Publications by authors named "Venu Lagishetty"

48 Publications

Pilot trial of vitamin D3 and calcifediol in healthy vitamin D deficient adults: does it change the fecal microbiome?

J Clin Endocrinol Metab 2021 Aug 3. Epub 2021 Aug 3.

Departments of Orthopaedic Surgery and Medicine, David Geffen School of Medicine and Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles.

Purpose: To determine whether correcting vitamin D deficiency with cholecalciferol (vitamin D3, D3) or calcifediol (25-hydroxyvitamin D3, 25(OH)D3) changes gut microbiome composition.

Methods: 18 adults with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <20 ng/ml) received 60 mcg/day of D3 or 20 mcg/day of 25(OH)D3 for 8 weeks. Changes in serum 25(OH)D, 1,25-diydroxyvitamin D (1,25(OH)2D), and 24,25-dihydroxyvitamin D (24,25(OH)2D) were assessed. We characterized composition of the fecal microbiota using 16S rRNA gene sequencing, and examined changes in α-diversity (Chao 1, Faith's Phylogenetic Diversity, Shannon Index), β-diversity (DEICODE), and genus-level abundances (DESeq2).

Results: Vitamin D3 and 25(OH)D3 groups were similar. After 8 weeks of vitamin D3, mean 25(OH)D and 24,25(OH)2D increased significantly, but 1,25(OH)2D did not (25(OH)D: 17.8 to 30.1 ng/ml [p=0.002]; 24,25(OH)2D: 1.1 to 2.7 ng/ml [p=0.003]; 1,25(OH)2D: 49.5 to 53.0 pg/ml [p=0.9]). After 8 weeks of 25(OH)D3, mean 25(OH)D, 24,25(OH)2D, and 1,25(OH)2D increased significantly (25(OH)D: 16.7 to 50.6 ng/ml [p<0.0001]; 24,25(OH)2D: 1.3 to 6.2 ng/ml [p=0.0001]; 1,25(OH)2D: 56.5 to 74.2 pg/ml [p=0.05]). Fecal microbial α-diversity and β-diversity did not change with D3 or 25D3 supplementation. Mean relative abundance of Firmicutes increased and mean relative abundance of Bacterioidetes decreased from baseline to four weeks, but returned to baseline by study completion. DESeq2 analysis did not confirm any statistically significant taxonomic changes.

Main Conclusions: In a small sample of healthy adults with vitamin D deficiency, restoration of vitamin D sufficiency with vitamin D3 or 25(OH)D3 did not lead to lasting changes in the fecal microbiota.
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http://dx.doi.org/10.1210/clinem/dgab573DOI Listing
August 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

Unhealthy Lifestyle and Gut Dysbiosis: A Better Understanding of the Effects of Poor Diet and Nicotine on the Intestinal Microbiome.

Front Endocrinol (Lausanne) 2021 8;12:667066. Epub 2021 Jun 8.

Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States.

The study of the intestinal or gut microbiome is a newer field that is rapidly gaining attention. Bidirectional communication between gut microbes and the host can impact numerous biological systems regulating immunity and metabolism to either promote or negatively impact the host's health. Habitual routines, dietary choices, socioeconomic status, education, host genetics, medical care and environmental factors can all contribute to the composition of an individual's microbiome. A key environmental factor that may cause negative outcomes is the consumption of nicotine products. The effects of nicotine on the host can be exacerbated by poor dietary choices and together can impact the composition of the gut microbiota to promote the development of metabolic disease including non-alcoholic fatty liver disease. This review explores the contribution of nicotine, poor dietary choices and other unhealthy lifestyle factors to gut dysbiosis.
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http://dx.doi.org/10.3389/fendo.2021.667066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218903PMC
June 2021

Development of the infant gut microbiome predicts temperament across the first year of life.

Dev Psychopathol 2021 Jun 10:1-12. Epub 2021 Jun 10.

Department of Psychology, Chapman University, Orange, CA, USA.

Perturbations to the gut microbiome are implicated in altered neurodevelopmental trajectories that may shape life span risk for emotion dysregulation and affective disorders. However, the sensitive periods during which the microbiome may influence neurodevelopment remain understudied. We investigated relationships between gut microbiome composition across infancy and temperament at 12 months of age. In 67 infants, we examined if gut microbiome composition assessed at 1-3 weeks, 2, 6, and 12 months of age was associated with temperament at age 12 months. Stool samples were sequenced using the 16S Illumina MiSeq platform. Temperament was assessed using the Infant Behavior Questionnaire-Revised (IBQ-R). Beta diversity at age 1-3 weeks was associated with surgency/extraversion at age 12 months. Bifidobacterium and Lachnospiraceae abundance at 1-3 weeks of age was positively associated with surgency/extraversion at age 12 months. Klebsiella abundance at 1-3 weeks was negatively associated with surgency/extraversion at 12 months. Concurrent composition was associated with negative affectivity at 12 months, including a positive association with Ruminococcus-1 and a negative association with Lactobacillus. Our findings support a relationship between gut microbiome composition and infant temperament. While exploratory due to the small sample size, these results point to early and late infancy as sensitive periods during which the gut microbiome may exert effects on neurodevelopment.
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http://dx.doi.org/10.1017/S0954579421000456DOI Listing
June 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

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

Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota.

Science 2020 10;370(6515):467-472

Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

Colon mucus segregates the intestinal microbiota from host tissues, but how it organizes to function throughout the colon is unclear. In mice, we found that colon mucus consists of two distinct O-glycosylated entities of Muc2: a major form produced by the proximal colon, which encapsulates the fecal material including the microbiota, and a minor form derived from the distal colon, which adheres to the major form. The microbiota directs its own encapsulation by inducing Muc2 production from proximal colon goblet cells. In turn, O-glycans on proximal colon-derived Muc2 modulate the structure and function of the microbiota as well as transcription in the colon mucosa. Our work shows how proximal colon control of mucin production is an important element in the regulation of host-microbiota symbiosis.
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http://dx.doi.org/10.1126/science.aay7367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132455PMC
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

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

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

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice.

Aging (Albany NY) 2019 01;11(1):209-229

Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1 mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1 lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1 lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.
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http://dx.doi.org/10.18632/aging.101742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339797PMC
January 2019

Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome.

Mucosal Immunol 2018 09 9;11(5):1466-1476. Epub 2018 Jul 9.

F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated. We demonstrate that the pro-fibrotic and inflammatory phenotype resulting from Tl1a-overexpression is abrogated in the absence of resident microbiota. To evaluate if this is due to the absence of a unique bacterial population, as opposed to any bacteria per se, we gavaged germ-free (GF) wild-type and Tl1a-transgenic (Tl1a-Tg) mice with stool from specific pathogen free (SPF) mice and a healthy human donor (Hu). Reconstitution with SPF, but not Hu microbiota, resulted in increased intestinal collagen deposition and fibroblast activation in Tl1a-Tg mice. Notably, there was reduced fibroblast migration and activation under GF conditions compared to native conditions. We then identified several candidate organisms that correlated directly with increased fibrosis in reconstituted mice and showed that these organisms directly impact fibroblast function in vitro. Thus, Tl1a-mediated intestinal fibrosis and fibroblast activation are dependent on specific microbial populations.
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http://dx.doi.org/10.1038/s41385-018-0055-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162160PMC
September 2018

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

Ceragenin CSA13 Reduces Clostridium difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites.

Gastroenterology 2018 05 31;154(6):1737-1750. Epub 2018 Jan 31.

Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California. Electronic address:

Background & Aims: Clostridium difficile induces intestinal inflammation by releasing toxins A and B. The antimicrobial compound cationic steroid antimicrobial 13 (CSA13) has been developed for treating gastrointestinal infections. The CSA13-Eudragit formulation can be given orally and releases CSA13 in the terminal ileum and colon. We investigated whether this form of CSA13 reduces C difficile infection (CDI) in mice.

Methods: C57BL/6J mice were infected with C difficile on day 0, followed by subcutaneous administration of pure CSA13 or oral administration of CSA13-Eudragit (10 mg/kg/d for 10 days). Some mice were given intraperitoneal vancomycin (50 mg/kg daily) on days 0-4 and relapse was measured after antibiotic withdrawal. The mice were monitored until day 20; colon and fecal samples were collected on day 3 for analysis. Blood samples were collected for flow cytometry analyses. Fecal pellets were collected each day from mice injected with CSA13 and analyzed by high-performance liquid chromatography or 16S sequencing; feces were also homogenized in phosphate-buffered saline and fed to mice with CDI via gavage.

Results: CDI of mice caused 60% mortality, significant bodyweight loss, and colonic damage 3 days after infection; these events were prevented by subcutaneous injection of CSA13 or oral administration CSA13-Eudragit. There was reduced relapse of CDI after administration of CSA13 was stopped. Levels of CSA13 in feces from mice given CSA13-Eudragit were significantly higher than those of mice given subcutaneous CSA13. Subcutaneous and oral CSA13 each significantly increased the abundance of Peptostreptococcaceae bacteria and reduced the abundance of C difficile in fecal samples of mice. When feces from mice with CDI and given CSA13 were fed to mice with CDI that had not received CSA13, the recipient mice had significantly increased rates of survival. CSA13 reduced fecal levels of inflammatory metabolites (endocannabinoids) and increased fecal levels of 4 protective metabolites (ie, citrulline, 3-aminoisobutyric acid, retinol, and ursodeoxycholic acid) in mice with CDI. Oral administration of these CSA13-dependent protective metabolites reduced the severity of CDI.

Conclusions: In studies of mice, we found the CSA13-Eudragit formulation to be effective in eradicating CDI by modulating the intestinal microbiota and metabolites.
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http://dx.doi.org/10.1053/j.gastro.2018.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927842PMC
May 2018

CSA13 inhibits colitis-associated intestinal fibrosis via a formyl peptide receptor like-1 mediated HMG-CoA reductase pathway.

Sci Rep 2017 11 27;7(1):16351. Epub 2017 Nov 27.

Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, 90095, USA.

Many Crohn's disease (CD) patients develop intestinal strictures, which are difficult to prevent and treat. Cationic steroid antimicrobial 13 (CSA13) shares cationic nature and antimicrobial function with antimicrobial peptide cathelicidin. As many functions of cathelicidin are mediated through formyl peptide receptor-like 1 (FPRL1), we hypothesize that CSA13 mediates anti-fibrogenic effects via FPRL1. Human intestinal biopsies were used in clinical data analysis. Chronic trinitrobenzene sulfonic acid (TNBS) colitis-associated intestinal fibrosis mouse model with the administration of CSA13 was used. Colonic FPRL1 mRNA expression was positively correlated with the histology scores of inflammatory bowel disease patients. In CD patients, colonic FPRL1 mRNA was positively correlated with intestinal stricture. CSA13 administration ameliorated intestinal fibrosis without influencing intestinal microbiota. Inhibition of FPRL1, but not suppression of intestinal microbiota, reversed these protective effects of CSA13. Metabolomic analysis indicated increased fecal mevalonate levels in the TNBS-treated mice, which were reduced by the CSA13 administration. CSA13 inhibited colonic HMG-CoA reductase activity in an FPRL1-dependent manner. Mevalonate reversed the anti-fibrogenic effect of CSA13. The increased colonic FPRL1 expression is associated with severe mucosal disease activity and intestinal stricture. CSA13 inhibits intestinal fibrosis via FPRL1-dependent modulation of HMG-CoA reductase pathway.
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http://dx.doi.org/10.1038/s41598-017-16753-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703874PMC
November 2017

Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts.

BMJ Open Gastroenterol 2017 1;4(1):e000134. Epub 2017 Apr 1.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Objective: To compare faecal microbial composition in patients with systemic sclerosis (SSc) from 2 independent cohorts with controls and to determine whether certain genera are associated with SSc-gastrointestinal tract (GIT) symptoms.

Design: Adult patients with SSc from the University of California, Los Angeles (UCLA) and Oslo University Hospital (OUH) and healthy controls participated in this study (1:1:1). All participants provided stool specimens for 16S rRNA sequencing. Linear discriminant analysis effect size demonstrated genera with differential expression in SSc. Differential expression analysis for sequence count data identified specific genera associated with GIT symptoms as assessed by the GIT 2.0 questionnaire.

Results: The UCLA-SSc and OUH-SSc cohorts were similar in age (52.1 and 60.5 years, respectively), disease duration (median (IQR): 6.6 (2.5-16.4) and 7.0 (1.0-19.2) years, respectively), gender distribution (88% and 71%, respectively), and GIT symptoms (mean (SD) total GIT 2.0 scores of 0.7 (0.6) and 0.6 (0.5), respectively). Principal coordinate analysis illustrated significant microbial community differences between SSc and controls (UCLA: p=0.001; OUH: p=0.002). Patients with SSc had significantly lower levels of commensal genera deemed to protect against inflammation, such as (UCLA and OUH), (UCLA), (OUH); and significantly higher levels of pathobiont genera, such as (UCLA), compared with controls. Increased abundance of was associated with less severe GIT symptoms in both cohorts.

Conclusions: The present analysis detected specific aberrations in the lower GIT microbiota of patients with SSc from 2 geographically and ethnically distinct cohorts. These findings suggest that GIT dysbiosis may be a pathological feature of the SSc disease state.
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http://dx.doi.org/10.1136/bmjgast-2017-000134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508636PMC
April 2017

High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats.

Am J Physiol Regul Integr Comp Physiol 2017 Oct 19;313(4):R473-R486. Epub 2017 Jul 19.

CURE/Digestive Diseases Research Center and Center for Neurobiology of Stress and Resilience, Department of Medicine, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and.

High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity, while not modifying brain inflammation. In addition, expansion of cecal correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects.
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http://dx.doi.org/10.1152/ajpregu.00105.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668619PMC
October 2017

Surgically Induced Changes in Gut Microbiome and Hedonic Eating as Related to Weight Loss: Preliminary Findings in Obese Women Undergoing Bariatric Surgery.

Psychosom Med 2017 Oct;79(8):880-887

From the Ingestive Behavior and Obesity Program (Sanmiguel, Gupta, Ju, Stains, Coveleskie, Mayer, Labus), Oppenheimer Center for Neurobiology of Stress & Resilience; Department of Surgery (Balioukova, Chen, Dutson), Center for Obesity and Metabolic Health; UCLA Microbiome Center (Sanmiguel, Jacobs, Lagishetty, Mayer, Labus); and David Geffen School of Medicine at UCLA (Sanmiguel, Jacobs, Gupta, Ju, Stains, Lagishetty, Balioukova, Chen, Dutson, Mayer, Labus), Los Angeles, California.

Objective: Weight loss surgery results in significant changes in the anatomy, function, and intraluminal environment of the gastrointestinal tract affecting the gut microbiome. Although bariatric surgery results in sustained weight loss, decreased appetite, and hedonic eating, it is unknown whether the surgery-induced alterations in gut microbiota play a role in the observed changes in hedonic eating. We explored the following hypotheses: (1) laparoscopic sleeve gastrectomy (LSG) results in changes in gut microbial composition; (2) alterations in gut microbiota are related to weight loss; (3) alterations in gut microbiome are associated with changes in appetite and hedonic eating.

Methods: Eight obese women underwent LSG. Their body mass index, body fat mass, food intake, hunger, hedonic eating scores, and stool samples were obtained at baseline and 1-month postsurgery. 16S ribosomal RNA gene sequencing was performed on stool samples. DESeq2 changes in microbial abundance. Multilevel-sparse partial least squares discriminant analysis was applied to genus-level abundance for discriminative microbial signatures.

Results: LSG resulted in significant reductions in body mass index, food intake, and hedonic eating. A microbial signature composed of five bacterial genera discriminated between pre- and postsurgery status. Several bacterial genera were significantly associated with weight loss (Bilophila, q = 3E-05; Faecalibacterium q = 4E-05), lower appetite (Enterococcus, q = 3E-05), and reduced hedonic eating (Akkermansia, q = .037) after surgery.

Conclusions: In this preliminary analysis, changes in gut microbial abundance discriminated between pre- and postoperative status. Alterations in gut microbiome were significantly associated with weight loss and with reduced hedonic eating after surgery; however, a larger sample is needed to confirm these findings.
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http://dx.doi.org/10.1097/PSY.0000000000000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628115PMC
October 2017

Isolation and characterization of canine perivascular stem/stromal cells for bone tissue engineering.

PLoS One 2017 10;12(5):e0177308. Epub 2017 May 10.

UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, California, United States of America.

For over 15 years, human subcutaneous adipose tissue has been recognized as a rich source of tissue resident mesenchymal stem/stromal cells (MSC). The isolation of perivascular progenitor cells from human adipose tissue by a cell sorting strategy was first published in 2008. Since this time, the interest in using pericytes and related perivascular stem/stromal cell (PSC) populations for tissue engineering has significantly increased. Here, we describe a set of experiments identifying, isolating and characterizing PSC from canine tissue (N = 12 canine adipose tissue samples). Results showed that the same antibodies used for human PSC identification and isolation are cross-reactive with canine tissue (CD45, CD146, CD34). Like their human correlate, canine PSC demonstrate characteristics of MSC including cell surface marker expression, colony forming unit-fibroblast (CFU-F) inclusion, and osteogenic differentiation potential. As well, canine PSC respond to osteoinductive signals in a similar fashion as do human PSC, such as the secreted differentiation factor NEL-Like Molecule-1 (NELL-1). Nevertheless, important differences exist between human and canine PSC, including differences in baseline osteogenic potential. In summary, canine PSC represent a multipotent mesenchymogenic cell source for future translational efforts in tissue engineering.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177308PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425216PMC
September 2017

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients.

Clin Immunol 2017 02 21;175:82-90. Epub 2016 Dec 21.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.
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http://dx.doi.org/10.1016/j.clim.2016.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040888PMC
February 2017

Dysregulation of CLOCK gene expression in hyperoxia-induced lung injury.

Am J Physiol Cell Physiol 2014 Jun 2;306(11):C999-C1007. Epub 2014 Apr 2.

Division of Allergy and Immunology, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida

Hyperoxic acute lung injury (HALI) is characterized by inflammation and epithelial cell death. CLOCK genes are master regulators of circadian rhythm also implicated in inflammation and lung diseases. However, the relationship of CLOCK genes in hyperoxia-induced lung injury has not been studied. This study will determine if HALI alters CLOCK gene expression. To test this, wild-type and NALP3(-/-) mice were exposed to room air or hyperoxia for 24, 48, or 72 h. In addition, mice were exposed to different concentrations of hyperoxia (50, 75, or 100% O2) or room air for 72 h. The mRNA and protein levels of lung CLOCK genes, based on quantitative PCR and Western blot analysis, respectively, and their target genes are significantly elevated in mice exposed to hyperoxia compared with controls. Alterations in CLOCK genes are associated with increased inflammatory markers in bronchoalveolar lavage fluid of hyperoxic mice compared with controls. Histological examination of mice lungs exposed to hyperoxia show increased inflammation and alveolar congestion compared with controls. Our results indicate sequential increase in CLOCK gene expression in lungs of mice exposed to hyperoxia compared with controls. Additionally, data suggest a dose-dependent increase in CLOCK gene expression with increased oxygen concentrations. To validate if the expression changes related to CLOCK genes are indeed associated with inflammation, NALP3(-/-) was introduced to analyze loss of function in inflammation. Western blot analysis showed significant CLOCK gene downregulation in NALP3(-/-) mice compared with wild-type controls. Together, our results demonstrate that hyperoxia-mediated lung inflammation is associated with alterations in CLOCK gene expression.
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http://dx.doi.org/10.1152/ajpcell.00064.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042094PMC
June 2014

Dietary vitamin D restriction in pregnant female mice is associated with maternal hypertension and altered placental and fetal development.

Endocrinology 2013 Jul 15;154(7):2270-80. Epub 2013 May 15.

Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Epidemiology has linked vitamin D deficiency with preeclampsia in humans. We hypothesized that low vitamin D status in pregnant mice may lead to symptoms of preeclampsia. Female BL6 mice were raised on vitamin D-sufficient or -deficient diets from weeks 4 of age and then mated with vitamin D-sufficient BL6 males at week 8. The resulting pregnant mice were either allowed to deliver pups and monitored for blood pressure (BP) and weight of offspring or euthanized at day 14 or 18 of gestation (E14 or E18) for analysis of serum, placental/kidney tissues, and fetuses. At E14 serum concentrations of 25-hydroxyvitamin D (30.1 ± 5.0 vs 1.8 ± 0.6 ng/mL, P < .001) and 1,25-dihydroxyvitamin D (119.5 ± 18.7 vs 37.4 ± 5.1 pg/mL, P < .01) were higher in sufficient vs deficient pregnant mice. At E14 BP was significantly elevated in vitamin D-deficient pregnant mice relative to vitamin D-sufficient mice for both systolic BP (124.89 ± 2.28 vs 105.34 ± 3.61 mm Hg, P < .001) and mean arterial pressure (115.33 ± 1.93 vs 89.33 ± 5.02 mm Hg, P < .001). This elevation continued through pregnancy until 7 days postpartum (PP7) but returned to baseline by PP14. Analysis of maternal kidneys showed increased expression of mRNA for renin and the angiotensin II receptor (3- and 4-fold, respectively) in vitamin D-deficient vs -sufficient mice at E14. Histological analysis of E14 placentas from vitamin D-deficient mice showed decreased vascular diameter within the labyrinth region. E14 and E18 fetuses from vitamin D-deficient mice were larger than those from vitamin D-sufficient mothers. However, by PP14 pups from vitamin D-deficient mothers weighed significantly less than those from vitamin D-sufficient mothers. Resupplementation of vitamin D periconceptually partially reversed the effects of vitamin D deficiency. These data provide further evidence that low vitamin D status may predispose pregnant women to dysregulated placental development and elevated blood pressure.
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http://dx.doi.org/10.1210/en.2012-2270DOI Listing
July 2013
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