Chronobiology of Cancers in the Liver and Gut.

Circadian rhythms dictate the timing of cellular and organismal physiology to maintain homeostasis. Within the liver and gut, circadian rhythms influence lipid and glucose homeostasis, xenobiotic metabolism, and nutrient absorption. Disruption of this orchestrated timing is known to negatively impact human health and contribute to disease progression, including carcinogenesis. Dysfunctional core clock timing has been identified in malignant growths and may be used as a molecular signature of disease progression. Likewise, the circadian clock and its downstream effectors also represent potential for novel therapeutic targets. Here, the role of circadian rhythms in the pathogenesis of cancers of the liver and gut will be reviewed, and chronotherapy and chronopharmacology will be explored as potential treatment options.

Pathophysiological Relationship between Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Therapeutic Approaches.

Type 2 diabetes mellitus (T2DM), often featuring hyperglycemia or insulin resistance, is a global health concern that is increasing in prevalence in the United States and worldwide. A common complication is metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome that is also rapidly increasing in prevalence. The majority of patients with T2DM will experience MASLD, and likewise, individuals with MASLD are at an increased risk for developing T2DM. These two disorders may act synergistically, in part due to increased lipotoxicity and inflammation within the liver, among other causes. However, the pathophysiological mechanisms by which this occurs are unclear, as is how the improvement of one disorder can ameliorate the other. This review aims to discuss the pathogenic interactions between T2D and MASLD, and will highlight novel therapeutic targets and ongoing clinical trials for the treatment of these diseases.

Antimicrobial effects of cannabidiol on select agriculturally important Clostridia.

Amino acid-fermenting Clostridia have undesirable effects in agricultural systems, which can be mitigated by antibiotics, but resistance necessitates alternatives. Here, we demonstrate the efficacy of cannabidiol on growth and ammonia inhibition of five agriculturally relevant Clostridia: Clostridium sporogenes, Peptostreptococcus spp., Clostridioides difficile, Acetoanaerobium sticklandii, and Clostridium aminophilum.

Fibroblast Growth Factor 19 Alters Bile Acids to Induce Dysbiosis in Mice With Alcohol-Induced Liver Disease.

BACKGROUND & AIMS: Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding. METHODS: After injection of adeno-associated virus-green fluorescent protein or AAV-FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge. RESULTS: Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfß, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens. CONCLUSIONS: Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.

Impact of nicotine and cotinine on macrophage inflammatory plasticity via vesicular modifications in gastrointestinal bacteria.

OBJECTIVES: This study aimed to elucidate mechanistic explanation(s) for compositional changes to enteric microbiota by determining the impacts of continuous nicotine/cotinine exposure on representative gastrointestinal bacteria and how these alterations impact innate immune cell plasticity. METHODS: In vitro cultures of the gastrointestinal bacteria (Bacteroides fragilis 25285, Prevotella bryantii B14, and Acetoanaerobium sticklandii SR) were continuously exposed to nicotine or cotinine. Supernatant samples were collected for fermentation acid analysis. Vesicles were collected and analyzed for physiological changes in number, size, and total protein cargo. Cultured macrophages were stimulated to a tolerogenic phenotype, exposed to control or altered (nicotine or cotinine - exposed) vesicles, and inflammatory plasticity assessed via inflammatory cytokine production. RESULTS: Nicotine/cotinine exposure differentially affected metabolism of all bacteria tested in a Gram (nicotine) and concentration-dependent (cotinine) manner. Physiological studies demonstrated changes in vesiculation number and protein cargo following nicotine/cotinine exposures. Continuous exposure to 1 µM nicotine and 10 µM cotinine concentrations reduced total protein cargo of Gram (-) - 25285 and B14 vesicles, while cotinine generally increased total protein in Gram (+) - SR vesicles. We found that theses physiological changes to the vesicles of 25285 and SR formed under nicotine and cotinine, respectively, challenged the plasticity of tolerogenic macrophages. Tolerogenic macrophages exposed to vesicles from 1 µM nicotine, and 5 or 10 µΜ cotinine cultures produced significantly less IL-12p70, TNFα, or KC/GRO, regardless of macrophage exposure to nicotine/cotinine. CONCLUSIONS: Nicotine/cotinine exposure differentially alters bacterial metabolism and vesicle physiology, ultimately impacting the inflammatory response of tolerogenic macrophages.

Apolipoprotein E genotype affects innate susceptibility to Listeria monocytogenes infection in aged male mice.

Apolipoprotein E (ApoE) is a lipid transport protein that is hypothesized to suppress proinflammatory cytokine production, particularly after stimulation with Toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). Studies using transgenic ApoE human replacement mice (APOE) expressing one of three different allelic variants suggest that there is a hierarchy in terms of responsiveness to proinflammatory stimuli such as APOE4/E4 > APOE3/E3 > APOE2/E2. In this study, we test the hypothesis that APOE genotype can also predict susceptibility to infection with the facultative intracellular gram-positive bacterium Listeria monocytogenes. We found that bone-marrow-derived macrophages isolated from aged APOE4/E4 mice expressed elevated levels of nitric oxide synthase 2 and were highly resistant to in vitro infection with L. monocytogenes compared to APOE3/E3 and APOE2/E2 mice. However, we did not find statistically significant differences in cytokine or chemokine output from either macrophages or whole splenocytes isolated from APOE2/E2, APOE3/E3, or APOE4/E4 mice following L. monocytogenes infection. In vivo, overall susceptibility to foodborne listeriosis also did not differ by APOE genotype in either young (2 mo old) or aged (15 mo old) C57BL/6 mice. However, we observed a sex-dependent susceptibility to infection in aged APOE2/E2 male mice and a sex-dependent resistance to infection in aged APOE4/E4 male mice that was not present in female mice. Thus, these results suggest that APOE genotype does not play an important role in innate resistance to infection with L. monocytogenes but may be linked to sex-dependent changes that occur during immune senescence.

Tgr5-/- mice are protected from ethanol-induced metabolic alterations through enhanced leptin and Fgf21 signaling.

BACKGROUND: Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury. METHODS: Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways. RESULTS: Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet. CONCLUSIONS: Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.

Deletion of Smooth Muscle O-GlcNAc Transferase Prevents Development of Atherosclerosis in Western Diet-Fed Hyperglycemic ApoE-/- Mice In Vivo.

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of O-GlcNAc signaling, in the evolution of diabetic atherosclerosis remains elusive. The goal of this study was to determine whether smooth muscle OGT (smOGT) plays a direct role in hyperglycemia-induced atherosclerotic lesion formation and SMC de-differentiation. Using tamoxifen-inducible Myh11-CreERT2 and Ogtfl/fl mice, we generated smOGTWT and smOGTKO mice, with and without ApoE-null backgrounds. Following STZ-induced hyperglycemia, smOGTWT and smOGTKO mice were kept on a standard laboratory diet for the study duration. In a parallel study, smOGTWTApoE-/- and smOGTKOApoE-/- were initiated on Western diet at 8-wks-age. Animals harvested at 14-16-wks-age were used for plasma and tissue collection. Loss of smOGT augmented SM contractile marker expression in aortic vessels of STZ-induced hyperglycemic smOGTKO mice. Consistently, smOGT deletion attenuated atherosclerotic lesion lipid burden (Oil red O), plaque area (H&E), leukocyte (CD45) and smooth muscle cell (ACTA2) abundance in Western diet-fed hyperglycemic smOGTKOApoE-/- mice. This was accompanied by increased SM contractile markers and reduced inflammatory and proliferative marker expression. Further, smOGT deletion attenuated YY1 and SRF expression (transcriptional regulators of SM contractile genes) in hyperglycemic smOGTKOApoE-/- and smOGTKO mice. These data uncover an athero-protective outcome of smOGT loss-of-function and suggest a direct regulatory role of OGT-mediated O-GlcNAcylation in VSMC de-differentiation in hyperglycemia.

Egress of Listeria monocytogenes from Mesenteric Lymph Nodes Depends on Intracellular Replication and Cell-to-Cell Spread.

The mesenteric lymph nodes (MLN) function as a barrier to systemic spread for both commensal and pathogenic bacteria in the gut. Listeria monocytogenes, a facultative intracellular foodborne pathogen, readily overcomes this barrier and spreads into the bloodstream, causing life-threatening systemic infections. We show here that intracellular replication protected L. monocytogenes from clearance by monocytes and neutrophils and promoted colonization of the small intestine-draining MLN (sMLN) but was not required for dissemination to the colon-draining MLN (cMLN). Intestinal tissue had enough free lipoate to support LplA2-dependent extracellular growth of L. monocytogenes, but exogenous lipoate in the MLN was severely limited, and so the bacteria could replicate only inside cells, where they used LplA1 to scavenge lipoate from host peptides. When foodborne infection was manipulated to allow ΔlplA1 L. monocytogenes to colonize the MLN to the same extent as wild-type bacteria, the mutant was still never recovered in the spleen or liver of any animal. We found that intracellular replication in the MLN promoted actin-based motility and cell-to-cell spread of L. monocytogenes and that rapid efficient exit from the MLN was actA dependent. We conclude that intracellular replication of L. monocytogenes in intestinal tissues is not essential and serves primarily to amplify bacterial burdens above a critical threshold needed to efficiently colonize the cMLN. In contrast, intracellular replication in the MLN is absolutely required for further systemic spread and serves primarily to promote ActA-mediated cell-to-cell spread.

Red clover supplementation modifies rumen fermentation and promotes feed efficiency in ram lambs.

Red clover produces isoflavones, including biochanin A, which have been shown to have microbiological effects on the rumen while also promoting growth in beef cattle. The objective was to determine if supplementation of biochanin A via red clover hay would produce similar effects on the rumen microbiota and improve growth performance of lambs. Twenty-four individually-housed Polypay ram lambs (initial age: 114 ± 1 d; initial weight: 38.1 ± 0.59 kg) were randomly assigned to one of three experimental diets (85:15 concentrate:roughage ratio; N = 8 rams/treatment): CON-control diet in which the roughage component (15.0%, w/w, of the total diet) consisted of orchardgrass hay; 7.5-RC-red clover hay substituted for half (7.5%, w/w, of the total diet) of the roughage component; and 15-RC-the entire roughage component (15.0%, w/w, of the total diet) consisted of red clover hay. Feed intake and weight gain were measured at 14-d intervals for the duration of the 56-d trial, and rumen microbiological measures were assessed on days 0, 28, and 56. Red clover supplementation impacted growth performance of ram lambs. Average daily gains (ADG) were greater in ram lambs supplemented with red clover hay (7.5-RC and 15-RC) than for those fed the CON diet (P < 0.05). Conversely, dry matter intake (DMI) was lower in 7.5-RC and 15-RC than for CON lambs (P = 0.03). Differences in ADG and DMI resulted in greater feed efficiency in ram lambs supplemented with red clover hay (both 7.5-RC and 15-RC) compared to CON (P < 0.01). Rumen microbiota were also altered by red clover supplementation. The total viable number of hyper-ammonia-producing bacteria in 7.5-RC and 15-RC decreased over the course of the experiment and were lower than CON by day 28 (P ≤ 0.04). Amylolytic bacteria were also lower in 15-RC than in CON (P = 0.03), with a trend for lower amylolytic bacteria in 7.5-RC (P = 0.08). In contrast, there was tendency for greater cellulolytic bacteria in red clover supplemented lambs than in CON (P = 0.06). Red clover supplementation also increased fiber utilization, with greater ex vivo dry matter digestibility of hay for both 7.5-RC and 15-RC compared to CON by day 28 (P < 0.03). Results of this study indicate that low levels of red clover hay can elicit production benefits in high-concentrate lamb finishing systems through alteration of the rumen microbiota.

Red clover is rich in the bioactive isoflavone, biochanin A. The goal was to evaluate the impacts of biochanin A supplementation via red clover hay on growth performance of ram lambs as well as the rumen microbiota and fermentation. Low levels of red clover hay inclusion (7.5% and 15.0%, w/w, of the total diet) in high-concentrate finishing diets improved feed efficiency of ram lambs, promoting weight gain while decreasing feed intake. Red clover hay supplementation suppressed ruminal protein-wasting, peptide- and amino-acid degrading and starch-utilizing bacteria compared to control diets without isoflavones. Red clover hay also promoted fiber degrading bacteria and fiber utilization. Lamb growth and microbiological effects of red clover were consistent regardless of supplementation level in the diet. Results of this study indicate that low levels of red clover hay can produce production benefits in lamb finishing systems and demonstrated the efficacy of red clover as a functional feed, or feed with biological activities, in the context of its traditional use as a forage feedstuff.

Sex-specific differences in atherosclerosis, thrombospondin-1, and smooth muscle cell differentiation in metabolic syndrome versus non-metabolic syndrome mice.

Introduction: Metabolic syndrome (MetS) amplifies the risks of atherosclerosis. Despite well-known sexual dimorphism in atherosclerosis, underlying mechanisms are poorly understood. Our previous findings highlight a proatherogenic protein, thrombospondin-1 (TSP-1), in hyperglycemia- or hyperleptinemia (mimicking obesity)-induced atherosclerosis. However, the role of TSP-1 in the development of atherosclerosis prompted by co-existing hyperglycemia and obesity, characteristic of MetS, is unknown. The goal of this study was to examine sex-specific differences in lesion progression in a model of combined MetS and atherosclerosis (KKAyApoE) and interrogate how these differences relate to TSP-1 expression. Methods: Male and female KKAy+/-ApoE-/- (with ectopic agouti gene expression) and age-matched non-agouti KKAy-/-ApoE-/- littermates were placed on a standard laboratory diet from 4 to 24 weeks age followed by blood and tissue harvests for biochemical, molecular, and aortic root morphometric studies. Results: Metabolic profiling confirmed MetS phenotype of KKAy+/-ApoE-/-; however, only male genotypes were glucose intolerant with elevated VLDL-cholesterol and VLDL-triglyceride levels. Aortic root morphometry demonstrated profound lipid-filled lesions, increased plaque area, and augmented inflammatory and SMC abundance in MetS vs non-MetS males. This increase in lesion burden was accompanied with elevated TSP-1 and attenuated LMOD-1 (SM contractile marker) and SRF (transcriptional activator of SM differentiation) expression in male MetS aortic vessels. In contrast, while lipid burden, plaque area, and TSP-1 expression increased in MetS and non-MetS female mice, there was no significant difference between these genotypes. Increased collagen content was noted in MetS and non-MetS genotypes, specific to female mice. Measurement of plasma testosterone revealed a link between the atherogenic phenotype and abnormally high or low testosterone levels. To interrogate whether TSP-1 plays a direct role in SMC de-differentiation in MetS, we generated KKAy+/- mice with and without global TSP-1 deletion. Immunoblotting showed increased SM contractile markers in male KKAy+/-TSP-1-/- aortic vessels vs male KKAy+/-TSP-1+/ +. In contrast, TSP-1 deletion had no effect on SM contractile marker expression in female genotypes. Conclusion: Together, the current study implicates a role of plasma testosterone in sex-specific differences in atherosclerosis and TSP-1 expression in MetS vs non-MetS mice. Our data suggest a sex-dependent differential role of TSP-1 on SMC de-differentiation in MetS. Collectively, these findings underscore a fundamental link between TSP-1 and VSMC phenotypic transformation in MetS.

Effects of ruminal lipopolysaccharides on growth and fermentation end products of pure cultured bacteria.

Elevated levels of ruminal lipopolysaccharides (LPS) have been linked to ruminal acidosis; however, they result in reduced endotoxicity compared to LPS derived from species like Escherichia coli. Additionally, there is a knowledge gap on the potential effect of LPS derived from ruminal microbiome on ruminal bacteria species whose abundance is associated with ruminal acidosis. The objective of this study was to evaluate the effects of LPS-free anaerobic water (CTRL), E. coli-LPS (E. COLI), ruminal-LPS (RUM), and a 1:1 mixture of E. coli and ruminal-LPS (MIX) on the growth characteristics and fermentation end products of lactate-producing bacteria (Streptococcus bovis JB1, Selenomonas ruminantium HD4) and lactate-utilizing bacterium (Megasphaera elsdenii T81). The growth characteristics were predicted based on the logistic growth model, the ammonia concentration was determined by the phenolic acid/hypochlorite method and organic acids were analyzed with high performance liquid chromatography. Results indicate that, compared to the CTRL, the maximum specific growth rate of S. bovis JB1 decreased by approximately 19% and 23% when RUM and MIX were dosed, respectively. In addition, acetate and lactate concentrations in Se. ruminantium HD4 were reduced by approximately 30% and 18%; respectively, in response to MIX dosing. Compared to CTRL, lactate concentration from S. bovis JB1 was reduced approximately by 31% and 22% in response to RUM and MIX dosing; respectively. In summary, RUM decreased the growth and lactate production of some lactate-producing bacteria, potentially mitigating the development of subacute ruminal acidosis by restricting lactate availability to some lactate-utilizing bacteria that metabolize lactate into VFAs thus further contributing to the development of acidosis. Also, RUM did not affect Megasphaera elsdenii T81 growth.

Discovery of farnesoid X receptor and its role in bile acid metabolism.

In 1995, the nuclear hormone orphan receptor farnesoid X receptor (FXR, NR1H4) was identified as a farnesol receptor expressed mainly in liver, kidney, and adrenal gland of rats. In 1999, bile acids were identified as endogenous FXR ligands. Subsequently, FXR target genes involved in the regulation of hepatic bile acid synthesis, secretion, and intestinal re-absorption were identified. FXR signaling was proposed as a mechanism of feedback regulation of the rate-limiting enzyme for bile acid synthesis, cholesterol 7⍺-hydroxylase (CYP7A1). The primary bile acids synthesized in the liver are transformed to secondary bile acids by the gut microbiota. The gut-to-liver axis plays a critical role in the regulation of bile acid synthesis, composition and circulating bile acid pool size, which in turn regulates glucose, lipid, and energy metabolism. Dysregulation of bile acid metabolism and FXR signaling in the gut-to-liver axis contributes to metabolic diseases including obesity, diabetes, and non-alcoholic fatty liver disease. This review will cover the discovery of FXR as a bile acid sensor in the regulation of bile acid metabolism and as a metabolic regulator of lipid, glucose, and energy homeostasis. It will also provide an update of FXR functions in the gut-to-liver axis and the drug therapies targeting bile acids and FXR for the treatment of liver metabolic diseases.

Neurotropic Lineage III Strains of Listeria monocytogenes Disseminate to the Brain without Reaching High Titer in the Blood.

Listeria monocytogenes is thought to colonize the brain using one of three mechanisms: direct invasion of the blood-brain barrier, transportation across the barrier by infected monocytes, and axonal migration to the brain stem. The first two pathways seem to occur following unrestricted bacterial growth in the blood and thus have been linked to immunocompromise. In contrast, cell-to-cell spread within nerves is thought to be mediated by a particular subset of neurotropic L. monocytogenes strains. In this study, we used a mouse model of foodborne transmission to evaluate the neurotropism of several L. monocytogenes isolates. Two strains preferentially colonized the brain stems of BALB/cByJ mice 5 days postinfection and were not detectable in blood at that time point. In contrast, infection with other strains resulted in robust systemic infection of the viscera but no dissemination to the brain. Both neurotropic strains (L2010-2198, a human rhombencephalitis isolate, and UKVDL9, a sheep brain isolate) typed as phylogenetic lineage III, the least characterized group of L. monocytogenes Neither of these strains encodes InlF, an internalin-like protein that was recently shown to promote invasion of the blood-brain barrier. Acute neurologic deficits were observed in mice infected with the neurotropic strains, and milder symptoms persisted for up to 16 days in some animals. These results demonstrate that neurotropic L. monocytogenes strains are not restricted to any one particular lineage and suggest that the foodborne mouse model of listeriosis can be used to investigate the pathogenic mechanisms that allow L. monocytogenes to invade the brain stem.IMPORTANCE Progress in understanding the two naturally occurring central nervous system (CNS) manifestations of listeriosis (meningitis/meningoencephalitis and rhombencephalitis) has been limited by the lack of small animal models that can readily distinguish between these distinct infections. We report here that certain neurotropic strains of Listeria monocytogenes can spread to the brains of young otherwise healthy mice and cause neurological deficits without causing a fatal bacteremia. The novel strains described here fall within phylogenetic lineage III, a small collection of L. monocytogenes isolates that have not been well characterized to date. The animal model reported here mimics many features of human rhombencephalitis and will be useful for studying the mechanisms that allow L. monocytogenes to disseminate to the brain stem following natural foodborne transmission.

Bile Acid Biology, Pathophysiology, and Therapeutics.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-chiang a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-chiang an interview with the author.

Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy.

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.

Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: Data from the ARTFL/LEFFTDS Consortium.

INTRODUCTION: We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. METHODS: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. RESULTS: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants. DISCUSSION: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Bile Acid and Cholesterol Metabolism in Atherosclerotic Cardiovascular Disease and Therapy.

Dysregulation of lipid metabolism is a major factor contributing to atherosclerotic cardiovascular disease (ACVD), which is the number one cause of death in western countries. The liver plays a central role in maintaining whole body cholesterol homeostasis via catabolism of cholesterol to bile acids, as well as biliary cholesterol excretion. The liver synthesizes lipoproteins that transport dietary cholesterol and fats to muscle and adipose tissue, directs reverse cholesterol transport of excess cholesterol from extrahepatic tissues and macrophages to the liver to convert to bile acids, and thus, protects against metabolism-related nonalcoholic fatty liver disease (NAFLD) and ACVD. Liver fibrosis/nonalcoholic steatohepatitis increases the risk and prevalence of cardiovascular disease morbidity and mortality. Bile acids are signaling molecules and metabolic regulators that activate farnesoid X receptor and G protein-coupled bile acid receptor-1 to regulate lipid, glucose, and energy metabolism. The bidirectional regulation of bile acids and the gut microbiota determine the rate of bile acid synthesis, the bile acid pool size, and the composition of the circulating bile acid pool. The liver-intestine-heart axis regulates lipid metabolism, inflammation, and the pathogenesis of metabolic diseases such as ACVD, NAFLD, diabetes, and obesity. This review focuses on the roles of liver-to-intestine, liver-to-heart and intestine-to-heart axes in cholesterol, lipoprotein, and bile acid metabolism; signaling in heart health and ACVD; and drug therapies for atherosclerosis.