Publications by authors named "Tien Dong"

32 Publications

The human microbiome in transplantation: the past, present, and future.

Curr Opin Organ Transplant 2021 Sep 20. Epub 2021 Sep 20.

The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation Department of Medicine, Vatche & Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Purpose Of Review: Over the past 20 years, DNA sequencing technology has transformed human microbiome research from identity characterizations to metagenomics approaches that reveal how microbials correlate with human health and disease. New studies are showing unprecedented opportunity for deep characterization of the human microbial ecosystem, with benefits to the field of organ transplantation.

Recent Findings: In the present review, we focus on past milestones of human-associated microbiota research, paying homage to microbiota pioneers. We highlight the role of sequencing efforts to provide insights beyond taxonomic identification. Recent advances in microbiome technology is now integrating high-throughput datasets, giving rise to multi'omics - a comprehensive assessment modeling dynamic biologic networks. Studies that show benefits and mechanisms in peritransplant antibiotic (Abx)-conditioned recipients are reviewed. We describe how next-generation microbial sequencing has the potential to combine with new technologies like phage therapy (PT) to translate into life-saving therapeutics.

Summary: The study of the microbiome is advancing the field of transplantation by enhancing our knowledge of precision medicine. Sequencing technology has allowed the use of the microbiome as a biomarker to risk stratify patients. Further research is needed to better understand how microbiomes shape transplantation outcomes while informing immune cell - tissue crosstalk platforms.
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http://dx.doi.org/10.1097/MOT.0000000000000922DOI Listing
September 2021

The Intestinal Microbiome Predicts Weight Loss on a Calorie-Restricted Diet and Is Associated With Improved Hepatic Steatosis.

Front Nutr 2021 8;8:718661. Epub 2021 Jul 8.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

The microbiome has been shown in pre-clinical and epidemiological studies to be important in both the development and treatment of obesity and metabolic associated fatty liver disease (MAFLD). However, few studies have examined the role of the microbiome in the clinical response to calorie restriction. To explore this area, we performed a prospective study examining the association of the intestinal microbiome with weight loss and change in hepatic steatosis on a calorie-restricted diet. A prospective dietary intervention study of 80 overweight and obese participants was performed at the Greater West Los Angeles Veterans Affair Hospital. Patients were placed on a macronutrient standardized diet for 16 weeks, including 14 weeks of calorie restriction (500 calorie deficit). Body composition analysis by impedance, plasma lipid measurements, and ultrasound elastography to measure hepatic steatosis were performed at baseline and week 16. Intestinal microbiome composition was assessed using 16S rRNA gene sequencing. A per protocol analysis was performed on all subjects completing the trial ( = 46). Study completers showed significant reduction in weight, body mass index, total cholesterol, low density lipoprotein, and triglyceride. Subjects who lost at least 5% of their body weight had significantly greater reduction in serum triglyceride and hepatic steatosis than those with <5% body weight loss. and were reduced at the end of the trial while and were increased. There were also significant baseline microbiome differences between patients who had at least 5% weight loss as compared to those that did not. was positively associated with hepatic steatosis and was positively associated with hepatic steatosis and weight. Baseline microbiome profiles were able to predict which patients lost at least 5% of their body weight with an AUROC of 0.80. Calorie restriction alters the intestinal microbiome and improves hepatic steatosis in those who experience significant weight loss. Baseline microbiome differences predict weight loss on a calorie-restricted diet and are associated with improvement in hepatic steatosis, suggesting a role of the gut microbiome in mediating the clinical response to calorie restriction.
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http://dx.doi.org/10.3389/fnut.2021.718661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295485PMC
July 2021

Early life adversity predicts brain-gut alterations associated with increased stress and mood.

Neurobiol Stress 2021 Nov 25;15:100348. Epub 2021 May 25.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, USA.

Alterations in the brain-gut system have been implicated in various disease states, but little is known about how early-life adversity (ELA) impacts development and adult health as mediated by brain-gut interactions. We hypothesize that ELA disrupts components of the brain-gut system, thereby increasing susceptibility to disordered mood. In a sample of 128 healthy adult participants, a history of ELA and current stress, depression, and anxiety were assessed using validated questionnaires. Fecal metabolites were measured using liquid chromatography tandem mass spectrometry-based untargeted metabolomic profiling. Functional brain connectivity was evaluated by magnetic resonance imaging. Sparse partial least squares-discriminant analysis, controlling for sex, body mass index, age, and diet was used to predict brain-gut alterations as a function of ELA. ELA was correlated with four gut-regulated metabolites within the glutamate pathway (5-oxoproline, malate, urate, and glutamate gamma methyl ester) and alterations in functional brain connectivity within primarily sensorimotor, salience, and central executive networks. Integrated analyses revealed significant associations between these metabolites, functional brain connectivity, and scores for perceived stress, anxiety, and depression. This study reveals a novel association between a history of ELA, alterations in the brain-gut axis, and increased vulnerability to negative mood and stress. Results from the study raise the hypothesis that select gut-regulated metabolites may contribute to the adverse effects of critical period stress on neural development via pathways related to glutamatergic excitotoxicity and oxidative stress.
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http://dx.doi.org/10.1016/j.ynstr.2021.100348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170500PMC
November 2021

Effect of Exclusion Diets on Symptom Severity and the Gut Microbiota in Patients With Irritable Bowel Syndrome.

Clin Gastroenterol Hepatol 2021 May 20. Epub 2021 May 20.

Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California; G Oppenheimer Center for Neurobiology of Stress and Resilience, Los Angeles, California. Electronic address:

Background & Aims: Altered fecal microbiota have been reported in irritable bowel syndrome (IBS), although studies vary, which could be owing to dietary effects. Many IBS patients may eliminate certain foods because of their symptoms, which in turn may alter fecal microbiota diversity and composition. This study aimed to determine if dietary patterns were associated with IBS, symptoms, and fecal microbiota differences reported in IBS.

Methods: A total of 346 IBS participants and 170 healthy controls (HCs) completed a Diet Checklist reflecting the diet(s) consumed most frequently. An exclusion diet was defined as a diet that eliminated food components by choice. Within this group, a gluten-free, dairy-free, or low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet was further defined as restrictive because they often are implicated in reducing symptoms. Stool samples were obtained from 171 IBS patients and 98 HCs for 16S ribosomal RNA gene sequencing and microbial composition analysis.

Results: Having IBS symptoms was associated with consuming a restrictive diet (27.17% of IBS patients vs 7.65% of HCs; odds ratio, 3.25; 95% CI, 1.66-6.75; P value .006). IBS participants on an exclusion or restrictive diet reported more severe IBS symptoms (P = .042 and .029, respectively). The composition of the microbiota in IBS patients varied depending on the diet consumed. IBS participants on an exclusion diet had a greater abundance of Lachnospira and a lower abundance of Eubacterium (q value, <.05), and those on a restrictive diet had a lower abundance of Lactobacillus (q value, <.05).

Conclusions: Restrictive diets likely are consumed more by IBS patients than HCs to reduce GI symptom severity. Dietary patterns influence the composition of the fecal microbiota and may explain some of the differences between IBS and HCs.
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http://dx.doi.org/10.1016/j.cgh.2021.05.027DOI Listing
May 2021

The intestinal microbiota as a predictor for antidepressant treatment outcome in geriatric depression: a prospective pilot study.

Int Psychogeriatr 2021 Mar 24:1-13. Epub 2021 Mar 24.

Department of Psychiatry, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA, USA.

Objectives: (1) To investigate if gut microbiota can be a predictor of remission in geriatric depression and to identify features of the gut microbiota that is associated with remission. (2) To determine if changes in gut microbiota occur with remission in geriatric depression.

Design: Secondary analysis of a parent randomized placebo-controlled trial (NCT02466958).

Setting: Los Angeles, CA, USA (2016-2018).

Participants: Seventeen subjects with major depressive disorder, over 60 years of age, 41.2% female.

Intervention: Levomilacipran (LVM) or placebo.

Measurements: Remission was defined by Hamilton Depression Rating Scale score of 6 or less at 12 weeks. 16S-ribosomal RNA sequencing based fecal microbiota composition and diversity were measured at baseline and 12 weeks. Differences in fecal microbiota were evaluated between remitters and non-remitters as well as between baseline and post-treatment samples. LVM and placebo groups were combined in all the analyses.

Results: Baseline microbiota showed no community level α-diversity or β-diversity differences between remitters and non-remitters. At the individual taxa level, a random forest classifier created with nine genera from the baseline microbiota was highly accurate in predicting remission (AUC = .857). Of these, baseline enrichment of Faecalibacterium, Agathobacter and Roseburia relative to a reference frame was associated with treatment outcome of remission. Differential abundance analysis revealed significant genus level changes from baseline to post-treatment in remitters, but not in non-remitters.

Conclusions: This is the first study demonstrating fecal microbiota as a potential predictor of treatment response in geriatric depression. Our findings need to be confirmed in larger prospective studies.
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http://dx.doi.org/10.1017/S1041610221000120DOI Listing
March 2021

Specimen Collection and Analysis of the Duodenal Microbiome.

J Vis Exp 2021 01 12(167). Epub 2021 Jan 12.

Cedars-Sinai Cancer and Department of Medicine, Cedars-Sinai Medical Center;

Shifts in the microbiome have been correlated with the physiology and pathophysiology of many organ systems both in humans and in mouse models. The gut microbiome has been typically studied through fecal specimen collections. The ease of obtaining fecal samples has resulted in many studies that have revealed information concerning the distal luminal gastrointestinal tract. However, few studies have addressed the importance of the microbiome in the proximal gut. Given that the duodenum is a major site for digestion and absorption, its microbiome is relevant to nutrition and liver disease and warrants further investigation. Here we detail a novel method for sampling the proximal luminal and mucosal gut microbiome in human subjects undergoing upper endoscopy by obtaining duodenal aspirate and biopsies. Specimen procurement is facile and unaffected by artifacts such as patient preparatory adherence, as might be the case in obtaining colonic samples during colonoscopy. The preliminary results show that the luminal and mucosal microbiomes differ significantly, which is likely related to environmental conditions and barrier functions. Therefore, a combination of duodenal aspirate and biopsies reveal a more comprehensive picture of the microbiome in the duodenum. Biopsies are obtained from the descending and horizontal segments of the duodenum, which are anatomically close to the liver and biliary tree. This is important in studying the role of bile acid biology and the gut-liver axis in liver disease. Biopsies and aspirate can be used for 16S ribosomal RNA sequencing, metabolomics, and other similar applications.
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http://dx.doi.org/10.3791/61900DOI Listing
January 2021

Understanding the Heterogeneity of Obesity and the Relationship to the Brain-Gut Axis.

Nutrients 2020 Nov 30;12(12). Epub 2020 Nov 30.

Division of Hematology and Oncology, University of California, Los Angeles, CA 90095, USA.

Obesity is best understood as a multifactorial metabolic imbalances disorder. In a cross-sectional study, we aimed to explore sociodemographic and dietary determinants of obesity in relation to brain-gut homeostasis among overweight and obese individuals. Multivariate logistic regression models were used to examine obesity and its association with sociodemographic and dietary factors. Biological variables examined included the gut microbiome, fecal amino acid metabolites and brain structural volumes. Among 130 participants, there were higher odds of obesity if individuals were Hispanic (adjusted odds ratio (aOR) 1.56, = 0.014). Compared to non-Hispanics, Hispanics differed in gut microbial composition ( = 0.046) with lower microbial species richness (Chao1) ( = 0.032) and evenness (Shannon) ( = 0.0029). Fourteen of the twenty fecal amino acids including branch-chain- and aromatic- amino acids were increased among Hispanics ( < 0.05). Brain structural volumes in reward regions were decreased in Hispanics (pallidum, = 0.036; brainstem, = 0.011). Correlation patterns suggest complex brain-gut interactions differ by Hispanic ethnicity. In conclusion, Hispanics expressed a unique brain-gut microbial signature, which was associated with obesity despite sociodemographic and dietary differences. Addressing ethnic disparities guided by biologic phenotypes may unlock novel understanding of obesity heterogeneity and treatment strategies.
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http://dx.doi.org/10.3390/nu12123701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761087PMC
November 2020

Shifts in microbial diversity, composition, and functionality in the gut and genital microbiome during a natural SIV infection in vervet monkeys.

Microbiome 2020 11 6;8(1):154. Epub 2020 Nov 6.

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Background: The microbiota plays an important role in HIV pathogenesis in humans. Microbiota can impact health through several pathways such as increasing inflammation in the gut, metabolites of bacterial origin, and microbial translocation from the gut to the periphery which contributes to systemic chronic inflammation and immune activation and the development of AIDS. Unlike HIV-infected humans, SIV-infected vervet monkeys do not experience gut dysfunction, microbial translocation, and chronic immune activation and do not progress to immunodeficiency. Here, we provide the first reported characterization of the microbial ecosystems of the gut and genital tract in a natural nonprogressing host of SIV, wild vervet monkeys from South Africa.

Results: We characterized fecal, rectal, vaginal, and penile microbiomes in vervets from populations heavily infected with SIV from diverse locations across South Africa. Geographic site, age, and sex affected the vervet microbiome across different body sites. Fecal and vaginal microbiome showed marked stratification with three enterotypes in fecal samples and two vagitypes, which were predicted functionally distinct within each body site. External bioclimatic factors, biome type, and environmental temperature influenced microbiomes locally associated with vaginal and rectal mucosa. Several fecal microbial taxa were linked to plasma levels of immune molecules, for example, MIG was positively correlated with Lactobacillus and Escherichia/Shigella and Helicobacter, and IL-10 was negatively associated with Erysipelotrichaceae, Anaerostipes, Prevotella, and Anaerovibrio, and positively correlated with Bacteroidetes and Succinivibrio. During the chronic phase of infection, we observed a significant increase in gut microbial diversity, alterations in community composition (including a decrease in Proteobacteria/Succinivibrio in the gut) and functionality (including a decrease in genes involved in bacterial invasion of epithelial cells in the gut), and partial reversibility of acute infection-related shifts in microbial abundance observed in the fecal microbiome. As part of our study, we also developed an accurate predictor of SIV infection using fecal samples.

Conclusions: The vervets infected with SIV and humans infected with HIV differ in microbial responses to infection. These responses to SIV infection may aid in preventing microbial translocation and subsequent disease progression in vervets, and may represent host microbiome adaptations to the virus. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00928-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648414PMC
November 2020

Frailty Does Not Impact Caregiver Burden in Patients with Cirrhosis.

Dig Dis Sci 2021 Oct 2;66(10):3343-3351. Epub 2020 Nov 2.

Departments of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

Background: Frailty is common and is associated with increased mortality, lower quality of life, and higher readmission rates in cirrhotic patients. Not only are these outcomes important, but further understanding the impact of frailty on a caregiver's life is crucial to better comprehend caregiver burden in cirrhotic patients and develop strategies to improve care for patients and their caregivers.

Methods: A single-center, prospective study was conducted of cirrhotic patients and their caregivers between 4/1/2019 and 11/1/2019. Frailty testing combined aspects from the Fried Frailty Instrument, Short Physical Performance Battery, and activities of daily living. Caregivers completed questionnaires to evaluate caregiver burden using the Zarit Burden Interview (ZBI-12), and perceived social support, using the Interpersonal Support Evaluation List.

Results: In total, 94 cirrhotic patients were included, 50% males with a median age of 63.1 years. The most common etiology of cirrhosis was nonalcoholic steatohepatitis. Frailty was prevalent (45.1%). In total, 12.8% of caregivers reported a high burden based on ZBI-12. There was no association between frailty and caregiver burden, hospitalization rates, or death. However, frailty was associated with a higher number of outpatient GI visits (p = 0.002). Lower perceived social support among caregivers was associated with a higher caregiver burden (p < 0.0001).

Conclusion: Frailty is prevalent in cirrhotic patients but is not associated with higher rates of caregiver burden. Low perceived social support among caregivers, however, was associated with higher caregiver burden. It is important to recognize the impact of caregiver burden on caregivers of cirrhotic patients and ensure caregivers have the appropriate support to mitigate burden.
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http://dx.doi.org/10.1007/s10620-020-06687-4DOI Listing
October 2021

A High Protein Calorie Restriction Diet Alters the Gut Microbiome in Obesity.

Nutrients 2020 Oct 21;12(10). Epub 2020 Oct 21.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Background: High protein calorie restriction diets have shown clinical efficacy for obesity, but the mechanisms are not fully known. The intestinal microbiome is a mediator of obesity and preclinical data support an effect of high protein diet (HPD) on the gut microbiome of obesity, but there are few studies in humans.

Methods: To address this, we conducted a dietary intervention trial of 80 overweight and obese subjects who were randomized to a calorie-restricted high protein diet (HPD) (30% calorie intake) or calorie-restricted normal protein diet (NPD) (15%) for 8 weeks. Baseline dietary intake patterns were assessed by the Diet History Questionnaire III. Longitudinal fecal sampling was performed at baseline, week 1, week 2, week 4, week 6, and week 8, for a total of 365 samples. Intestinal microbiome composition was assessed by 16S rRNA gene sequencing.

Results: At baseline, microbial composition was associated with fiber and protein intake. Subjects on the HPD showed a significant increase in microbial diversity as measured by the Shannon index compared to those on the NPD. The HPD was also associated with significant differences in microbial composition after treatment compared to the NPD. Both diets induced taxonomic shifts compared to baseline, including enrichment of and and depletion of Conclusion: These findings provide evidence that weight loss diets alter the gut microbiome in obesity and suggest differential effects of HPDs compared to NPDs which may influence the clinical response to HPD.
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http://dx.doi.org/10.3390/nu12103221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590138PMC
October 2020

Improvement in Uncontrolled Eating Behavior after Laparoscopic Sleeve Gastrectomy Is Associated with Alterations in the Brain-Gut-Microbiome Axis in Obese Women.

Nutrients 2020 Sep 24;12(10). Epub 2020 Sep 24.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Background: Bariatric surgery is proven to change eating behavior and cause sustained weight loss, yet the exact mechanisms underlying these changes are not clearly understood. We explore this in a novel way by examining how bariatric surgery affects the brain-gut-microbiome (BGM) axis.

Methods: Patient demographics, serum, stool, eating behavior questionnaires, and brain magnetic resonance imaging (MRI) were collected before and 6 months after laparoscopic sleeve gastrectomy (LSG). Differences in eating behavior and brain morphology and resting-state functional connectivity in core reward regions were correlated with serum metabolite and 16S microbiome data.

Results: LSG resulted in significant weight loss and improvement in maladaptive eating behaviors as measured by the Yale Food Addiction Scale (YFAS). Brain imaging showed a significant increase in brain volume of the putamen (.adj < 0.05) and amygdala (.adj < 0.05) after surgery. Resting-state connectivity between the precuneus and the putamen was significantly reduced after LSG (.adj = 0.046). This change was associated with YFAS symptom count. , , and were associated with reduced connectivity between these areas. Metabolomic profiles showed a positive correlation between this brain connection and a phosphatidylcholine metabolite.

Conclusion: Bariatric surgery modulates brain networks that affect eating behavior, potentially through effects on the gut microbiota and its metabolites.
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http://dx.doi.org/10.3390/nu12102924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599899PMC
September 2020

A Distinct Brain-Gut-Microbiome Profile Exists for Females with Obesity and Food Addiction.

Obesity (Silver Spring) 2020 08;28(8):1477-1486

Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, Department of Medicine, Los Angeles, California, USA.

Background: Alterations in brain-gut-microbiome interactions have been implicated as an important factor in obesity. This study aimed to explore the relationship between food addiction (FA) and the brain-gut-microbiome axis, using a multi-omics approach involving microbiome data, metabolomics, and brain imaging.

Methods: Brain magnetic resonance imaging was obtained in 105 females. FA was defined by using the Yale Food Addiction Scale. Fecal samples were collected for sequencing and metabolomics. Statistical analysis was done by using multivariate analyses and machine learning algorithms.

Results: Of the females with obesity, 33.3% exhibited FA as compared with 5.3% and 0.0% of females with overweight and normal BMI, respectively (P = 0.0001). Based on a multilevel sparse partial least square discriminant analysis, there was a difference in the gut microbiome of females with FA versus those without. Differential abundance testing showed Bacteroides, Megamonas, Eubacterium, and Akkermansia were statistically associated with FA (q < 0.05). Metabolomics showed that indolepropionic acid was inversely correlated with FA. FA was also correlated with increased connectivity within the brain's reward network, specifically between the intraparietal sulcus, brain stem, and putamen.

Conclusions: This is the first study to examine FA along the brain-gut-microbiome axis and it supports the idea of targeting the brain-gut-microbiome axis for the treatment of FA and obesity.
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http://dx.doi.org/10.1002/oby.22870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494955PMC
August 2020

Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis.

Nutrients 2020 May 13;12(5). Epub 2020 May 13.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.

The gut microbiome is a key factor in chronic liver disease progression. In prior research, we found that the duodenal microbiome was associated with sex, ethnicity, and cirrhosis complications. Here, we examined the association between diet and the duodenal microbiome in patients with liver cirrhosis. This study included 51 participants who completed a detailed food frequency questionnaire and donated duodenal biopsies for microbiome characterization by 16S ribosomal RNA gene sequencing. Data were analyzed for alpha diversity, beta diversity, and association of taxa abundance with diet quality and components using QIIME 2 pipelines. Diet quality was assessed through calculation of the Healthy Eating Index 2010. Participants with higher adherence to protein recommendations exhibited increased microbial richness and evenness ( = 0.03) and a different microbial profile compared to those with lower adherence ( = 0.03). and were increased in association with increased protein adherence. Fiber consumption was also associated with the duodenal microbial profile ( = 0.01), with several taxa exhibiting significantly decreased or increased abundance in association with fiber intake. Coffee drinking was associated with microbial richness and evenness ( = 0.001), and there was a dose-response association between coffee drinking and relative abundance of ( = 0.01). We conclude that protein, fiber, and coffee are associated with diversity and composition of the duodenal microbiome in liver cirrhosis.
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http://dx.doi.org/10.3390/nu12051395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285216PMC
May 2020

A Microbial Signature Identifies Advanced Fibrosis in Patients with Chronic Liver Disease Mainly Due to NAFLD.

Sci Rep 2020 02 17;10(1):2771. Epub 2020 Feb 17.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

The presence of advanced fibrosis is an important measure of the severity of chronic liver disease. Prior works that have examined the gut microbiome as a novel biomarker for advanced fibrosis have only examined patients with nonalcoholic fatty liver disease. Therefore, our goal was to examine the gut microbiome across varying etiologies of liver disease to create a predictive model for liver fibrosis based upon a microbial signature. Stool samples were obtained from patients with chronic liver disease (n = 50) undergoing FibroScan (ultrasound elastography) at the VA Greater Los Angeles Healthcare System. Healthy control patients (n = 25) were also recruited as a reference population. Fecal samples underwent 16S ribosomal RNA sequencing. Using differentially abundant microbes, a random forest classifier model was created to distinguish advanced fibrosis from mild/moderate fibrosis. The findings were then validated in a separate cohort of chronic liver disease patients (n = 37). Etiologies for liver disease included non-alcoholic liver disease (58.0%), hepatitis C (26.0%), hepatitis B (10.0%), and alcohol (6.0%). Microbiome composition was distinct in liver patients with advanced fibrosis compared to those with minimal fibrosis and healthy controls (p = 0.003). In multivariate negative binomial modeling, 26 bacterial taxa were differentially abundant in patients with advanced fibrosis as compared to those with minimal/moderate fibrosis (q-value < 0.05). A random forests classifier based on these taxa had an AUROC of 0.90 to predict advanced fibrosis. Prevotella copri, which was enriched in patients with advanced fibrosis, was the most strongly predictive microbe in the classifier. The classifier had an AUROC of 0.82 for advanced fibrosis in the validation cohort and Prevotella copri remained the strongest predictive microbe for advanced fibrosis. There is a distinct microbial signature for patients with advanced fibrosis independent of liver disease etiology and other comorbidities. These results suggest that microbial profiles can be used as a non-invasive marker for advanced fibrosis and support the hypothesis that microbes and their metabolites contribute to hepatic fibrosis.
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http://dx.doi.org/10.1038/s41598-020-59535-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026172PMC
February 2020

A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.

Cancer 2020 04 5;126(8):1668-1682. Epub 2020 Feb 5.

Department of Surgery, Veterans Administration Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.

Background: Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target.

Methods: A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity.

Results: Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment.

Conclusions: The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy.

Lay Summary: Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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http://dx.doi.org/10.1002/cncr.32644DOI Listing
April 2020

Intraperitoneal Treatment of Kisspeptin Suppresses Appetite and Energy Expenditure and Alters Gastrointestinal Hormones in Mice.

Dig Dis Sci 2020 08 15;65(8):2254-2263. Epub 2019 Nov 15.

Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Background: Kisspeptin is a neuropeptide that plays an integral role in the regulation of energy intake and reproduction by acting centrally on the hypothalamus-pituitary-gonadal axis. Our current study explores for the first time the effects of a pharmacological treatment of intraperitoneal kisspeptin-10 on murine feeding behavior, respirometry parameters, energy balance, and metabolic hormones.

Methods: Two groups (n = 16) of age- and sex-matched C57BL/6 wild-type adult mice were individually housed in metabolic cages and intraperitoneally injected with either kisspeptin-10 (2 nmol in 200 µl of saline) (10 µM) or vehicle before the beginning of a dark-phase cycle. Microstructure of feeding and drinking behavior, respirometry gases, respiratory quotient (RQ), total energy expenditure (TEE), metabolic hormones, oral glucose tolerance, and lipid profiles were measured.

Results: Intraperitoneal treatment with kisspeptin-10 caused a significant reduction in food intake, meal frequency, meal size, and eating rate. Kisspeptin-10 significantly decreased TEE during both the dark and light phase cycles, while also increasing the RQ during the dark-phase cycle. In addition, mice injected with kisspeptin-10 had significantly higher plasma levels of insulin (343.8 pg/ml vs. 106.4 pg/ml; p = 0.005), leptin (855.5 pg/ml vs. 173.1 pg/ml; p = 0.02), resistin (9411.1 pg/ml vs. 4116.5 pg/ml; p = 0.001), and HDL (147.6 mg/dl vs 97.1 mg/dl; p = 0.04).

Conclusion: A pharmacological dose of kisspeptin-10 significantly altered metabolism by suppressing food intake, meal size, eating rate, and TEE while increasing the RQ. These changes were linked to increased levels of insulin, leptin, resistin, and HDL. The current results suggest that a peripheral kisspeptin treatment could alter metabolism and energy homeostasis by suppressing appetite, food intake, and fat accumulation.
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http://dx.doi.org/10.1007/s10620-019-05950-7DOI Listing
August 2020

Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity.

Am J Physiol Gastrointest Liver Physiol 2019 12 23;317(6):G763-G772. Epub 2019 Sep 23.

CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California.

Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a Kras mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin. Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.
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http://dx.doi.org/10.1152/ajpgi.00170.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962494PMC
December 2019

Microbial Profiles of Cirrhosis in the Human Small Intestine.

Curr Gastroenterol Rep 2019 Aug 23;21(10):50. Epub 2019 Aug 23.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 116 North Robertson Blvd., PACT 900A, Los Angeles, CA, 90048, USA.

Purpose Of Review: The aim of this review is to summarize the recent literature on associations of small intestinal microbial and bile acid profiles with liver cirrhosis and its complications.

Recent Findings: Recent studies into the duodenal microbiome of patients with cirrhosis have linked the microbiome to certain etiologies of chronic liver disease as well as complications of cirrhosis. In particular, microbial differences in the duodenum of patients with cirrhosis have been linked to the presence of hepatic encephalopathy and varices. While the fecal microbiome of patients with liver cirrhosis is well characterized, the small intestinal microbiome of cirrhotic patients is an active area of research. This review focuses on the current understanding of the small intestinal microbiome in human cirrhosis as well as future directions of the field.
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http://dx.doi.org/10.1007/s11894-019-0717-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292805PMC
August 2019

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome.

Nutrients 2019 Aug 14;11(8). Epub 2019 Aug 14.

Department of Psychiatry and Biobehavioral Sciences, Hatos Center for the Study of Opioids Receptors and Drugs of Abuse, UCLA Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.
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http://dx.doi.org/10.3390/nu11081900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723154PMC
August 2019

Nonalcoholic fatty liver disease and the gut microbiome: Are bacteria responsible for fatty liver?

Exp Biol Med (Maywood) 2019 04 14;244(6):408-418. Epub 2019 Mar 14.

1 Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90025, USA.

Impact Statement: This invited minireview for the upcoming thematic issue on the microbiome addresses the role of the microbiome in nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD has increased greatly in recent years in parallel with the rise in obesity and is now believed to have a population prevalence of 20-40%. It is anticipated to soon become the primary cause of liver-related morbidity and mortality, and unfortunately, there are few treatment options. Therefore, there is a critical need for improved understanding of NAFLD pathophysiology to provide new avenues for therapeutic intervention. In this paper, we have reviewed evidence from human and animal model studies that have associated microbiome composition and microbial metabolites with development and progression of NAFLD. We have also discussed proposed mechanisms by which the microbiome could contribute to NAFLD pathogenesis and addressed future directions for this field.
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http://dx.doi.org/10.1177/1535370219836739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547005PMC
April 2019

Machine Learning-based Development and Validation of a Scoring System for Screening High-Risk Esophageal Varices.

Clin Gastroenterol Hepatol 2019 08 29;17(9):1894-1901.e1. Epub 2019 Jan 29.

Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, California. Electronic address:

Background & Aims: Many patients with cirrhosis who undergo esophagogastroduodenoscopy (EGD) screening for esophageal varices (EVs) are found to have no or only small EVs. Endoscopic screening for EVs is therefore a potentially deferrable procedure that increases patient risk and healthcare cost. We developed and validated a scoring system, based on readily-available data, to reliably identify patients with EVs that need treatment.

Methods: We collected data from 238 patients with cirrhosis undergoing screening EGD from January 2016 through December 2017 at 3 separate hospitals in Los Angeles (training cohort). We abstracted data on patient sex, age, race/ethnicity, platelet counts, and levels of hemoglobin, serum sodium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, international normalized ratio, albumin, urea nitrogen, and creatinine. We also included etiology of cirrhosis, presence of ascites, and presence of hepatic encephalopathy. We used a random forest algorithm to identify factors significantly associated with the presence of EVs and varices needing treatment (VNT) and calculated area under the receiver operating characteristic curve (AUROC). We called the resulting formula the EVendo score. We tested the accuracy of EVendo in a prospective study of 109 patients undergoing screening EGDs at the same medical centers from January 2018 through December 2018 (validation cohort).

Results: We developed an algorithm that identified patients with EVs and VNT based on international normalized ratio, level of aspartate aminotransferase, platelet counts, urea nitrogen, hemoglobin, and presence of ascites. The EVendo score identified patients with EVs in the training set with an AUROC of 0.84, patients with EVs in the validation set with and AUROC of 0.82, and EVs in patients with cirrhosis Child-Turcotte-Pugh class A (n = 235) with an AUROC of 0.81. The score identified patients with VNT in the training set with an AUROC of 0.74, VNT in the validation set with and AUROC of 0.75, and VNT in patients with cirrhosis Child-Turcotte-Pugh class A with and AUROC of 0.75. An EVendo score below 3.90 would have spared 30.5% patients from EGDs, missing only 2.8% of VNT. The same cutoff would have spared 40.0% of patients with Child-Turcotte-Pugh class A cirrhosis from EGDs, missing only 1.1% of VNT.

Conclusions: We algorithmically developed a formula, called the EVendo score, that can be used to predict EVs and VNT based on readily available data in patients with cirrhosis. This score could help patients at low risk for VNT avoid unnecessary EGDs.
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http://dx.doi.org/10.1016/j.cgh.2019.01.025DOI Listing
August 2019

Patient Satisfaction and Healthcare Utilization Using Telemedicine in Liver Transplant Recipients.

Dig Dis Sci 2019 05 5;64(5):1150-1157. Epub 2018 Dec 5.

Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

Background: Post-liver transplantation care is limited to tertiary care centers. Concentration at expert centers leads to high-volume clinics with long wait times and decreased accessibility.

Aim: To assess whether telemedicine can be utilized to overcome barriers to care while sustaining strong patient-physician relationships.

Methods: The Patient Satisfaction Questionnaire-18, Telemedicine Satisfaction Questionnaire, and Health Utilization Questionnaire were used to assess patient satisfaction and healthcare utilization among patients who received care via video connection (telemedicine group) and in clinic (control group). Propensity matching was performed. Scores for questionnaires were reported as mean and standard deviations (SD) and were compared by one-way multivariate analysis of variance and one-way analysis of variance.

Results: There were 21 matched telemedicine patients in our study. Overall mean age (± SD) was 51 (± 5.62) years and 52 (± 6.12) years for telemedicine group and control group, respectively. General patient satisfaction was similar between the two groups (p = 0.89). While telemedicine patients were just as satisfied with communication and interpersonal approach compared to clinic patients, they experienced significantly less commute (p < 0.0001) and waiting (p < 0.0001) times. Given ease of using telemedicine without compromising patient-physician interaction, 90% (19/21) of the telemedicine patients opted to use the service again.

Conclusion: Telemedicine appeared to be both a time and cost-saving alternative to clinic follow-up without compromise of the valuable patient-physician relationship. Telemedicine has the potential to improve clinic flow, reduce wait times, and decrease costs for liver transplant recipients.
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http://dx.doi.org/10.1007/s10620-018-5397-5DOI Listing
May 2019

Metabolic syndrome does not affect sustained virologic response of direct-acting antivirals while hepatitis C clearance improves hemoglobin A1c.

World J Hepatol 2018 Sep;10(9):612-621

the Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States.

Aim: To determine whether successful treatment with directacting antivirals (DAA) is associated with improvements in hemoglobin A1c (HbA1c) and if type 2 diabetes mellitus (T2DM) or metabolic syndrome affects sustained virologic response (SVR).

Methods: We performed a retrospective analysis of all hepatitis C virus (HCV) patients at the VA Greater Los Angeles Healthcare System treated with varying DAA therapy between 2014-2016. Separate multivariable logistic regression was performed to determine predictors of HbA1c decrease ≥ 0.5 after DAA treatment and predictors of SVR 12-wk post treatment (SVR12).

Results: A total of 1068 patients were treated with DAA therapy between 2014-2016. The presence of T2DM or metabolic syndrome did not adversely affect SVR12. 106 patients had both HCV and T2DM. Within that cohort, patients who achieved SVR12 had lower mean HbA1c pre treatment (7.35 8.60, = 0.02), and lower mean HbA1c post-treatment compared to non-responders (6.55 8.61, = 0.01). The mean reduction in HbA1c after treatment was greater for those who achieved SVR12 than for non-responders (0.79 0.01, = 0.03). In adjusted models, patients that achieved SVR12 were more likely to have a HbA1c decrease of ≥ 0.5 than those that did not achieve SVR12 (adjusted OR = 7.24, 95%CI: 1.22-42.94).

Conclusion: In HCV patients with T2DM, successful treatment with DAA was associated with a significant reduction in HbA1c suggesting that DAA may have a role in improving insulin sensitivity. Furthermore, the presence of T2DM or metabolic syndrome does not adversely affect SVR12 rates in patients treated with DAA.
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http://dx.doi.org/10.4254/wjh.v10.i9.612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177571PMC
September 2018

The Relative Ability of Comorbidity Ascertainment Methodologies to Predict In-Hospital Mortality Among Hospitalized Community-acquired Pneumonia Patients.

Med Care 2018 11;56(11):950-955

Department of Internal Medicine, Section of Hospital Medicine.

Background: Despite widespread use of comorbidities for population health descriptions and risk adjustment, the ideal method for ascertaining comorbidities is not known. We sought to compare the relative value of several methodologies by which comorbidities may be ascertained.

Methods: This is an observational study of 1596 patients admitted to the University of Chicago for community-acquired pneumonia from 1998 to 2012. We collected data via chart abstraction, administrative data, and patient report, then performed logistic regression analyses, specifying comorbidities as independent variables and in-hospital mortality as the dependent variable. Finally, we compared area under the curve (AUC) statistics to determine the relative ability of each method of comorbidity ascertainment to predict in-hospital mortality.

Results: Chart review (AUC, 0.72) and administrative data (Charlson AUC, 0.83; Elixhauser AUC, 0.84) predicted in-hospital mortality with greater fidelity than patient report (AUC, 0.61). However, multivariate logistic regression analyses demonstrated that individual comorbidity derivation via chart review had the strongest relationship with in-hospital mortality. This is consistent with prior literature suggesting that administrative data have inherent, paradoxical biases with important implications for risk adjustment based solely on administrative data.

Conclusions: Although comorbidities derived through administrative data did produce an AUC greater than chart review, our analyses suggest a coding bias in several comorbidities with a paradoxically protective effect. Therefore, chart review, while labor and resource intensive, may be the ideal method for ascertainment of clinically relevant comorbidities.
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http://dx.doi.org/10.1097/MLR.0000000000000989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185751PMC
November 2018

Passing the "Acid Test": Do Proton Pump Inhibitors Affect the Composition of the Microbiome?

Dig Dis Sci 2018 11;63(11):2817-2819

Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, USA.

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http://dx.doi.org/10.1007/s10620-018-5273-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408263PMC
November 2018

Influence of Early Life, Diet, and the Environment on the Microbiome.

Clin Gastroenterol Hepatol 2019 01 7;17(2):231-242. Epub 2018 Sep 7.

Vatche and Tamar Manoukin Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, California. Electronic address:

Advances in sequencing technology and bioinformatics have greatly enhanced our ability to understand the human microbiome. Over the last decade, a growing body of literature has linked nutrition and the environment to the microbiome and is now thought to be an important contributor to overall health. This paper reviews the literature from the past 10 years to highlight the influence of environmental factors such as diet, early life adversity and stress in shaping and modifying our microbiome towards health and disease. The review shows that many factors such as the mode of delivery, breast milk, stress, diet and medications can greatly influence the development of our gut microbiome and potentially make us more prone to certain diseases. By incorporating environmental factors into models that study the microbiome in the setting of health and disease, may provide a better understanding of disease and potentially new areas of treatment. To highlight this, we will additionally explore the role of the environment and the microbiome in the development of obesity and functional bowel disorders.
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http://dx.doi.org/10.1016/j.cgh.2018.08.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422042PMC
January 2019

Microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis: The Microbiome, Microbial Markers and Liver Disease Study.

Hepatol Res 2018 Dec 30;48(13):1108-1117. Epub 2018 Jul 30.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Aim: Cirrhosis is a leading cause of death worldwide, yet there are no well-established risk stratifying tools for lethal complications, including hepatocellular carcinoma (HCC). Patients with liver cirrhosis undergo routine endoscopic surveillance, providing ready access to duodenal aspirate samples that could be a source for identifying novel biomarkers. The aim of this study was to characterize the microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis to assess the feasibility of developing biomarkers for HCC risk stratification.

Methods: Thirty patients with liver cirrhosis were enrolled in the Microbiome, Microbial Markers, and Liver Disease study between May 2015 and March 2017. Detailed clinical and epidemiological data were collected at baseline and at 6-monthly follow-up visits. Duodenal aspirate fluid was collected at baseline for microbial characterization using 16S ribosomal RNA sequencing and bile acid quantification using mass spectroscopy.

Results: Alcohol-related cirrhosis was associated with reductions in the Bacteroidetes phylum, particularly Prevotella (13-fold reduction), and expansion of Staphylococcus (13-fold increase), compared to hepatitis C virus-related cirrhosis. Participants with hepatic encephalopathy (HE) had less microbial diversity compared to patients without HE (P < 0.05), and were characterized by expansion of Mycobacterium (45-fold increase) and Gram-positive cocci including Granulicatella (3.1-fold increase), unclassified Planococcaceae (3.3-fold increase), and unclassified Streptococcaceae (4.5-fold increase). Non-Hispanic White patients had reduced microbial richness (P < 0.01) and diversity (P < 0.05), and increased levels of conjugated ursodeoxycholic acid (glycoursodeoxycholic acid and tauroursodeoxycholic acid, P < 0.05) compared to Hispanic patients.

Conclusion: Microbial profiles of duodenal aspirates differed by cirrhosis etiology, HE, and Hispanic ethnicity.
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http://dx.doi.org/10.1111/hepr.13207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334634PMC
December 2018

Race affects SVR12 in a large and ethnically diverse hepatitis C-infected patient population following treatment with direct-acting antivirals: Analysis of a single-center Department of Veterans Affairs cohort.

Pharmacol Res Perspect 2018 04 22;6(2):e00379. Epub 2018 Feb 22.

Division of Gastroenterology, Hepatology and Parenteral Nutrition Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA USA.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. HCV cure has been linked to improved patient outcomes. In the era of direct-acting antivirals (DAAs), HCV cure has become the goal, as defined by sustained virological response 12 weeks (SVR12) after completion of therapy. Historically, African-Americans have had lower SVR12 rates compared to White people in the interferon era, which had been attributed to the high prevalence of non-CC interleukin 28B (IL28B) type. Less is known about the association between race/ethnicity and SVR12 in DAA-treated era. The aim of the study is to evaluate the predictors of SVR12 in a diverse, single-center Veterans Affairs population. We conducted a retrospective study of patients undergoing HCV therapy with DAAs from 2014 to 2016 at the VA Greater Los Angeles Healthcare System. We performed a multivariable logistic regression analysis to determine predictors of SVR12, adjusting for age, HCV genotype, DAA regimen and duration, human immunodeficiency virus (HIV) status, fibrosis, nonalcoholic fatty liver disease (NAFLD) fibrosis score, homelessness, mental health, and adherence. Our cohort included 1068 patients, out of which 401 (37.5%) were White people and 400 (37.5%) were African-American. Genotype 1 was the most common genotype (83.9%, N = 896). In the adjusted models, race/ethnicity and the presence of fibrosis were statistically significant predictors of non-SVR. African-Americans had 57% lower odds for reaching SVR12 (adj.OR = 0.43, 95% CI = 1.5-4.1) compared to White people. Advanced fibrosis (adj.OR = 0.40, 95% CI = 0.26-0.68) was also a significant predictor of non-SVR. In a single-center VA population on DAAs, African-Americans were less likely than White people to reach SVR12 when adjusting for covariates.
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http://dx.doi.org/10.1002/prp2.379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821896PMC
April 2018

Impact of sustained virologic response on chronic kidney disease progression in hepatitis C.

World J Hepatol 2017 Dec;9(36):1352-1360

Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States.

Aim: To determine how sustained virological response at 12 wk (SVR12) with direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection affects chronic kidney disease (CKD) progression.

Methods: A retrospective analysis was performed in patients aged ≥ 18 years treated for HCV with DAAs at the VA Greater Los Angeles Healthcare System from 2014-2016. The treatment group was compared to patients with HCV from 2011-2013 who did not undergo HCV treatment, prior to the introduction of DAAs; the control group was matched to the study group in terms of age, gender, and ethnicity. Analysis of variance and co-variance was performed to compare means between SVR12 subgroups adjusting for co-variates.

Results: Five hundred and twenty-three patients were evaluated. When comparing the rate of change in estimated glomerular filtration rate (eGFR) one-year after HCV treatment to one-year before treatment, patients who achieved SVR12 had a decline in GFR of 3.1 mL/min ± 0.75 mL/min per 1.73 m compared to a decline in eGFR of 11.0 mL/min ± 2.81 mL/min per 1.73 m in patients who did not achieve SVR12 ( = 0.002). There were no significant clinical differences between patients who achieved SVR12 compared to those who did not in terms of cirrhosis, treatment course, treatment experience, CKD stage prior to treatment, diuretic use or other co-morbidities. The decline in eGFR in those with untreated HCV over 2 years was 2.8 mL/min ± 1.0 mL/min per 1.73 m, which was not significantly different from the eGFR decline noted in HCV-treated patients who achieved SVR12 ( = 0.43).

Conclusion: Patients who achieve SVR12 have a lesser decline in renal function, but viral eradication in itself may not be associated improvement in renal disease progression.
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http://dx.doi.org/10.4254/wjh.v9.i36.1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756725PMC
December 2017

Discharge disposition as an independent predictor of readmission among patients hospitalised for community-acquired pneumonia.

Int J Clin Pract 2017 Mar;71(3-4)

Section of Hospital Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.

Background: Community-acquired pneumonia (CAP) is the most common non-obstetrical reason for hospital admission, the leading infectious cause of death, and a target for public reporting. CAP has thus become a target of quality improvement and pay-for-performance efforts. However, the relationship between discharge disposition and readmission risk has not been investigated.

Methods: We studied CAP patients admitted to the University of Chicago from 11/2011 to 04/2015. We collected demographic information, comorbidities, laboratory values, vital signs, a modified pneumonia severity index (PSI), length of stay (LOS), clinical instabilities before discharge, discharge disposition and 30-day all-cause readmission. A multivariate logistic regression was performed, specifying readmission as the dependent variable, including as independent variables gender, ethnicity, insurance status, discharge disposition, PSI tertile, the number of clinical instabilities, LOS and comorbidities.

Results: Of the 2892 CAP patients identified, 14.9% were readmitted. The distribution of discharge disposition was: 43.0% home without services, 26.1% home with home health care (HHC), 16.2% to a skilled nursing or subacute rehabilitation facility and 14.8% to an acute rehabilitation or long-term acute care facility. Of patients discharged home with HHC, 20.1% were readmitted, compared to 11.5% discharged home without services. In the multivariate regression model, being discharged home with HHC was associated with a markedly greater risk of readmission (Odds ratio 1.58 [95% confidence interval 1.21-2.07]).

Conclusions: Discharge home with HHC is an independent predictor of readmission risk among hospitalised CAP patients. Discharging providers should carefully consider follow-up care and social factors that may impact the risk of readmission among such patients.
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http://dx.doi.org/10.1111/ijcp.12935DOI Listing
March 2017
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