Publications by authors named "Susrutha Puthanmadhom Narayanan"

9 Publications

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Sex- and Gender-Related Differences in Common Functional Gastroenterologic Disorders.

Mayo Clin Proc 2021 04;96(4):1071-1089

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address:

Functional gastrointestinal (GI) disorders (FGIDs) result from central and peripheral mechanisms, cause chronic remitting-relapsing symptoms, and are associated with comorbid conditions and impaired quality of life. This article reviews sex- and gender-based differences in the prevalence, pathophysiologic factors, clinical characteristics, and management of functional dyspepsia (FD) and irritable bowel syndrome (IBS) that together affect approximately 1 in 4 people in the United States. These conditions are more common in women. Among patients with IBS, women are more likely to have severe symptoms and coexistent anxiety or depression; constipation or bloating and diarrhea are more common in women and men, respectively, perhaps partly because defecatory disorders, which cause constipation, are more common in women. Current concepts suggest that biological disturbances (eg, persistent mucosal inflammation after acute gastroenteritis) interact with other environmental factors (eg, abuse) and psychological stressors, which influence the brain and gut to alter GI tract motility or sensation, thereby causing symptoms. By comparison to a considerable understanding of sex-based differences in the pathogenesis of visceral hypersensitivity in animal models, we know less about the contribution of these differences to FGID in humans. Slow gastric emptying and colon transit are more common in healthy women than in men, but effects of gonadal hormones on colon transit are less important than in rodents. Although increased visceral sensation partly explains symptoms, the effects of sex on visceral sensation, colonic permeability, and the gut microbiome are less prominent in humans than rodents. Whether sex or gender affects response to medications or behavioral therapy in FD or IBS is unclear because most patients in these studies are women.
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http://dx.doi.org/10.1016/j.mayocp.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075061PMC
April 2021

Duodenal mucosal mitochondrial gene expression is associated with delayed gastric emptying in diabetic gastroenteropathy.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Hindered by a limited understanding of the mechanisms responsible for diabetic gastroenteropathy (DGE), management is symptomatic. We investigated the duodenal mucosal expression of protein-coding genes and microRNAs (miRNA) in DGE and related them to clinical features. The diabetic phenotype, gastric emptying, mRNA, and miRNA expression and ultrastructure of duodenal mucosal biopsies were compared in 39 DGE patients and 21 controls. Among 3175 differentially expressed genes (FDR < 0.05), several mitochondrial DNA-encoded (mtDNA-encoded) genes (12 of 13 protein coding genes involved in oxidative phosphorylation [OXPHOS], both rRNAs and 9 of 22 transfer RNAs) were downregulated; conversely, nuclear DNA-encoded (nDNA-encoded) mitochondrial genes (OXPHOS) were upregulated in DGE. The promoters of differentially expressed genes were enriched in motifs for transcription factors (e.g., NRF1), which regulate mitochondrial biogenesis. Seventeen of 30 differentially expressed miRNAs targeted differentially expressed mitochondrial genes. Mitochondrial density was reduced and correlated with expression of 9 mtDNA OXPHOS genes. Uncovered by principal component (PC) analysis of 70 OXPHOS genes, PC1 was associated with neuropathy (P = 0.01) and delayed gastric emptying (P < 0.05). In DGE, mtDNA- and nDNA-encoded mitochondrial genes are reduced and increased - associated with reduced mitochondrial density, neuropathy, and delayed gastric emptying - and correlated with cognate miRNAs. These findings suggest that mitochondrial disturbances may contribute to delayed gastric emptying in DGE.
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http://dx.doi.org/10.1172/jci.insight.143596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934845PMC
January 2021

Duodenal mucosal secretory disturbances in functional dyspepsia.

Neurogastroenterol Motil 2021 01 9;33(1):e13955. Epub 2020 Aug 9.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD.

Methods: Duodenal mucosal ion transport (basal and acetylcholine- and glucose-evoked changes in short-circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls.

Results: Basal Isc (FD: 88.2 [52.6] μA/cm vs healthy: 20.3 [50.2] μA/cm ; P ≤ .0001), acetylcholine-evoked Isc (FD: Emax 50.4 [35.8] μA/cm vs healthy: 16.6 [15] μA/cm ; P ≤ .001), and glucose-evoked Isc responses (FD: E 69.8 [42.1] μA/cm vs healthy: 40.3 [24.6] μA/cm ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4, which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa-miR-590-3p, hsa-miR-32-5p) that target genes associated with ionic transport were upregulated in FD.

Conclusions: Compared to controls, FD patients had greater baseline and agonist-evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.
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http://dx.doi.org/10.1111/nmo.13955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772227PMC
January 2021

Improving the utility of high-resolution manometry for the diagnosis of defecatory disorders in women with chronic constipation.

Neurogastroenterol Motil 2020 10 1;32(10):e13910. Epub 2020 Jul 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: We compared the utility of existing and modified versions of high-resolution manometry for diagnosing defecatory disorders (DD).

Methods: In 64 healthy and 136 constipated women, we compared left lateral (LL) and seated manometry, and analyzed with existing (ManoView™) and new methods, for discriminating between constipated patients with normal and prolonged rectal balloon expulsion time (BET). In both positions, the rectoanal gradient (RAG) and, for the new analysis, the pressure topography pattern during evacuation were used to discriminate between constipated patients without and with DD.

Key Results: The BET was prolonged, suggestive of a DD, in 52 patients (38%). During evacuation, rectoanal pressures and the RAG were greater in the seated than the LL position (P≤.001). The new analysis identified 4 rectoanal pressure patterns. In the seated position, the BET was associated with the pattern (P=.0001), being prolonged in, respectively, 45%, 15%, 53%, and 0% of patients with minimal change, anal relaxation, paradoxical contraction, and transmission. Within each pattern, the RAG was greater (ie, less negative, P<.0001) in patients with a normal than a prolonged BET. Compared to the ManoView™ RAG in the LL position, the integrated analysis (ie, pattern and new RAG) in the LL position (P<.01) and the seated ManoView™ gradient (P=.02) were more effective for discriminating between constipated patients without and with DD.

Conclusions & Inferences: Anorectal HRM ideally should be performed in the more physiological seated position and analyzed by a two-tier approach, which incorporates the overall pattern followed by the rectoanal gradient. These findings reinforce the utility of manometry for diagnosing DD.
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http://dx.doi.org/10.1111/nmo.13910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529936PMC
October 2020

Epigenetic Alterations Are Associated With Gastric Emptying Disturbances in Diabetes Mellitus.

Clin Transl Gastroenterol 2020 03;11(3):e00136

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aim was to ascertain whether epigenetic alterations in whole blood discriminate among patients with DM with normal, delayed, and rapid gastric emptying (GE).

Methods: Using the ChIP-seq (chromatin immunoprecipitation combined with next-generation sequencing) assays, we compared the genome-wide enrichment of 3 histone modifications (i.e., H3K4me3, H3K9ac, and H3K27ac) in buffy coats from 20 diabetic patients with gastrointestinal symptoms and normal (n = 6), delayed (n = 8), or rapid (n = 6) GE.

Results: Between patients with DM with delayed vs normal GE, there were 108 and 54 genes that were differentially bound (false discovery rate < 0.05) with H3K27ac and H3K9ac, respectively; 100 genes were differentially bound with H3K9ac in patients with rapid vs normal GE. The differentially bound genes with H3K27ac were functionally linked to the type 2 immune response, particularly Th2 cell activation and function (e.g., CCR3, CRLF2, CXCR4, IL5RA, and IL1RL1) and glucose homeostasis (FBP-1, PDE4A, and CMKLR1). For H3K9ac, the differentially occupied genes were related to T-cell development and function (e.g., ICOS and CCR3) and innate immunity (RELB, CD300LB, and CLEC2D). Compared with normal GE, rapid GE had differential H3K9ac peaks at the promoter site of diverse immunity-related genes (e.g., TNFRSF25 and CXCR4) and genes related to insulin resistance and glucose metabolism. Motif analysis disclosed enrichment of binding sites for transcription factors relevant to the pathogenesis and complications of DM.

Discussion: GE disturbances in DM are associated with epigenetic alterations that pertain to dysimmunity, glucose metabolism, and other complications of DM.
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http://dx.doi.org/10.14309/ctg.0000000000000136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145053PMC
March 2020

Comparison of changes in rectal area and volume during MR evacuation proctography in healthy and constipated adults.

Neurogastroenterol Motil 2019 07 26;31(7):e13608. Epub 2019 Apr 26.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background: During proctography, rectal emptying is visually estimated by the reduction in rectal area. The correlation between changes in rectal area, which is a surrogate measure of volume, is unclear. Our aims were to compare the change in rectal area and volume during magnetic resonance (MR) proctography and to compare these parameters with rectal balloon expulsion time (BET).

Methods: In 49 healthy and 46 constipated participants, we measured BET and rectal area and volume with a software program before and after participants expelled rectal gel during proctography.

Key Results: All participants completed both tests; six healthy and 17 constipated patients had a prolonged (>60 seconds) BET. During evacuation, the reduction in rectal area and volume was lower in participants with an abnormal than a normal BET (P < 0.01). The reduction in rectal area and volume were strongly correlated (r = 0.93, P < 0.001) and equivalent for identifying participants with abnormal BET. Among participants with less evacuation, the reduction in rectal area underestimated the reduction in rectal volume. A rectocele larger than 2 cm was observed in eight of 18 (44%) participants in whom the difference between change in volume and area was ˃10% but only 14 of 77 (18%) participants in whom the difference was ≤10% (P = 0.03).

Conclusions: Measured with MR proctography, the rectal area is reasonably accurate for quantifying rectal emptying and equivalent to rectal volume for distinguishing between normal and abnormal BET. When evacuation is reduced, the change in rectal area may underestimate the change in rectal volume.
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http://dx.doi.org/10.1111/nmo.13608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559848PMC
July 2019

A Practical Guide to Biofeedback Therapy for Pelvic Floor Disorders.

Curr Gastroenterol Rep 2019 Apr 23;21(5):21. Epub 2019 Apr 23.

Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street, Rochester, MN, 55905, USA.

Purpose Of Review: Biofeedback therapy (BFT) is effective for managing pelvic floor disorders (i.e., defecatory disorders and fecal incontinence). However, even in controlled clinical trials, only approximately 60% of patients with defecatory disorders experienced long-term improvement. The review serves to update practitioners on recent advances and to identify practical obstacles to providing biofeedback therapy.

Recent Findings: The efficacy and safety of biofeedback therapy have been evaluated in defecatory disorders, fecal incontinence, and levator ani syndrome. Recent studies looked at outcomes in specific patient sub-populations and predictors of a response to biofeedback therapy. Biofeedback therapy is effective for managing defecatory disorders, fecal incontinence, and levator ani syndrome. Patients who have a lower bowel satisfaction score and use digital maneuvers fare better. Biofeedback therapy is recommended for patients with fecal incontinence who do not respond to conservative management. A subset of patients with levator ani syndrome who have dyssynergic defecation are more likely to respond to biofeedback therapy.
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http://dx.doi.org/10.1007/s11894-019-0688-3DOI Listing
April 2019

Pitavastatin attenuates cisplatin-induced renal injury by targeting MAPK and apoptotic pathways.

J Pharm Pharmacol 2019 Jul 7;71(7):1072-1081. Epub 2019 Apr 7.

Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.

Objective: Anti-neoplastic drug cisplatin is prescribed widely for treatment of a variety of malignancies. Its use has been restricted lately due to severe renal toxicity. The purpose of current study was to investigate the effect of pitavastatin (a hypolipidaemic drug) in cisplatin-induced acute kidney injury in rats.

Method: Male Wistar rats (150-200 g) were treated with different doses of pitavastatin (0.16, 0.32 and 0.64 mg/kg per day p.o.; 10 days). On 7th day of the study, rats were administered cisplatin (8 mg/kg i.p.). Rats were euthanized (11th day), and blood and tissues were processed to evaluate biochemical, histopathological and ultrastructural parameters along with the analysis of immunohistochemistry and DNA-fragmentation studies. Protein expressions were analysed to demonstrate the underlying molecular mechanisms.

Key Findings: In the study group with cisplatin insult, KFT parameters were found to be elevated, concentration of apoptotic markers was found to be increased, histopathological and ultramicroscopical architecture was found to be distorted and the expression of MAPK proteins was also found to be elevated as compared to the normal group rats. Pitavastatin treatment alleviated all these anomalies.

Conclusion: Cisplatin-induced acute renal injury was improved on administration of pitavastatin via inhibition of MAPK and apoptotic pathway.
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http://dx.doi.org/10.1111/jphp.13090DOI Listing
July 2019

Synchronous Triple Malignancies in an Indian Albino: A Case Report.

Cureus 2018 Aug 23;10(8):e3190. Epub 2018 Aug 23.

Pediatrics, Church of South India Kalyani Multispeciality Hospital, Chennai , IND.

Oculocutaneous albinism (OCA) is a heterogenous disorder of skin pigmentation characterized by hypopigmentation of the skin, hair, and eyes. The absence of melanin predisposes these individuals to ultraviolet rays induced malignancies. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in OCA have been rarely reported. Malignant melanoma (MM) of the skin is also very rarely reported. Synchronous BCC, SCC, and MM are exceedingly rare. We report one such case managed successfully with surgical treatment. All the three malignancies were localized cancers and hence the outcome was good. The importance of regular follow up and periodic self-examination in such predisposed individuals are highlighted.
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http://dx.doi.org/10.7759/cureus.3190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199145PMC
August 2018