Rupjyoti Talukdar

Role of the normal gut microbiota

Relation between the gut microbiota and human health is being increasingly recognised. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individuals life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbe-host interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Several factors play a role in shaping the normal gut microbiota. They include (1) the mode of delivery (vaginal or caesarean); (2) diet during infancy (breast milk or formula feeds) and adulthood (vegan based or meat based); and (3) use of antibiotics or antibiotic like molecules that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.

Pancreatic stellate cells: new target in the treatment of chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by progressive fibrosis, pain and/or loss of exocrine and endocrine functions. Recent in vitro and in vivo experiments have proven objectively the role of activated pancreatic stellate cells (PSC) in fibrogenesis in CP. Molecular mediators shown to regulate the pathogenesis include transforming growth factor beta (TGF‐β), platelet‐derived growth factor (PDGF), and pro‐inflammatory cytokines such as IL‐1, IL‐6 and TNF‐α. Furthermore, molecular pathways involving mitogen‐activated protein kinases (MAPK), phosphatidyl inositol 3‐kinase (PI3K), Ras superfamily G proteins, serine threonine protein kinase Raf‐1 and peroxisome proliferator activated receptor gamma (PPAR‐γ) have been elucidated. Understanding of the pathogenesis has led to identification of novel molecular targets and development of potential newer therapeutic agents. Those found to retard the progression of experimental CP and fibrosis in animal models include interferon (IFN) β and IFN‐γ; a Japanese herbal medicine called Saiko‐keishi‐to (TJ‐10); curcumin; PPAR‐γ ligand (troglitazone); antioxidants (vitamin A, vitamin E, DA 9601 and epigallocatechin‐3‐gallate); a protease inhibitor (camostat mesilate) and hydroxymethylglutaryl‐CoA inhibitor (lovastatin). This review summarizes the current literature addressing the role of different pharmacological agents aimed at reducing or preventing inflammation and the consequent fibrogenesis in CP.

Chronic pancreatitis: Evolving paradigms

Chronic pancreatitis (CP) is characterized by progressive fibrosis, pain and/or loss of exocrine and endocrine functions. With the identification and characterization of pancreatic stellate cells (PSCs), the pathogenesis of CP and pancreatic fibrosis is now better understood. Molecular mediators shown to regulate the pathogenesis include transforming growth factor-β, platelet-derived growth factor, and proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor-α. Besides these, the roles of cyclooxygenase (COX)-2 and apoptosis-related proteins have also been implicated in the pathogenesis. Furthermore, molecular pathways involving mitogen-activated protein kinases, phosphatidylinositol 3-kinase, Ras superfamily G proteins, serine threonine protein kinase Raf-1 and peroxisome proliferator-activated receptor-γ (PPAR-γ) have been elucidated. Newer pathobiologic concepts concerning pain generation have also been put forward. Understanding the pathogenesis has led to the identification of novel molecular targets and the development of newer potential therapeutic agents. Those found to retard the progression of experimental CP and fibrosis in animal models include antioxidants, a Japanese herbal medicine called Saiko-keisi-to (TJ 10), the PPAR-γ ligand troglitazone, the protease inhibitor Camostat mesilate, and Lovastatin.

Long-term clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific pancreatitis

BACKGROUND Long-term results of extracorporeal shockwave lithotripsy (ESWL) for large pancreatic duct (PD) stones in patients with idiopathic calcific pancreatitis (CP) are scanty. OBJECTIVE To evaluate intermediate and long-term results of ESWL in a large cohort of patients with idiopathic CP. DESIGN Cross-sectional study; retrospective chart review. SETTING A high-volume, tertiary-care center for endoscopy and GI diseases. PATIENTS A total of 636 patients with idiopathic CP who underwent ESWL and ERCP were followed-up. Patients were divided into intermediate (24-60 months) and long-term (>60 months) follow-up groups. INTERVENTION ESWL and ERCP. MAIN OUTCOME MEASUREMENTS Improvement in pain, analgesic use, hospitalization for pain, recurrence of calculi, need for additional intervention, and quality of life. RESULTS A total of 636 of 1006 patients who underwent ESWL between 2004 and 2009 were followed for a maximum of 96 months. There were 364 patients in the intermediate follow-up group and 272 in the long-term follow-up group. After ESWL and ERCP, absence of pain was seen in 250 patients (68.7%), mild-to-moderate pain in 94 patients (25.4%), and severe pain in 20 patients (5.5%) of the intermediate group. In the long-term group, 164 patients (60.3%) had no pain, 97 patients (35.7%) had mild or moderate episodes of pain, whereas 11 patients (4.04%) had episodic severe pain. Recurrence of calculi was seen in 51 patients (14.01%) in the intermediate follow-up group and in 62 patients (22.8%) in the long-term group. Quality of life improved in a significant number of patients in both groups. LIMITATIONS Retrospective study, single center, recall bias, and subjective pain and quality-of-life measurement scale. CONCLUSION ESWL for large PD calculi offers good results in patients of idiopathic CP on intermediate and long-term follow-up.

Moderately severe acute pancreatitis: prospective validation of this new subgroup of acute pancreatitis.

Objective We described the entity moderately severe acute pancreatitis (MSAP), characterized by local complications (LCs) without organ failure (OF). The aim of this study was to validate MSAP. Methods We classified a prospectively collected cohort of 137 acute pancreatitis patients admitted to Mayo Clinic Hospitals into (a) severe acute pancreatitis (SAP; n = 15), presence of OF with/without LCs; (b) MSAP (n = 27), presence of LCs without OF; and (c) mild acute pancreatitis (MAP; n = 95), no OF and LCs. Primary outcomes were need for intensive care unit (ICU) care, total ICU days, total hospital stay, need for interventions, and death. Results Scores in the Acute Physiology and Chronic Health Evaluation II during admission were significantly different among the 3 groups (MAP vs MSAP, P = 0.02; MSAP vs SAP, P = 0.001); scores in the systemic inflammatory response syndrome during admission were similar between MAP and MSAP. Compared with patients with MAP, patients with MSAP had a significantly longer hospital stay (4 [3.0–7.0] vs 6 [4.0–18.0] days). Compared with those with SAP, a significantly smaller proportion of patients with MSAP required ICU care (12% vs 80%); total hospital stay and need for interventions were similar (6 [4.0–18.0] vs 21 [11.8–27] days and 44% vs 33%, respectively). None of the MSAP patients died compared with 40% from the SAP group. Conclusions We have validated MSAP as an exclusive entity. Abbreviations AP - acute pancreatitis, SAP - severe acute pancreatitis, MSAP - moderately severe acute pancreatitis, MAP - mild acute pancreatitis, OF - organ failure, CT - computerized tomography, ICU - intensive care unit, BMI - body mass index, SIRS - systemic inflammatory response syndrome, APACHE - Acute Physiology and Chronic Health Evaluation, IQR - interquartile range

Gut bacterial diversity of the tribes of India and comparison with the worldwide data

The gut bacteria exert phenotypic traits to the host but the factors which determine the gut bacterial profile (GBP) is poorly understood. This study aimed to understand the effect of ethnicity and geography on GBP of Mongoloid and Proto-Australoid tribes of India. Fecal bacterial diversity was studied in fifteen tribal populations representing four geographic regions (Assam, Telangana, Manipur and Sikkim) by DGGE followed by NGS analysis on Illumina MiSeq platform. Geography and diet had significant effect on GBP of the Indian tribes which was dominated by Prevotella. The effects were more prominent with lower taxonomic levels, indicating probable functional redundancy of the core GBP. A comparison with the worldwide data revealed that GBP of the Indian population was similar to the Mongolian population (Mongolia). The bacterial genera Faecalibacterium, Eubacterium, Clostridium, Blautia, Ruminococcus and Roseburia were found to be core genera in the representative populations of the world.

β-Cell dysfunction in chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by irreversible destruction of pancreatic secretory parenchyma, fibrosis, exocrine atrophy, and endocrine insufficiency leading to diabetes. Secondary diabetes occurring in CP subsequent to destruction of pancreatic β-cells is distinct, since it involves β-cell dysfunction amidst an inflammatory milieu. Even though considerable knowledge is available on the pathophysiology and clinical management of CP, relatively much less is known about the molecular events leading to β-cell dysfunction. Investigators have demonstrated that altered morphology, reduced β-cell mass, and β-cell numbers result in endocrine insufficiency. However, recent reports and our observations suggest that β-cell dysfunction develops in the early stages of CP while clinical diabetes manifests later, when there is profound fibrosis. In the early stages, altered internal milieu and physiology arising due to inflammation and release of cytokines might lead to deranged signaling pathways and islet dysfunction. Subsequently, development of fibrosis causes islet destruction. This suggests that endocrine deficiency in CP is multifactorial. Although the role of transcription factors (Pdx-1, MafA, NeuroD) on β-cell functions is understood, alterations in internal milieu of pancreatic tissue that affects β-cell functions in CP has not been elucidated. In this review, we summarize the factors that have an effect on islet functions. Understanding molecular events of β-cell dysfunction in CP can lead to the development of targeted preventive and therapeutic modalities.

ERCP in the management of pancreatic diseases in children.

BACKGROUND ERCP experience in pancreatic disorders in children is limited. OBJECTIVE This study evaluated the utility and efficacy of ERCP in children with pancreatic diseases at a tertiary care referral center. PATIENTS AND SETTINGS Consecutive patients 18 years of age and younger who underwent ERCP for pancreatic diseases from January 2010 to June 2011 were identified. Indications, findings, interventions, adverse events, and outcomes were recorded. RESULTS A total of 221 ERCPs were performed in 172 children (102 boys, mean ± standard deviation age 13.8 ± 3.2 years, 157 therapeutic). A total of 143 children (83.1%) had chronic pancreatitis (CP), 19 (11%) had recurrent acute pancreatitis (RAP), and 10 (5.8%) had acute pancreatitis (AP). Indications included pain (153, 89.4%), pancreatic fistula (11, 6.3%), symptomatic pseudocyst (4, 2.3%), and jaundice (3, 1.7%). In chronic pancreatitis patients, findings included a dilated and irregular main pancreatic duct (92, 64.3%), pancreatic duct (PD) calculi (76, 53%), dominant PD stricture (23, 16%), PD leak (7, 4.9%), pancreas divisum (35, 24.5%), and common bile duct (CBD) stricture (3, 2%). Therapeutic procedures included major papilla sphincterotomy (93, 65%), minor papilla sphincterotomy (32, 22.3%), PD stenting (77, 53.8%), and CBD stenting (3, 2.2%). PD stones larger than 5 mm were retrieved endoscopically after 57 extracorporeal shock wave lithotripsy sessions in 50 patients (34.9%). In patients with RAP, 6 (31.5%) had complete and 1 partial pancreas divisum. All underwent minor papillotomy. In patients with AP, 4 (40%) had stenting for PD leak, 2 (20%) underwent CBD clearance for biliary pancreatitis, and 4 (40%) had transpapillary pseudocyst drainage. During 13 ± 4.7 months (range 6-22 months) of follow-up, improvement of symptoms was seen in 143 of 172 (83%) patients. Procedure-related adverse events were seen in 8 (4.7%) patients. LIMITATIONS Retrospective study. CONCLUSION ERCP is a safe therapeutic option for pancreatic disorders in children.

NF-κB in acute pancreatitis: Mechanisms and therapeutic potential

The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies. Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.

Clinical utility of the Revised Atlanta Classification of acute pancreatitis in a prospective cohort: Have all loose ends been tied?

BACKGROUND AND AIM Revision of the Atlanta classification for acute pancreatitis (AP) was long awaited. The Revised Atlanta Classification has been recently proposed. In this study, we aim to prospectively evaluate and validate the clinical utility of the new definitions. PATIENT AND METHODS 163 consecutive patients with AP were followed till death/6 mths after discharge. AP was categorized as mild (MAP) (no local complication[LC] and organ failure[OF]), moderate (MSAP)(transient OF and/or local/systemic complication but no persistent OF) and severe (SAP) AP (persistent OF). LC included acute peripancreatic fluid collections, pseudocyst, acute necrotic collection, walled-off necrosis, gastric outlet dysfunction, splenic/portal vein thrombosis, and colonic necrosis. Baseline characteristics (age/gender/hematocrit/BUN/SIRS/BISAP) and outcomes (total hospital stay/need for ICU care/ICU days/primary infected (peri)pancreatic necrosis[IN]/in-hospital death) were compared. RESULTS 43 (26.4%) patients had ANP, 87 (53.4%) patients had MAP, 58 (35.6%) MSAP and 18 (11.04%) SAP. Among the baseline characteristics, BISAP score was significantly higher in MSAP compared to MAP [1.6 (1.5-2.01) vs 1.2 (1.9-2.4); p = 0.002]; and BUN was significantly higher in SAP compared to MSAP[64.9 (50.7-79.1) vs 24.9 (20.7-29.1); p < 0.0001]. All outcomes except mortality were significantly higher in MSAP compared to MAP. Need for ICU care (83.3%vs43.1%; p = 0.01), total ICU days[7.9 (4.8-10.9) vs 3.5 (2.7-5.1); p = 0.04] and mortality (38.9%vs1.7%; p = 0.0002) was significantly more in SAP compared to MSAP. 8/18 (44.4%) patients had POF within seven days of disease onset (early OF). This was associated with 37.5% of total in-hospital mortality. Patients with MSAP who had primary IN (n = 10) had similar outcomes as SAP. CONCLUSIONS This study prospectively validates the clinical utility of the Revised Atlanta definitions of AP. However, MSAP patients with primary infected necrosis may behave as SAP. Furthermore, patients with early severe acute pancreatitis (early OF) could represent a subgroup that needs to be dealt with separately in classification systems.