be correlated with ethanol-induced liver injury (Chen et al., 2011; Yan et al., 2011; Mutlu et al., 2009; Mutlu et al., 2012; Tripathi et al., 2018; Ciocan et al., 2018; Llopis et al., 2016; Duan et al., 2019; Smirnova et al., 2020; Gao et al., 2019; Puri et al., 2018; Lang and Schnabl, 2020). It is important to note that both IMC (Figure and FMC (Figure altered the gut with yet several distinct of microbial distinct that both IMC and FMC clear of the microbiome in an ethanol-dependent manner (Figure and both IMC and FMC a reciprocal in the of and increase in (Figure and However, ethanol-fed conditions IMC resulted in increased and reduced and FMC treatment resulted in more modest in and increased (Figure and alterations at the we found that both pair- and ethanol-fed IMC treatment significant increases in and and in (Figure and most significantly altered and and it is important to note that these alterations were different between pair- and ethanol-fed (Figure and Collectively, these data demonstrate that inhibition of gut microbial choline to TMA transformation with a selective non-lethal small molecule inhibitor of the gut microbiome in an ethanol-dependent Figure 4 Download asset Open asset Small molecule choline trimethylamine (TMA) lyase inhibition remodeling of the gut microbiome in an ethanol-dependent Nine- to eleven-week-old female C57BL6/J mice were fed either ethanol-fed or pair-fed in the presence and absence of iodomethylcholine (IMC) or fluoromethylcholine (FMC) as described in the methods. (A) on the between the pair IMC, and IMC analysis was with analysis of variance and are in are for with significant and for variance by the of (B) Boxplots of patterns for and pair IMC and IMC analysis was with test the are in are and in are (C) of of the 20 across all pair IMC, and IMC between (D) pair-fed and pair-fed IMC and (E) EtOH-fed and EtOH-fed IMC analysis was with are in (F) on the between the pair and FMC analysis was with analysis of variance and are in are for with significant and for variance by the of Boxplots of patterns for and pair and FMC analysis was with test the are in are and in are of of the 20 across all pair and FMC between pair-fed and pair-fed and (J) EtOH-fed and EtOH-fed FMC analysis was with are in To more understand the effects of choline TMA lyase inhibitors on the host we RNA sequencing in mice undergoing pair or ethanol feeding treated either with or without IMC (Figure and analysis showed clear between all (Figure and B). In pair-fed IMC treatment significant in several genes and and enzymes while other genes in metabolism and (Figure IMC treatment most significantly altered genes in metabolism and RNA and and and (Figure and These data demonstrate that gut microbe-targeted choline TMA lyase inhibitors can alter the host liver transcriptome in an ethanol
Source: eLife
Authors: Robert N Helsley, Tatsunori Miyata, Anagha Kadam, Venkateshwari Varadharajan, Naseer Sangwan, Emily C Huang, Rakhee Banerjee, Amanda L Brown, Kevin K Fung, William J Massey, Chase Neumann, Danny Orabi, Lucas J Osborn, Rebecca C Schugar, Megan R McMullen, Annette Bellar, Kyle L Poulsen, Adam Kim, Vai Pathak, Marko Mrdjen, James T Anderson, Belinda Willard, Craig J McClain, Mack Mitchell, Arthur J McCullough, Svetlana Radaeva, Bruce Barton, Gyongyi Szabo, Srinivasan Dasarathy, Jose Carlos Garcia-Garcia, Daniel M Rotroff, Daniela S Allende, Zeneng Wang, Stanley L Hazen, Laura E Nagy, Jonathan Mark Brown
Institutions: University of Kentucky HealthCare, Cleveland Clinic, University of Kentucky, Cleveland Clinic Research, University of Louisville, The University of Texas Southwestern Medical Center, National Institute on Alcohol Abuse and Alcoholism, University of Massachusetts Chan Medical School, Beth Israel Deaconess Medical Center, Harvard University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W4212849811