Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management.

Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder in which retrograde flow of gastric content into the oesophagus causes uncomfortable symptoms and/or complications. It has a multifactorial and partially understood pathophysiology. GERD starts in the stomach, where the refluxate material is produced. Following the trajectory of reflux, the failure of the antireflux barrier, primarily the lower oesophageal sphincter and the crural diaphragm, enables the refluxate to reach the oesophageal lumen, triggering oesophageal or extra-oesophageal symptoms. Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage. Alterations of the oesophageal mucosal integrity, such as macroscopic oesophagitis or microscopic changes, determine the perception of symptoms. The intensity of the symptoms is affected by peripheral and central neural and psychological mechanisms. In this Review, we describe an updated understanding of the complex and multifactorial pathophysiology of GERD. It is now recognized that different GERD phenotypes have different degrees of reflux, severity of mucosal integrity damage and type, and severity of symptoms. These variations are probably due to the occurrence of a predominant pathophysiological mechanism in each patient. We also describe the main pathophysiological mechanisms of GERD and their implications for personalized diagnosis and management.

The colorectal cancer-associated faecal microbiome of developing countries resembles that of developed countries.

BACKGROUND: The incidence of colorectal cancer (CRC) is increasing in developing countries, yet limited research on the CRC- associated microbiota has been conducted in these areas, in part due to scarce resources, facilities, and the difficulty of fresh or frozen stool storage/transport. Here, we aimed (1) to establish a broad representation of diverse developing countries (Argentina, Chile, India, and Vietnam); (2) to validate a 'resource-light' sample-collection protocol translatable in these settings using guaiac faecal occult blood test (gFOBT) cards stored and, importantly, shipped internationally at room temperature; (3) to perform initial profiling of the collective CRC-associated microbiome of these developing countries; and (4) to compare this quantitatively with established CRC biomarkers from developed countries. METHODS: We assessed the effect of international storage and transport at room temperature by replicating gFOBT from five UK volunteers, storing two in the UK, and sending replicates to institutes in the four countries. Next, to determine the effect of prolonged UK storage, DNA extraction replicates for a subset of samples were performed up to 252 days apart. To profile the CRC-associated microbiome of developing countries, gFOBT were collected from 41 treatment-naïve CRC patients and 40 non-CRC controls from across the four institutes, and V4 16S rRNA gene sequencing was performed. Finally, we constructed a random forest (RF) model that was trained and tested against existing datasets from developed countries. RESULTS: The microbiome was stably assayed when samples were stored/transported at room temperature and after prolonged UK storage. Large-scale microbiome structure was separated by country and continent, with a smaller effect from CRC. Importantly, the RF model performed similarly to models trained using external datasets and identified similar taxa of importance (Parvimonas, Peptostreptococcus, Fusobacterium, Alistipes, and Escherichia). CONCLUSIONS: This study demonstrates that gFOBT, stored and transported at room temperature, represents a suitable method of faecal sample collection for amplicon-based microbiome biomarkers in developing countries and suggests a CRC-faecal microbiome association that is consistent between developed and developing countries.

High-resolution manometry features of paraesophageal hernia.

BACKGROUND: Paraesophageal hernias (PEH) can be associated with obstructive symptoms, but high-resolution manometry (HRM) characteristics have not been described in detail. METHODS: HRM studies of confirmed PEH patients (n = 60, 66.3 ± 1.5 years, 76.7% F), axial hernias (n = 125, 56.1 ± 1.1 years, 58.4% F), and healthy controls (n = 20, 27.9 ± 0.7 years, 45% F) were analyzed. Axial hernias (type 1) were compared to PEH subtyped as isolated PEH (type 2), PEH with axial hernia (type 3), PEH with herniated abdominal organs (type 4), and unknown. Distal contractile integral (DCI), esophageal length, lower esophageal sphincter pressures (LESP), EGJ contractile integral (EGJ-CI), and integrated relaxation pressure (IRP) were extracted. Intra-luminal pressures were measured proximal (intrabolus pressure, IBP) and distal (intragastric pressure, IGP) to EGJ. Univariate and multivariate analyses were performed to characterize esophageal and EGJ motor physiology in PEH. KEY RESULTS: PEH patients had LESP and EGJ-CI similar to controls; axial hernia patients had lower LESP. While IRP was within normal limits, PEH had elevated IBP and IGP, and shorter esophageal length compared to axial hernia and normal controls (P ≤ .0001 across groups). Short esophageal length was consistent across PEH subtypes (P = .06). On multivariate regression analysis, IBP remained an independent predictor of PEH (P < .0001). Within PEH subtypes, gastric pressure was higher when axial HH was also present, in contrast to isolated PEH (P = .03); other metrics did not differ. CONCLUSIONS & INFERENCES: Luminal pressure increase both upstream and downstream of the EGJ on HRM likely represents obstructive phenomena in PEH, identification of which may support suspicion of PEH.

Investigación traslacional en microbioma (InTraMic): un área de interés común y creciente en el IMTIB, Hospital Italiano e Instituto Universitario / Translational research in microbiome (InTraMic): an area of common and growing interest at IMTIB, Hospital Italiano and Instituto Universitario

Se estima que aproximadamente 100 trillones de microorganismos (incluidos bacterias, virus y hongos) residen en el intestino humano adulto y que el total del material genético del microbioma es 100 veces superior al del genoma humano. Esta comunidad, conocida como microbioma se adquiere al momento del nacimiento a través de la flora comensal de la piel, vagina y heces de la madre y se mantiene relativamente estable a partir de los dos años desempeñando un papel crítico tanto en el estado de salud como en la enfermedad. El desarrollo de nuevas tecnologías, como los secuenciadores de próxima generación (NGS), permiten actualmente realizar un estudio mucho más preciso de ella que en décadas pasadas cuando se limitaba a su cultivo. Si bien esto ha llevado a un crecimiento exponencial en las publicaciones, los datos sobre las poblaciones Latinoamérica son casi inexistentes. La investigación traslacional en microbioma (InTraMic) es una de las líneas que se desarrollan en el Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB). Esta se inició en 2018 con la línea de cáncer colorrectal (CCR) en una colaboración con el Colorectal Cancer Research Group del Leeds Institute of Medical Research en el proyecto Large bowel microbiome disease network: Creation of a proof of principle exemplar in colorectal cancer across three continents. A fines de 2019 se cumplió el objetivo de comprobar la factibilidad de la recolección, envío y análisis de muestras de MBF en 5 continentes, incluyendo muestras provenientes de la Argentina, Chile, India y Vietnam. Luego de haber participado de capacitaciones en Inglaterra, se ha cumplido con el objetivo de la etapa piloto, logrando efectivizar la recolección, envío y análisis metagenómico a partir de la secuenciación de la región V4 del ARNr 16S. En 2019, la línea de enfermedad de hígado graso no alcohólico se sumó a la InTraMic iniciando una caracterización piloto en el marco de una colaboración con el laboratorio Novartis. Los resultados de ese estudio, así como el de cáncer colorrectal, están siendo enviados a publicación. En 2020, con la incorporación de la línea de trasplante alogénico de células progenitoras hematopoyéticas, fue presentado un proyecto para un subsidio del CONICET que ha superado la primera etapa de evaluación. En el presente artículo se brinda una actualización sobre la caracterización taxonómica de microbioma y se describen las líneas de investigación en curso. (AU)

It is estimated that approximately 100 trillion microorganisms (including bacteria, viruses, and fungi) reside in the adult human intestine, and that the total genetic material of the microbiome is 100 times greater than that of the human genome. This community, known as the microbiome, is acquired at birth through the commensal flora of the mother's skin, vagina, and feces and remains relatively stable after two years, playing a critical role in both the state of health and in disease. The development of new technologies, such as next-generation sequencers (NGS), currently allow for a much more precise study of it than in past decades when it was limited to cultivation. Although this has led to exponential growth in publications, data on Latin American populations is almost non-existent. Translational research in microbiome (InTraMic) is one of the lines developed at the Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB). This started in 2018 with the Colorectal Cancer Line (CRC) in a collaboration with the Colorectal Cancer Research Group of the Leeds Institute of Medical Research in the project "Large bowel microbiome disease network: Creation of a proof of principle exemplar in colorectal cancer across three continents". At the end of 2019, the objective of verifying the feasibility of collecting, sending and analyzing MBF samples on 5 continents, including samples from Argentina, Chile, India and Vietnam, was met. After having participated in training in England, the objective of the pilot stage has been met, achieving the collection, delivery and metagenomic analysis from the sequencing of the V4 region of the 16S rRNA. In 2019, the non-alcoholic fatty liver disease line joined InTraMic, initiating a pilot characterization in the framework of a collaboration with the Novartis laboratory. The results of that study, as well as that of colorectal cancer, are being published. In 2020, with the incorporation of the allogeneic hematopoietic stem cell transplantation line, a project was presented for a grant from the CONICET that has passed the first stage of evaluation. This article provides an update on the taxonomic characterization of the microbiome and describes the lines of ongoing research. (AU)

200 mL Rapid Drink Challenge During High-resolution Manometry Best Predicts Objective Esophagogastric Junction Obstruction and Correlates With Symptom Severity.

BACKGROUND/AIMS: Single swallow integrated relaxation pressure (IRP) on high-resolution manometry (HRM) does not always accurately predict esophagogastric outflow obstruction on timed barium esophagogram (TBE). Furthermore, neither single swallow IRP or TBE is reliable in predicting symptoms, particularly after treatment with dilatation or myotomy. A 200 mL rapid drink challenge (RDC) has been proposed as an adjunctive test during HRM. This serves as a "stress-test" to the esophagogastric junction, and may yield clinically useful parameters. We aim to assess HRM parameters during RDC, and their ability to predict outflow obstruction on TBE in patients with dysphagia, and to correlate with symptoms in patients' achalasia. METHODS: Thirty patients with dysphagia were recruited. All underwent standard single swallow HRM analysis, 200 mL RDC, then TBE. RDC parameters, including esophagogastric pressure gradient, IRP, and RDC duration were evaluated. Multiple regression analysis was performed to assess the best predictive parameter for obstruction on TBE. A further 21 patients with achalasia were evaluated with Eckhardt score, single swallow HRM, RDC, and TBE. Parameter correlation with Eckhardt score was evaluated. RESULTS: Mean IRP during RDC was the best HRM parameter at predicting outflow obstruction on TBE. This performed much better in untreated patients (sensitivity 100% and specificity 85.5%) than in previously treated patients (sensitivity 50% and specificity 66%). In patients with achalasia, mean IRP during RDC was the only parameter that correlated with symptom score. CONCLUSION: Mean IRP during RDC appears to be a clinically useful "stress test" to the esophagogastric junction during HRM.