Browsing by Author "Gupta, Anita"
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Item Application of Physiological Autonomic Activity Tracking GUI and Computational Algorithms for Measuring Persistent Vagal Nerve Dysfunction After Recovery from SARS‐CoV‐2 Infection(Wiley, 2022) Wilson, Damen A.; Nowak, Thomas; Gupta, Anita; McKinnon, Michael; Clements, Isaac; Everett, Thomas; Powley, Terry; Ward, Matthew; Medicine, School of MedicinePost‐Acute Sequelae of SARS‐CoV‐2 infection (PASC) is now recognized as a constellation of symptoms such as postural hypotension, anxiety, and “brain fog” in addition to autonomic nervous system dysfunction such as tachycardia and labile hypertension. Better quantification of these conditions, specifically, autonomic nervous system dysfunction, is desired for future diagnostics, treatment modalities, and gaining a further understanding of PASC. This research has led to application of a novel autonomic activity tracking algorithm and GUI suite from previous work, see Figure 1, to study the physiological autonomic activity in six patients who had recovered from acute SARS‐CoV‐2 infection a mean of six months prior but were still experiencing symptoms. By measuring skin sympathetic nervous activity (SKNA), heart rate variability, and the cutaneous electrogastrogram (EGG), all before and after a water meal challenge, the data was fed into a custom analysis pipeline, shown in Figure 1. Each of the PASC patients were compared to a mean response of 34 healthy controls, each undergoing a 20‐minute baseline recording and another 20‐minute recording after ingestion of an 8 oz water test meal. All six patients showed significantly abnormal heart rate variability on frequency domain analysis in predominantly the low frequency (LF) and very low frequency (VLF) bands, and less so in the high frequency (HF) band, suggesting sympathetic nerve dysfunction. Three patients showed a significant decrease in SKNA while two showed a significant increase. All patients showed an abnormal cutaneous EGG. As shown in Figure 2, the temporal responses of aSKNA, VLF, LF, HF, and EGG for the PASC patients revealed that on average they were statistically different (p<0.05) from the healthy controls’ responses respectively during 98.4%, 78.4%, 86.76%, 47.9%, and 86.1% of the 40‐minute time period in testing, 20 minutes of baseline and 20 minutes after ingestion. In conclusion, we are looking at the sympathetic, parasympathetic, and enteric nervous systems synced temporally for applications with classification and further stratification of PASC based on the temporal dynamics of their autonomic nervous system mediated coordination from digestion. This shows that SARS‐CoV02 infection appears to have a significant effect on sympathetic and parasympathetic autonomic nervous system function and may be responsible for the disturbances noted in PASC. This work provides the framework and example of use for further applications in autonomic disorder physiological response exploration and furthermore can be expanded to other areas of neuromodulation.Item Associations of Fecal Short Chain Fatty Acids With Colonic Transit, Fecal Bile Acid, and Food Intake in Irritable Bowel Syndrome(Wolters Kluwer, 2023-01-01) Waseem, Mohammed Ray; Shin, Andrea; Siwiec, Robert; James-Stevenson, Toyia; Bohm, Matthew; Rogers, Nicholas; Wo, John; Waseem, Lina; Gupta, Anita; Jarrett, Megan; Kadariya, Jhalka; Xu, Huiping; Medicine, School of MedicineIntroduction: Short-chain fatty acids (SCFAs) correlate with colonic transit time (CTT) and may influence irritable bowel syndrome (IBS) pathophysiology. However, the clinical significance of fecal SCFAs, relationships between SCFAs and other metabolites (bile acids [BAs]), and real-time diet effects on SCFAs in IBS are uncertain. The aim was to evaluate fecal SCFA associations with IBS phenotype and mechanisms and explore effects of real-time diet. Methods: We conducted a prospective observational study of fecal SCFA, BAs, and CTT in healthy controls (HCs) and participants with IBS. We compared study end points across groups, analyzed relationships between end points, and evaluated the discriminative ability of SCFAs. Diet effects were explored in participants with dietary data. Results: Among 21 HCs and 43 participants with IBS, fecal SCFAs (total, individual) were inversely correlated with overall (all P < 0.01) and segmental (all P < 0.05) CTT; similar associations were observed within HC and IBS groups. The acetate-to-butyrate ratio correlated with slower overall and left CTT in all and in HCs (both P < 0.01). SCFAs (total, acetate) correlated with BAs (total, % primary) in all participants and in those with IBS with diarrhea. Logistic regression analyses demonstrated associations of acetate with slower transit (odds ratio = 0.988, P = 0.002) and BA diarrhea (BAD; odds ratio = 1.014, P = 0.001). Acetate accurately predicted delayed CTT (area under the receiving operating characteristic curve = 0.84) and BAD (area under the receiver operating characteristic curve = 0.79). Adjusting for diet strengthened correlations of total SCFAs with overall CTT ( R = [-0.46], P = 0.04) and SCFAs with transverse CTT (all P < 0.05). Discussion: Fecal SCFAs correlate with CTT and fecal BAs and reliably exclude delayed CTT and BAD. Accounting for diet strengthens SCFA associations with transit.Item Associations of Habitual Dietary Intake With Fecal Short-Chain Fatty Acids and Bowel Functions in Irritable Bowel Syndrome(Wolters Kluwer, 2022) Calderon, Gerardo; Patel, Chirag; Camilleri, Michael; James-Stevenson, Toyia; Bohm, Matthew; Siwiec, Robert; Rogers, Nicholas; Wo, John; Lockett, Carolyn; Gupta, Anita; Xu, Huiping; Shin, Andrea; Medicine, School of MedicineBackground goals: Diet may contribute to symptoms of irritable bowel syndrome (IBS) and luminal production of putative IBS biomarkers including short-chain fatty acids (SCFAs). Study aims were to to assess relationships of habitual fiber or starch intake with fecal SCFAs in patients with IBS and healthy volunteers (HVs). Study: In 18 HVs and 30 patients with IBS (13 constipation-predominant [IBS-C] and 17 diarrhea-predominant [IBS-D]), habitual diet using a food frequency questionnaire; bowel functions using a validated bowel diary; and fecal SCFAs by HPLC-mass spectrometry were assessed. Associations of fiber and starch with SCFAs were analyzed using Spearman (rs) and Pearson (R) correlations. Relationships between other dietary endpoints, SCFAs, and bowel functions were explored. Results: Habitual fiber or starch intakes were not significantly correlated with SCFAs or bowel functions in all participants or HVs nor with SCFAs in IBS. Starch was negatively correlated (R=-0.53; P=0.04) with complete evacuation in IBS-D. Fiber (rs=0.65; P=0.02) and starch (rs=0.56; P=0.05) were correlated with ease of passage in IBS-C. Stool form, frequency, and ease of passage were positively correlated with total SCFAs (all P<0.05), acetate (all P<0.01), propionate (all P<0.05), and butyrate (form P=0.01; ease of passage P=0.05) among all participants, but not in IBS. Complete evacuation was negatively correlated with propionate (R=-0.34; P=0.04) in all participants. Total (P=0.04) and individual SCFAs (all P<0.05) were positively correlated with stool form in HVs. Conclusions: Habitual fiber and starch intake does not influence fecal SCFAs but may influence bowel functions in IBS. Fecal SCFAs correlate with bowel functions among all participants including HVs.Item Characterization of Proximal Small Intestinal Microbiota in Patients With Suspected Small Intestinal Bacterial Overgrowth: A Cross-Sectional Study(Lippincott, Williams & Wilkins, 2019-08) Shin, Andrea S.; Gao, Xiang; Bohm, Matthew; Lin, Huaiying; Gupta, Anita; Nelson, David E.; Toh, Evelyn; Teagarden, Sean; Siwiec, Robert; Dong, Qunfeng; Wo, John M.; Medicine, School of MedicineOBJECTIVES: The composition of the small intestinal microbiota has not yet been characterized thoroughly using culture-independent techniques. We compared small intestinal microbial communities in patients with and without small intestinal bacterial overgrowth (SIBO) using culture-dependent and culture-independent bacterial identification approaches. METHODS: Small bowel aspirate and mucosal samples were collected from patients with suspected SIBO. The aspirates were cultured to diagnose SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL upper aerodigestive tract bacteria. Bacteria in the aspirates and mucosa were identified using 16S rRNA gene sequencing. We compared small intestinal microbiome composition between groups with and without a culture-based SIBO diagnosis. RESULTS: Analysis of the aspirate and mucosal microbial communities from 36 patients revealed decreased α-diversity but no differences in β-diversity in patients with SIBO compared with those without SIBO. There were no significant differences in the relative abundance of individual taxa from the aspirates or mucosa after adjustment for false discovery rate between patients with and without SIBO. Subgroup analysis revealed significant differences in mucosal β-diversity between the coliform and upper aerodigestive tract subgroups. Relative abundances of a mucosal Clostridium spp. (P = 0.05) and an aspirate Granulicatella spp. (P = 0.02) were higher in coliform SIBO vs non-SIBO subgroups. The microbial composition and relative abundance of multiple taxa significantly differed in the mucosal and aspirate specimens. DISCUSSION: Culture-based results of small bowel aspirates do not correspond to aspirate microbiota composition but may be associated with species richness of the mucosal microbiota.Item Delayed Gastric Emptying Is Not Associated with a Microbiological Diagnosis of Small Intestinal Bacterial Overgrowth(Springer, 2021) Calderon, Gerardo; Siwiec, Robert M.; Bohm, Matthew E.; Nowak, Thomas V.; Wo, John M.; Gupta, Anita; Xu, Huiping; Shin, Andrea; Medicine, School of MedicineBackground: Clinical symptoms of patients with small intestinal bacterial overgrowth (SIBO) may overlap with symptoms of gastroparesis. Prior studies suggest delayed small intestinal transit is associated with SIBO, but have not shown an association between delayed gastric emptying and SIBO. However, these studies have generally relied on the indirect method of breath testing to diagnose SIBO. Aims: The aim of this study was to examine the association between a microbiological diagnosis of SIBO and delayed gastric emptying by scintigraphy. Methods: In a single-center retrospective study of previous research participants who presented for small bowel enteroscopy for diagnostic evaluation of SIBO, we identified 73 participants who underwent gastric emptying study by scintigraphy. A microbiological diagnosis of SIBO was made in patients based on culture results of jejunal aspirates. Clinical symptoms were assessed using the total gastroparesis cardinal symptom index (GCSI) score. We compared delayed gastric emptying, 2- and 4-h gastric retention, and gastroparesis symptoms between patients with and without a microbiological diagnosis of SIBO. Key results: Among 29 participants with SIBO and 44 without SIBO, 33 (45%) had evidence of delayed gastric emptying. There was no significant association between a microbiological diagnosis of SIBO and delayed gastric emptying by scintigraphy. Percent retained at 2 and 4 h, and total GCSI scores did not differ significantly between those with and without SIBO. Conclusions: Although delayed gastric emptying is common in patients with suspected SIBO, gastric emptying is not associated with a microbiological diagnosis of SIBO.Item An emerging method to noninvasively measure and identify vagal response markers to enable bioelectronic control of gastroparesis symptoms with gastric electrical stimulation(Elsevier, 2020-04-15) Ward, Matthew P.; Gupta, Anita; Wo, John M.; Rajwa, Bartek; Furness, John B.; Powley, Terry L.; Nowak, Thomas V.; Medicine, School of MedicineBackground: Gastric electrical stimulation (GES) can be a life-changing, device-based treatment option for drug-resistant nausea and vomiting associated with diabetic or idiopathic gastroparesis (GP). Despite over two decades of clinical use, the mechanism of action remains unclear. We hypothesize a vagal mechanism. New method: Here, we describe a noninvasive method to investigate vagal nerve involvement in GES therapy in 66 human subjects through the compound nerve action potential (CNAP). Results: Of the 66 subjects, 28 had diabetic GP, 35 had idiopathic GP, and 3 had postsurgical GP. Stimulus charge per pulse did not predict treatment efficacy, but did predict a significant increase in total symptom score in type 1 diabetics as GES stimulus charge per pulse increased (p < 0.01), representing a notable side effect and providing a method to identify it. In contrast, the number of significant left and right vagal fiber responses that were recorded directly related to patient symptom improvement. Increased vagal responses correlated with significant decreases in total symptom score (p < 0.05). Comparison with existing method(s): We have developed transcutaneous recording of cervical vagal activity that is synchronized with GES in conscious human subjects, along with methods of discriminating the activity of different nerve fiber groups with respect to conduction speed and treatment response. Conclusions: Cutaneous vagal CNAP analysis is a useful technique to unmask relationships among GES parameters, vagal recruitment, efficacy and side-effect management. Our results suggest that CNAP-guided GES optimization will provide the most benefit to patients with idiopathic and type 1 diabetic gastroparesis.Item Fecal bile acids, fecal short-chain fatty acids, and the intestinal microbiota in patients with irritable bowel syndrome (IBS) and control volunteers(Cambridge University Press, 2018-06) Shin, Andrea; Nelson, David; Wo, John; Camilleri, Michael; James-Stevenson, Toyia; Siwiec, Robert; Bohm, Matthew; Gupta, Anita; Medicine, School of MedicineOBJECTIVES/SPECIFIC AIMS: Objectives and goals of this study will be to: (1) compare fecal microbiota and fecal organic acids in irritable bowel syndrome (IBS) patients and controls and (2) investigate the association between colonic transit and fecal microbiota in IBS patients and controls. METHODS/STUDY POPULATION: We propose an investigation of fecal organic acids, colonic transit and fecal microbiota in 36 IBS patients and 18 healthy controls. The target population will be adults ages 18–65 years meeting Rome IV criteria for IBS (both diarrhea- and constipation-predominant, IBS-D and IBS-C) and asymptomatic controls. Exclusion criteria are: (a) history of microscopic colitis, inflammatory bowel disease, celiac disease, visceral cancer, chronic infectious disease, immunodeficiency, uncontrolled thyroid disease, liver disease, or elevated AST/ALT>2.0× the upper limit of normal, (b) prior radiation therapy of the abdomen or abdominal surgeries with the exception of appendectomy or cholecystectomy >6 months before study initiation, (c) ingestion of prescription, over the counter, or herbal medications affecting gastrointestinal transit or study interpretation within 6 months of study initiation for controls or within 2 days before study initiation for IBS patients, (d) pregnant females, (e) antibiotic usage within 3 months before study participation, (f) prebiotic or probiotic usage within the 2 weeks before study initiation, (g) tobacco users. Primary outcomes will be fecal bile acid excretion and profile, short-chain fatty acid excretion and profile, colonic transit, and fecal microbiota. Secondary outcomes will be stool characteristics based on responses to validated bowel diaries. Stool samples will be collected from participants during the last 2 days of a 4-day 100 g fat diet and split into 3 samples for fecal microbiota, SCFA, and bile acid analysis and frozen. Frozen aliquots will be shipped to the Metabolite Profiling Facility at Purdue University and the Mayo Clinic Department of Laboratory Medicine and Pathology for SCFA and bile acid measurements, respectively. Analysis of fecal microbiota will be performed in the research laboratory of Dr David Nelson in collaboration with bioinformatics expertise affiliated with the Nelson lab. Colonic transit time will be measured with the previously validated method using radio-opaque markers. Generalized linear models will be used as the analysis framework for comparing study endpoints among groups. RESULTS/ANTICIPATED RESULTS: This study seeks to examine the innovative concept that specific microbial signatures are associated with increased fecal excretion of organic acids to provide unique insights on a potential mechanistic link between altered intraluminal organic acids and fecal microbiota. DISCUSSION/SIGNIFICANCE OF IMPACT: Results may lead to development of targets for novel therapies and diagnostic biomarkers for IBS, emphasizing the role of the fecal metabolome.Item Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice(Wiley, 2019-02) Herring, B. Paul; Hoggatt, April M.; Gupta, Anita; Wo, John M.; Cellular and Integrative Physiology, School of MedicineBackground and Aims The transcription factors FOXF1 and FOXF2 have been implicated in the development of the gastrointestinal tract but their role in adults or in gastrointestinal diseases is poorly understood. We have recently shown that expression of serum response factor (SRF), a transcription factor whose activity is modulated by FOXF proteins, is decreased in the stomach muscularis of patients with gastroparesis. The aim of the current study was to determine whether FOXF expression is decreased in gastroparesis patients and whether loss of FOXF1 and/or FOXF2 from adult smooth muscle is sufficient to impair gastric emptying in mice. Methods Full‐thickness stomach biopsy samples were collected from control subjects and from patients with gastroparesis. mRNA was isolated from the muscularis externa, and FOXF mRNA expression levels were determined by quantitative reverse transcriptase (RT)‐PCR. Foxf1 and Foxf2 were knocked out together and separately from smooth muscle cells in adult mice, and the subsequent effect on liquid gastric emptying and contractile protein expression was determined. Key Results Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients. Knockout of Foxf1 and Foxf2 together, but not alone, from mouse smooth muscle resulted in delayed liquid gastric emptying. Foxf1/2 double knockout mice had decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis. Conclusions and Inferences Our findings suggest that decreased expression of FOXF1 and FOXF2 may be contributing to the impaired gastric emptying seen in gastroparesis patients.Item Heart Rate Variability Parameters Indicate Altered Autonomic Tone in Patients with COVID‐19(Wiley, 2022) Gruionu, Gabriel; Gupta, Anita; Rattin, Megan; Nowak, Thomas V.; Ward, Matthew; Everett, Thomas H.; Medicine, School of MedicineThe COVID‐19 disease induces long term heart health complications and may induce autonomic nervous system dysfunction. Heart Rate Variability (HRV) is a measure of sympathetic (SNS) and parasympathetic (PNS) control of heart function. Recently, studies have shown that HRV analysis may be used as a predictor of COVID‐19 symptoms and correlates with progression of the disease. We aimed to uncover the interplay between SNS and PNS in hospitalized COVID‐19 patients at the time of admission and compare it with similar measurements in healthy patients (no comorbidities) and patients with cardiovascular disease. We hypothesized that COVID‐19 would induce autonomic dysfunction similar to patients with cardiovascular disease (CVD). ECG telemetry recordings of 30‐60 minutes in duration were acquired from patients that were admitted to Indiana University Health system hospitals for either COVID‐19 complications or for complications associated with cardiovascular disease (CVD) states (arrhythmia, heart failure, coronary artery disease). In addition, 20‐minute ECG Lead I recordings were obtained from healthy volunteers with no associated comorbidities. HRV parameters were calculated during sinus rhythm in the time, frequency, and nonlinear domains from the ECG telemetry recordings. The patient population was composed of 50 COVID‐19 patients (average age 63, range 26‐94), 32 healthy (average age 32.7, range 17‐69) and 49 patients with cardiovascular disease (average age 65.4, range 30‐88) as control groups. The COVID‐19 group had a higher percentage of patients with BMI>30 (obese) than the control groups (55% vs 36%). Also, the COVID‐19 and CVD patients had significantly higher heart rate and time‐domain HRV parameters (including SDRR, RMSSD, SDSD) and SD1 in the non‐linear domain when compared to healthy patients (88.8±53.0 and 87.9±55.2 vs 49.5±31.3, p<0.01). In the frequency domain, the LF/HF ratio was significantly lower in the COVID and CVD groups compared to healthy controls (0.5±0.76 and 0.55±0.50 vs 1.05±0.96, p<0.01). COVID‐19 patients have significant HRV alterations which suggest increased vagal tone than in healthy volunteers but similar to patients with severe cardiovascular disease comorbidities. Even though the COVID patients had an increased heart rate, the results of the HRV analysis indicate increased vagal tone which would support autonomic nervous system dysfunction in these patients.Item Human organ donor-derived vagus nerve biopsies allow for well-preserved ultrastructure and high-resolution mapping of myelinated and unmyelinated fibers(Springer Nature, 2021) Havton, Leif A.; Biscola, Natalia P.; Stern, Esther; Mihaylov, Plamen V.; Kubal, Chandrashekhar A.; Wo, John M.; Gupta, Anita; Baronowsky, Elizabeth; Ward, Matthew P.; Jaffey, Deborah M.; Powley, Terry L.; Surgery, School of MedicineThe vagus nerve provides motor, sensory, and autonomic innervation of multiple organs, and electrical vagus nerve stimulation (VNS) provides an adjunctive treatment option for e.g. medication-refractory epilepsy and treatment-resistant depression. The mechanisms of action for VNS are not known, and high-resolution anatomical mapping of the human vagus nerve is needed to better understand its functional organization. Electron microscopy (EM) is required for the detection of both myelinated and unmyelinated axons, but access to well-preserved human vagus nerves for ultrastructural studies is sparse. Intact human vagus nerve samples were procured intra-operatively from deceased organ donors, and tissues were immediately immersion fixed and processed for EM. Ultrastructural studies of cervical and sub-diaphragmatic vagus nerve segments showed excellent preservation of the lamellated wall of myelin sheaths, and the axolemma of myelinated and unmyelinated fibers were intact. Microtubules, neurofilaments, and mitochondria were readily identified in the axoplasm, and the ultrastructural integrity of Schwann cell nuclei, Remak bundles, and basal lamina was also well preserved. Digital segmentation of myelinated and unmyelinated axons allowed for determination of fiber size and myelination. We propose a novel source of human vagus nerve tissues for detailed ultrastructural studies and mapping to support efforts to refine neuromodulation strategies, including VNS.