Gopanandan Parthasarathy
Clinical Instructor, Medicine - Gastroenterology & Hepatology
Bio
Dr Nandan Parthasarathy is a hepatologist and physician-scientist in the Department of Gastroenterology and Hepatology at Stanford University.
After obtaining his medical degree in JIPMER, India, he completed a 2 year clinical research fellowship at Mayo Clinic, following which he completed his residency training at Cleveland Clinic, and GI and transplant hepatology fellowships at Mayo Clinic. During his fellowship, his research work was focused on exploring the immune mechanisms of liver injury in metabolic dysfunction associated steatohepatitis.
Clinically, he is focused on taking care of patients with MASH, cirrhosis and liver cancer.
His career goal is to study the gut-immune system-liver injury axis in order to bring novel therapeutics from the bench to bedside in patients with liver disease.
Professional Education
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Board Certification, American Board of Internal Medicine, Transplant Hepatology (2024)
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Board Certification, American Board of Internal Medicine, Gastroenterology and Hepatology (2022)
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Board Certification, American Board of Internal Medicine, Internal Medicine (2019)
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Fellowship, Mayo Clinic, Rochester, Transplant Hepatology (2023)
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Fellowship, Mayo Clinic, Rochester, Gastroenterology and Hepatology (2022)
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Residency, Cleveland Clinic, Cleveland, Internal Medicine (2019)
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MBBS, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India, Medicine (2014)
https://orcid.org/0000-0002-8847-1645All Publications
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Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH
HEPATOLOGY COMMUNICATIONS
2025; 9 (2)
Abstract
Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver.The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry.Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol-fed S1pr1MKO compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol-fed S1pr1MKO mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator-activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1MKO consistent with attenuated MASH in mice.Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.
View details for DOI 10.1097/HC9.0000000000000613
View details for Web of Science ID 001411415000001
View details for PubMedID 39899672
View details for PubMedCentralID PMC12333770
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Therapeutic manipulation of the microbiome in liver disease
HEPATOLOGY
2024
Abstract
Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.
View details for DOI 10.1097/HEP.0000000000000987
View details for Web of Science ID 001272319000003
View details for PubMedID 38922826
View details for PubMedCentralID PMC12167619
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Macrophage RAGE activation is proinflammatory in NASH
JCI INSIGHT
2024; 9 (3)
Abstract
Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.
View details for DOI 10.1172/jci.insight.169138
View details for Web of Science ID 001160672400001
View details for PubMedID 38175729
View details for PubMedCentralID PMC10967390
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Extracellular Vesicles in Hepatobiliary Health and Disease
COMPREHENSIVE PHYSIOLOGY
2023; 13 (3): 4631-4658
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
View details for DOI 10.1002/cphy.c210046
View details for Web of Science ID 001054228600001
View details for PubMedID 37358519
View details for PubMedCentralID PMC10798368
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Hepatology highlights.
Hepatology (Baltimore, Md.)
2022; 76 (4): 901-902
View details for DOI 10.1002/hep.32683
View details for PubMedID 36121757
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Assessment of Lipotoxic Endoplasmic Reticulum (ER) Stress in Nonalcoholic Steatohepatitis (NASH).
Methods in molecular biology (Clifton, N.J.)
2022; 2455: 243-254
Abstract
Hepatocyte lipotoxicity is a hallmark of nonalcoholic steatohepatitis (NASH), and lipid induced liver injury occurs, in part, via activation of endoplasmic reticulum (ER) stress. Consequently, the unfolded protein response (UPR) is initiated, driven by three key ER transmembrane proteins, resulting in downstream responses that are dynamic and interconnected. Thus, careful interrogation of these pathways is required to investigate the complex role of ER stress in NASH. Herein, we describe different mechanisms of, and in vitro assays for assessment of lipotoxic ER stress in mouse hepatocytes.
View details for DOI 10.1007/978-1-0716-2128-8_19
View details for PubMedID 35212999
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2022; 75 (1): 1-2
View details for DOI 10.1002/hep.32267
View details for PubMedID 34923661
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Circulating extracellular vesicles are a biomarker for NAFLD resolution and response to weight loss surgery
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
2021; 36: 102430
Abstract
There is increasing interest in the development of minimally invasive biomarkers for the diagnosis and prognosis of NAFLD via extracellular vesicles (EV). Plasma EVs were isolated by differential ultracentrifugation and quantified by nanoparticle tracking analysis from pre (n = 28) and post (n = 28) weight loss patients. In the pre weight loss group 22 had NAFLD. Nanoplasmon enhanced scattering (nPES) of gold nanoparticles conjugated to hepatocyte-specific antibodies was employed to identify hepatocyte-specific EVs. Complex lipid panel and targeted sphingolipids were performed. Logistic regression analysis was used to identify predictors of NAFLD. Plasma levels of EVs and hepatocyte-derived EVs are dynamic and decrease following NAFLD resolution due to weight loss surgery. Hepatocyte-derived EVs correlate with steatosis in NAFLD patients and steatosis and inflammation in NASH patients. Plasma levels of small EVs correlate with EV sphingolipids in patients with NASH. Hepatocyte-derived EVs measured by the nPES assay could serve as a point-of-care test for NAFLD.
View details for DOI 10.1016/j.nano.2021.102430
View details for Web of Science ID 000687935400004
View details for PubMedID 34174416
View details for PubMedCentralID PMC8418232
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2021; 73 (6): 2085-2088
View details for DOI 10.1002/hep.31883
View details for PubMedID 34145622
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Macrophage Heterogeneity in NASH: More Than Just Nomenclature
HEPATOLOGY
2021; 74 (1): 515-518
View details for DOI 10.1002/hep.31790
View details for Web of Science ID 000652803400001
View details for PubMedID 33666272
View details for PubMedCentralID PMC8662756
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2021; 73 (4): 1245-1247
View details for DOI 10.1002/hep.31813
View details for PubMedID 33851455
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Hepatic steatosis and steatohepatitis: a functional meta-analysis of sex-based differences in transcriptomic studies
BIOLOGY OF SEX DIFFERENCES
2021; 12 (1): 29
Abstract
Previous studies have described sex-based differences in the epidemiological and clinical patterns of non-alcoholic fatty liver disease (NAFLD); however, we understand relatively little regarding the underlying molecular mechanisms. Herein, we present the first systematic review and meta-analysis of NAFLD transcriptomic studies to identify sex-based differences in the molecular mechanisms involved during the steatosis (NAFL) and steatohepatitis (NASH) stages of the disease.Transcriptomic studies in the Gene Expression Omnibus database were systematically reviewed following the PRISMA statement guidelines. For each study, NAFL and NASH in premenopausal women and men were compared using a dual strategy: gene-set analysis and pathway activity analysis. Finally, the functional results of all studies were integrated into a meta-analysis.We reviewed a total of 114 abstracts and analyzed seven studies that included 323 eligible patients. The meta-analyses identified significantly altered molecular mechanisms between premenopausal women and men, including the overrepresentation of genes associated with DNA regulation, vinculin binding, interleukin-2 responses, negative regulation of neuronal death, and the transport of ions and cations in premenopausal women. In men, we discovered the overrepresentation of genes associated with the negative regulation of interleukin-6 and the establishment of planar polarity involved in neural tube closure.Our meta-analysis of transcriptomic data provides a powerful approach to identify sex-based differences in NAFLD. We detected differences in relevant biological functions and molecular terms between premenopausal women and men. Differences in immune responsiveness between men and premenopausal women with NAFLD suggest that women possess a more immune tolerant milieu, while men display an impaired liver regenerative response.
View details for DOI 10.1186/s13293-021-00368-1
View details for Web of Science ID 000632912700001
View details for PubMedID 33766130
View details for PubMedCentralID PMC7995602
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2021; 73 (3): 877-880
View details for DOI 10.1002/hep.31753
View details for PubMedID 33728693
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2021; 73 (2): 475-478
View details for DOI 10.1002/hep.31717
View details for PubMedID 33586814
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2021; 73 (1): 1-3
View details for DOI 10.1002/hep.31693
View details for PubMedID 33616975
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2020; 72 (6): 1893-1896
View details for DOI 10.1002/hep.31637
View details for PubMedID 33617006
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2020; 72 (5): 1505-1508
View details for DOI 10.1002/hep.31591
View details for PubMedID 33159409
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A natural language-based tool for diagnosis of serrated polyposis syndrome
GASTROINTESTINAL ENDOSCOPY
2020; 92 (4): 886-890
Abstract
Serrated polyposis syndrome (SPS) is common but under-recognized and is associated with an increased risk of colorectal cancer. The diagnosis is based on the World Health Organization (WHO) criteria and is inclusive of the cumulative number of lifetime serrated polyps. We used natural language processing (NLP) to extract colonoscopy and pathology data from the electronic medical record (EMR). The aim of this study was to assess feasibility of using an NLP-based SPS tool to identify patients with SPS.NLP was used to extract data from 323,494 colonoscopies performed in 255,074 distinct patients between August 1998 and March 2016 to identify individuals who met SPS criteria. The accuracy of diagnosis of SPS was assessed by manual review of the EMR.Of 255,074 patients, 71 were identified as meeting 1 WHO criteria for SPS. Manual review confirmed the diagnosis of SPS to be accurate in 66 cases (93%). Erroneous diagnosis in the remaining 5 cases occurred because of duplicate polyp data by NLP extraction. Only 25 of 66 patients (38%) were diagnosed with SPS by a clinician in the EMR. Of these, SPS was diagnosed by NLP at least 2 years before the clinician in 5 of 25 patients (20%).In a large cohort, NLP accurately identified SPS in over 90% of cases, most of which were not previously recognized. NLP can assist in collating colonoscopy and pathology data across multiple procedures in the same patient to make an accurate and earlier diagnosis of SPS.
View details for DOI 10.1016/j.gie.2020.04.077
View details for Web of Science ID 000574357800011
View details for PubMedID 32417299
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Hepatology Highlights.
Hepatology (Baltimore, Md.)
2020; 72 (3): 791-793
View details for DOI 10.1002/hep.31544
View details for PubMedID 33464576
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Development of an Automated Algorithm to Generate Guideline-based Recommendations for Follow-up Colonoscopy
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
2020; 18 (9): 2038-+
Abstract
Physician adherence to published colonoscopy surveillance guidelines varies. We aimed to develop and validate an automated clinical decision support algorithm that can extract procedure and pathology data from the electronic medical record (EMR) and generate surveillance intervals congruent with guidelines, which might increase physician adherence.We constructed a clinical decision support (CDS) algorithm based on guidelines from the United States Multi-Society Task Force on Colorectal Cancer. We used a randomly generated validation dataset of 300 outpatient colonoscopies performed at the Cleveland Clinic from 2012 through 2016 to evaluate the accuracy of extracting data from reports stored in the EMR using natural language processing (NLP). We compared colonoscopy follow-up recommendations from the CDS algorithm, endoscopists, and task force guidelines. Using a testing dataset of 2439 colonoscopies, we compared endoscopist recommendations with those of the algorithm.Manual review of the validation dataset confirmed the NLP program accurately extracted procedure and pathology data for all cases. Recommendations made by endoscopists and the CDS algorithm were guideline-concordant in 62% and 99% of cases, respectively. Discrepant recommendations by endoscopists were earlier than recommended in 94% of the cases. In the testing dataset, 69% of endoscopist and NLP-CDS algorithm recommendations were concordant. Discrepant recommendations by endoscopists were earlier than guidelines in 91% of cases.We constructed and tested an automated CDS algorithm that can use NLP-extracted data from the EMR to generate follow-up colonoscopy surveillance recommendations based on published guidelines.
View details for DOI 10.1016/j.cgh.2019.10.013
View details for Web of Science ID 000550173100028
View details for PubMedID 31622739
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Pathogenesis of Nonalcoholic Steatohepatitis: An Overview
HEPATOLOGY COMMUNICATIONS
2020; 4 (4): 478-492
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid-induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage- and pathogen-associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut-liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.
View details for DOI 10.1002/hep4.1479
View details for Web of Science ID 000507479800001
View details for PubMedID 32258944
View details for PubMedCentralID PMC7109346
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Aging, Obesity, and the Incidence of Diverticulitis: A Population-Based Study
MAYO CLINIC PROCEEDINGS
2018; 93 (9): 1256-1265
Abstract
To understand why the population-based incidence of diverticulitis has increased over time, we studied temporal changes in age, body mass index (BMI), and diverticulitis in Olmsted County, Minnesota.We compared the BMIs of 2967 patients with diverticulitis and 9795 people without diverticulitis from January 1, 1980, through December 31, 2007. Because BMI is a surrogate for adipose tissue, computed tomographic estimations of abdominal fat content were compared between 381 diverticulitis cases and 381 age- and sex-matched controls.Between 1980 and 2007, the prevalence of obesity increased from 12% to 49% in the population and from 19% to 40% in patients with diverticulitis (P<.001 for both). Temporal trends in age, BMI, and the increased incidence of diverticulitis in people with normal BMI accounted for 48%, 47%, and 20%, respectively, of corresponding trends in diverticulitis. The secular decline in the proportion of people with normal BMI was partly offset by an increased incidence of diverticulitis in such people. In the case-control study, BMI was greater in cases than in controls (P=.001). However, after incorporating abdominal visceral (odds ratio [OR], 2.4; 95% CI, 1.6-3.7) and subcutaneous (OR, 2.9; 95% CI, 1.7-5.2) fat content (both associated with diverticulitis), BMI was associated with lower risk (OR, 0.8; 95% CI, 0.7-0.8) of diverticulitis.Aging, increasing obesity, and the increased incidence of diverticulitis in people with normal BMI account for the temporal increase in diverticulitis. Rather than BMI per se, increased abdominal visceral and subcutaneous fat are independently associated with diverticulitis. The incidence of diverticulitis, which is among the most common gastrointestinal diagnoses in hospitalized patients, has increased markedly since 2000. This study suggests that aging, increasing obesity, and the increased incidence of diverticulitis in people with normal BMI account for the temporal increase in diverticulitis.
View details for DOI 10.1016/j.mayocp.2018.03.005
View details for Web of Science ID 000443582100019
View details for PubMedID 30193674
View details for PubMedCentralID PMC6200415
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Assessing the colonic microbiome, hydrogenogenic and hydrogenotrophic genes, transit and breath methane in constipation
NEUROGASTROENTEROLOGY AND MOTILITY
2017; 29 (10): 1-9
Abstract
Differences in the gut microbiota and breath methane production have been observed in chronic constipation, but the relationship between colonic microbiota, transit, and breath tests remains unclear.In 25 healthy and 25 constipated females we evaluated the sigmoid colonic mucosal and fecal microbiota using 16S rRNA gene sequencing, abundance of hydrogenogenic FeFe (FeFe-hydA) and hydrogenotrophic (methyl coenzyme M reductase A [mrcA] and dissimilatory sulfite reductase A [dsrA]) genes with real-time qPCR assays, breath hydrogen and methane levels after oral lactulose, and colonic transit with scintigraphy.Breath hydrogen and methane were not correlated with constipation, slow colon transit, or with abundance of corresponding genes. After adjusting for colonic transit, the abundance of FeFehydA, dsrA, and mcrA were greater (P<.005) in colonic mucosa, but not stool, of constipated patients. The abundance of the selected functional gene targets also correlated with that of selected taxa. The colonic mucosal abundance of FeFe-hydA, but not mcrA, correlated positively (P<.05) with breath methane production, slow colonic transit, and overall microbiome composition. In the colonic mucosa and feces, the abundance of hydrogenogenic and hydrogenotrophic genes were positively correlated (P<.05). Breath methane production was not associated with constipation or colonic transit.Corroborating our earlier findings with 16S rRNA genes, colonic mucosal but not fecal hydrogenogenic and hydrogenotrophic genes were more abundant in constipated vs. healthy subjects independent of colonic transit. Breath gases do not directly reflect the abundance of target genes contributing to their production.
View details for DOI 10.1111/nmo.13056
View details for Web of Science ID 000410149700002
View details for PubMedID 28295896
View details for PubMedCentralID PMC5593760
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Reproducibility of assessing fecal microbiota in chronic constipation
NEUROGASTROENTEROLOGY AND MOTILITY
2017; 29 (10): 1-10
Abstract
While limited data suggest that the fecal microbiota in healthy people is stable over time, the intraindividual variability of the fecal microbiota in constipated patients is unknown.This study evaluated the intraindividual reproducibility of fecal microbiota analyzed with 16S rRNA gene sequencing in two stool samples collected without and after a laxative, respectively, in 25 healthy people and 25 constipated women. Participants completed a food record for 3 d before the stool collection. Colonic transit was measured with scintigraphy.The constipated patients were older (48±15 vs 39±10 y, P=.02) than healthy participants but had a similar BMI. The total daily caloric intake was less (P=.005) in constipated (1265±350 kcal) than healthy participants (1597±402 kcal). Fourteen patients but only two controls (P<.005), had delayed colonic transit. For most measures of alpha (eg, Observed OTU number, Shannon index) and beta diversity (eg, Bray-Curtis dissimilarity, UniFrac, phyla level abundance), the ICCs between two stool samples were high, indicating moderate or strong agreement, and similar in healthy people and constipated patients. The ICC for the weighted UniFrac distance, which is weighted by abundance, was lower than its unweighted counterpart, indicating that the unweighted measure is more robust and reproducible.The intraindividual reproducibility of fecal microbiota in constipated patients is high and comparable to healthy participants. For most purposes, evaluating the fecal microbiota in a single stool sample should generally suffice in adequately powered studies of healthy and constipated patients.
View details for DOI 10.1111/nmo.13172
View details for Web of Science ID 000410149700011
View details for PubMedID 28752633
View details for PubMedCentralID PMC5593773
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High-resolution Anorectal Manometry for Identifying Defecatory Disorders and Rectal Structural Abnormalities in Women
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
2017; 15 (3): 412-420
Abstract
Contrary to conventional wisdom, the rectoanal gradient during evacuation is negative in many healthy people, undermining the utility of anorectal high-resolution manometry (HRM) for diagnosing defecatory disorders. We aimed to compare HRM and magnetic resonance imaging (MRI) for assessing rectal evacuation and structural abnormalities.We performed a retrospective analysis of 118 patients (all female; 51 with constipation, 48 with fecal incontinence, and 19 with rectal prolapse; age, 53 ± 1 years) assessed by HRM, the rectal balloon expulsion test (BET), and MRI at Mayo Clinic, Rochester, Minnesota, from February 2011 through March 2013. Thirty healthy asymptomatic women (age, 37 ± 2 years) served as controls. We used principal components analysis of HRM variables to identify rectoanal pressure patterns associated with rectal prolapse and phenotypes of patients with prolapse.Compared with patients with normal findings from the rectal BET, patients with an abnormal BET had lower median rectal pressure (36 vs 22 mm Hg, P = .002), a more negative median rectoanal gradient (-6 vs -29 mm Hg, P = .006) during evacuation, and a lower proportion of evacuation on the basis of MRI analysis (median of 40% vs 80%, P < .0001). A score derived from rectal pressure and anorectal descent during evacuation and a patulous anal canal was associated (P = .005) with large rectoceles (3 cm or larger). A principal component (PC) logistic model discriminated between patients with and without prolapse with 96% accuracy. Among patients with prolapse, there were 2 phenotypes, which were characterized by high (PC1) or low (PC2) anal pressures at rest and squeeze along with higher rectal and anal pressures (PC1) or a higher rectoanal gradient during evacuation (PC2).In a retrospective analysis of patients assessed by HRM, measurements of rectal evacuation by anorectal HRM, BET, and MRI were correlated. HRM alone and together with anorectal descent during evacuation may identify rectal prolapse and large rectoceles, respectively, and also identify unique phenotypes of rectal prolapse.
View details for DOI 10.1016/j.cgh.2016.09.154
View details for Web of Science ID 000397246700020
View details for PubMedID 27720913
View details for PubMedCentralID PMC5316318
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Relationship Between Gastric Emptying and Diurnal Glycemic Control in Type 1 Diabetes Mellitus: A Randomized Trial
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2017; 102 (2): 398-406
Abstract
In type 1 diabetes (T1D), delayed gastric emptying (GE) may predispose to a mismatch between insulin delivery and glucose absorption. Previous studies evaluated, only partly, the relationship between delayed GE and postprandial, but not diurnal, glycemia.To assess the relationship between GE disturbances and glycemic control in T1D and the effects of accelerating GE on glycemic control.This was a randomized placebo-controlled trial in 30 patients with T1D on an insulin pump at an academic medical center.GE was evaluated with a [13C]-Spirulina breath test at baseline (GEbaseline), during intravenous saline or erythromycin (2 or 3 mg/kg; GEiv), and after 7 days of oral erythromycin or placebo (GEoral). Weighed meals were provided throughout the study.These were GE and continuous glucose monitoring (CGM).The baseline glycosylated hemoglobin was 7.6% ± 0.8% (60 ± 8.7 mmol/mol); 12 patients (40%) had delayed GE; faster GE was associated with a greater postprandial CGM-based glucose, but slower GE was not associated with postprandial hypoglycemia (<70 mg/dL). Intravenous (3 mg/kg) but not oral erythromycin accelerated GE. The relationship between GE and glycemia differed between the postprandial periods and the entire day. After adjusting for carbohydrate intake and insulin consumption, faster GE was associated with more hyperglycemia during the postprandial period but lower glucose values across the entire study.In T1D, pharmacologically mediated acceleration of GE increases postprandial CGM-based glucose. In contrast, delayed GE is associated with greater CGM-based glucose values over the entire day.
View details for DOI 10.1210/jc.2016-2809
View details for Web of Science ID 000397240900011
View details for PubMedID 27880079
View details for PubMedCentralID PMC5413165
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Determinants and clinical impact of pressure drift in manoscan anorectal high resolution manometry system
NEUROGASTROENTEROLOGY AND MOTILITY
2016; 28 (9): 1433-1437
Abstract
Pressure drift (PD), resulting from differences between room and body temperature, reduces the accuracy of pressure measurements with the Manoscan high resolution manometry (HRM) system. Our aims were to assess PD during anorectal HRM.Defined as the residual pressure measured immediately after the catheter was removed, PD was calculated for each sensor and averaged across all 12 sensors in 454 anorectal consecutive studies recorded with 3 HRM catheters. The relationship between PD and study duration, number of prior uses of a catheter, and peak and average pressure exposure during a study were evaluated. The correction of PD with a software algorithm (thermal compensation) was evaluated in 76 studies where the most distal sensor was outside the body.The PD varied among sensors and across catheters. The average PD (7.3 ± 0.2 mmHg) was significantly greater for newer catheters, during longer studies, or when sensors were exposed to higher pressures. Together, these factors explained 81% of the variance in overall PD. After thermal compensation, the uncorrected median PD for the most distal sensor was 2.5-5 mmHg over the study duration. Correcting this changed the interpretation (e.g., as abnormal instead of normal) of at least 1 anorectal parameter in eight of 76 studies.During anorectal HRM, PD declines with catheter use and is greater for newer catheters, when sensors are exposed to higher pressures, and for studies of longer duration. While PD is partially corrected with thermal compensation algorithms, the impact on interpretation is modest.
View details for DOI 10.1111/nmo.12830
View details for Web of Science ID 000385370000015
View details for PubMedID 27061208
View details for PubMedCentralID PMC5002233
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Evaluating the safety and the effects on colonic compliance of neostigmine during motility testing in patients with chronic constipation
NEUROGASTROENTEROLOGY AND MOTILITY
2016; 28 (6): 871-878
Abstract
Neostigmine, an acetyl cholinesterase inhibitor, stimulates colonic motor activity and may induce vagally mediated cardiovascular effects. Our aim was to evaluate effects of i.v. neostigmine on colonic compliance and its safety in patients with chronic constipation.We retrospectively reviewed medical records of a selected group of 144 outpatients with chronic constipation who were refractory to treatment. These patients had undergone intracolonic motility and compliance measurements with an infinitely compliant balloon linked to a barostat. Data abstracted included barostat balloon mean volumes with increases in pressure (4 mmHg steps from 0 to 44 mmHg) before and after i.v. neostigmine. Vital signs and oxygen saturation before and after neostigmine were recorded.Of the 144 patients, 133 were female, mean age was 41.0 ± 15.4 years (SD), and duration of constipation was 12.9 ± 13.8 years. Among patients who had undergone colonic transit measurement by scintigraphy, the overall colonic transit at 24 h (geometric center, GC24 [n = 115]) was 1.5 ± 0.7 (normal >1.3), and at 48 h (GC48 [n = 75]) it was 2.3 ± 0.9 (normal >1.9). Neostigmine decreased colonic compliance at lower distension pressures (e.g., 12 and 20 mmHg [both p < 0.001]), but not at 40 mmHg. There were expected minor changes in vital signs in response to neostigmine in 144 patients; however, one patient developed unresponsiveness, significant bradycardia, hypotension, and muscular rigidity that responded to 400 mcg i.v. atropine.Neostigmine significantly decreases colonic compliance in patients with refractory chronic constipation. Symptomatic bradycardia in response to neostigmine should be promptly reversed with atropine.
View details for DOI 10.1111/nmo.12786
View details for Web of Science ID 000383290600010
View details for PubMedID 26840188
View details for PubMedCentralID PMC4877263
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Diaphragmatic breathing for rumination syndrome: efficacy and mechanisms of action
NEUROGASTROENTEROLOGY AND MOTILITY
2016; 28 (3): 384-391
Abstract
While high resolution esophageal manometry combined with impedancometry has demonstrated that gastric pressurizations lead to rumination, the contribution of upper esophageal sphincter (UES) and esophagogastric junction (EGJ) function to rumination is unclear. Behavioral therapy with diaphragmatic breathing (DB) can reduce rumination. We aimed to evaluate the pressures in the stomach, EGJ and UES during rumination and the effects of DB augmented with biofeedback therapy.Sixteen patients with rumination were studied with manometry and impedancometry before and after a meal. The postprandial assessment comprised three periods: before, during, and after DB augmented with biofeedback therapy.All patients had postprandial rumination, which was associated (p < 0.001) with increased gastric pressure and reversal of the postprandial gastroesophageal pressure gradient from -4 (-43 to 18) before to 20 (7-79) mmHg during rumination. The EGJ pressure was lower (p < 0.001) during gastric pressurizations that were associated with rumination vs those that were not. The UES also relaxed, almost completely, during rumination. Patients had a median (range) of 5 (2-10) rumination episodes before, 1 (0-2) (p < 0.001) during, and 3 (1-5) after (p < 0.001 vs during) diaphragmatic breathing. During manometry and impedancometry, DB was well-tolerated and learned within 5 min. Diaphragmatic breathing increased EGJ pressure (p < 0.001) and restored a negative gastroesophageal pressure gradient (-20 mmHg [-80 to 7]).Diaphragmatic breathing aided with high resolution esophageal manometry is well-tolerated, effective and averts the gastroesophageal pressure disturbance that leads to rumination.
View details for DOI 10.1111/nmo.12737
View details for Web of Science ID 000370648200009
View details for PubMedID 26661735
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Relationship Between Microbiota of the Colonic Mucosa vs Feces and Symptoms, Colonic Transit, and Methane Production in Female Patients With Chronic Constipation
GASTROENTEROLOGY
2016; 150 (2): 367-+
Abstract
In fecal samples from patients with chronic constipation, the microbiota differs from that of healthy subjects. However, the profiles of fecal microbiota only partially replicate those of the mucosal microbiota. It is not clear whether these differences are caused by variations in diet or colonic transit, or are associated with methane production (measured by breath tests). We compared the colonic mucosal and fecal microbiota in patients with chronic constipation and in healthy subjects to investigate the relationships between microbiota and other parameters.Sigmoid colonic mucosal and fecal microbiota samples were collected from 25 healthy women (controls) and 25 women with chronic constipation and evaluated by 16S ribosomal RNA gene sequencing (average, 49,186 reads/sample). We assessed associations between microbiota (overall composition and operational taxonomic units) and demographic variables, diet, constipation status, colonic transit, and methane production (measured in breath samples after oral lactulose intake).Fourteen patients with chronic constipation had slow colonic transit. The profile of the colonic mucosal microbiota differed between constipated patients and controls (P < .05). The overall composition of the colonic mucosal microbiota was associated with constipation, independent of colonic transit (P < .05), and discriminated between patients with constipation and controls with 94% accuracy. Genera from Bacteroidetes were more abundant in the colonic mucosal microbiota of patients with constipation. The profile of the fecal microbiota was associated with colonic transit before adjusting for constipation, age, body mass index, and diet; genera from Firmicutes (Faecalibacterium, Lactococcus, and Roseburia) correlated with faster colonic transit. Methane production was associated with the composition of the fecal microbiota, but not with constipation or colonic transit.After adjusting for diet and colonic transit, the profile of the microbiota in the colonic mucosa could discriminate patients with constipation from healthy individuals. The profile of the fecal microbiota was associated with colonic transit and methane production (measured in breath), but not constipation.
View details for DOI 10.1053/j.gastro.2015.10.005
View details for Web of Science ID 000368629900024
View details for PubMedID 26460205
View details for PubMedCentralID PMC4727996
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Effect of neostigmine on gastroduodenal motility in patients with suspected gastrointestinal motility disorders
NEUROGASTROENTEROLOGY AND MOTILITY
2015; 27 (12): 1736-1746
Abstract
Acetylcholinesterase inhibitors (ACIs), e.g., neostigmine, are known to increase upper and lower gastrointestinal (GI) motility and are used to treat acute colonic pseudoobstruction. However, their effects on gastroduodenal motility in humans are poorly understood. Our hypotheses were that, in patients with suspected GI motility disorders, neostigmine increases gastric and small intestinal motor activity, and these effects are greater in patients with cardiovagal neuropathy, reflecting denervation sensitivity.In this open label study, the effects of neostigmine (1 mg intravenously) on gastroduodenal motor activity recorded with manometry were assessed in 28 patients with a suspected GI motility disorder. Cardiovagal function was assessed with the heart rate response to deep breathing and GI transit by scintigraphy.The final diagnoses were gastroparesis (6 patients), gastroparesis with intestinal neuropathy (3 patients), intestinal neuropathy or pseudoobstruction (5 patients), functional dyspepsia (6 patients), chronic abdominal pain (3 patients), mechanical small intestinal obstruction (3 patients), and pelvic floor dysfunction (2 patients). Neostigmine increased both antral and intestinal phasic pressure activity (p < 0.001). Neostigmine increased antral and intestinal pressure activity in 81% and 50% of patients with reduced postprandial antral and intestinal contractile responses to meal, respectively. The antroduodenal pressure response to neostigmine was not higher in patients with cardiovagal dysfunction.Neostigmine increased antral and intestinal motor activity in patients with hypomotility, including intestinal dysmotility. These responses to neostigmine were not greater in patients with cardiovagal dysfunction. The use of longer-acting ACIs for treating antroduodenal dysmotility warrant further study.
View details for DOI 10.1111/nmo.12669
View details for Web of Science ID 000365679000005
View details for PubMedID 26387781
View details for PubMedCentralID PMC4659742
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Temporal Trends in the Incidence and Natural History of Diverticulitis: A Population-Based Study
AMERICAN JOURNAL OF GASTROENTEROLOGY
2015; 110 (11): 1588-1597
Abstract
Data on the incidence and natural history of diverticulitis are largely hospital-based and exclude the majority of diverticulitis patients, who are treated in an outpatient setting for uncomplicated diverticulitis. We assessed temporal trends in the epidemiology of diverticulitis in the general population.Through the Rochester Epidemiology Project we reviewed the records of all individuals with a diagnosis of diverticulitis from 1980 to 2007 in Olmsted County, Minnesota, USA.In 1980-1989, the incidence of diverticulitis was 115/100,000 person-years, which increased to 188/100,000 in 2000-2007 (P<0.001). Incidence increased with age (P<0.001); however, the temporal increase was greater in younger people (P<0.001). Ten years after the index and second diverticulitis episodes, 22% and 55% had a recurrence, respectively. This recurrence rate was greater in younger people (hazard ratio (HR) per decade 0.63; 95% confidence interval (CI), 0.59-0.66) and women (HR 0.68; 95% CI, 0.58-0.80). Complications were seen in 12%; this rate did not change over time. Recurrent diverticulitis was associated with a decreased risk of complications (P<0.001). Age was associated with increased risk of local (odds ratio (OR) 1.27 per decade; 95% CI, 1.04-1.57) and systemic (OR 1.83; 95% CI, 1.20-2.80) complications. Survival after diverticulitis was lower in older people (P<0.001) and men (P<0.001) and worsened over time (P<0.001). The incidence of surgery for diverticulitis did not change from 1980 to 2007.The incidence of diverticulitis has increased by 50% in 2000-2007 compared with 1990-1999, and more so in younger people. Complications are relatively uncommon. Recurrent diverticulitis is frequent but typically uncomplicated. Younger people with diverticulitis have less severe disease, more recurrence, and better survival.
View details for DOI 10.1038/ajg.2015.302
View details for Web of Science ID 000368269900015
View details for PubMedID 26416187
View details for PubMedCentralID PMC4676761
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Assessment of Sympathovagal Imbalance By Spectral Analysis of Heart Rate Variability in Prehypertensive and Hypertensive Patients in Indian Population
CLINICAL AND EXPERIMENTAL HYPERTENSION
2011; 33 (7): 478-483
Abstract
Though the incidence of hypertension has increased considerably in recent years, the pathophysiologic mechanism that causes progression from stage of prehypertension to hypertension has not been fully elucidated. Therefore, the present study was conducted to assess the sympathovagal imbalance in prehypertensives and hypertensives by spectral analysis of heart rate variability (HRV) to understand the nature of change in autonomic balance in this common dysfunction of mankind. Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), and spectral indices of HRV such as total power (TP), normalized low frequency power (LFnu), normalized high frequency power (HFnu), ratio of low frequency power to high frequency power (LF-HF ratio), mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals (RMSSD), the number of interval differences of successive NN intervals greater than 50 ms (NN50), and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in three groups of subjects: normotensives (n = 32), prehypertensives (n = 28), and hypertensives (n = 31). Sympathovagal balance was analyzed and correlated with BMI, BHR, and BP in all the groups. It was observed that autonomic imbalance in prehypertensives was due to proportionate increased sympathetic activity and vagal inhibition, whereas in hypertensives, vagal withdrawal was more prominent than sympathetic overactivity. The LF-HF ratio, the sensitive indicator of sympathovagal balance, was significantly correlated with BMI, BHR, and BP. It was concluded that vagal inhibition plays an important role in the critical alteration of sympathovagal balance in the development of clinical hypertension in prehypertensive subjects.
View details for DOI 10.3109/10641963.2010.549275
View details for Web of Science ID 000295618100007
View details for PubMedID 21978027