Computational Modeling of Drug Dissolution in the Human Stomach

A computational model of drug dissolution in the human stomach is developed to investigate the interaction between gastric flow and orally administrated drug in the form of a solid tablet. The stomach model is derived from the anatomical imaging data and the motion and dissolution of the drug in the stomach are modeled via fluid-structure interaction combined with mass transport simulations. The effects of gastric motility and the associated fluid dynamics on the dissolution characteristics are investigated. Two different pill densities are considered to study the effects of the gastric flow as well as the gravitational force on the motion of the pill. The average mass transfer coefficient and the spatial distributions of the dissolved drug concentration are analyzed in detail. The results show that the retropulsive jet and recirculating flow in the antrum generated by the antral contraction wave play an important role in the motion of the pill as well as the transport and mixing of the dissolved drug concentration. It is also found that the gastric flow can increase the dissolution mass flux, especially when there is substantial relative motion between the gastric flow and the pill.

Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research

There is considerable cellular diversity in the human stomach, which has helped to clarify cell plasticity in normal development and tumorigenesis. Thus, the stomach is an interesting model for understanding cellular plasticity and for developing prospective anticancer therapeutic agents. However, many questions remain regarding the development of cancers in vivo and in vitro in two- or three-dimensional (2D/3D) cultures, as well as the role of Helicobacter pylori (H. p.) infection. Here, we focus on the characteristics of cancer stem cells and their derived 3D organoids in culture, including the formation of stem cell niches. We define the conditions required for such organoid culture in vitro and examine the ability of such models for testing the use of anticancer agents. We also summarize the signaling cascades and the specific markers of stomach-cancer-derived organoids induced by H. p. infection, and their stem cell niches.

Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer

Barrett's esophagus (BE) and gastric intestinal metaplasia are related premalignant conditions in which areas of human stomach epithelium express mixed gastric and intestinal features. Intestinal transcription factors (TFs) are expressed in both conditions, with unclear causal roles and cis-regulatory mechanisms. Ectopic CDX2 reprogrammed isogenic mouse stomach organoid lines to a hybrid stomach–intestinal state transcriptionally similar to clinical metaplasia; squamous esophageal organoids resisted this CDX2-mediated effect. Reprogramming was associated with induced activity at thousands of previously inaccessible intestine-restricted enhancers, where CDX2 occupied DNA directly. HNF4A, a TF recently implicated in BE pathogenesis, induced weaker intestinalization by binding a novel shadow Cdx2 enhancer and hence activating Cdx2 expression. CRISPR/Cas9-mediated germline deletion of that cis-element demonstrated its requirement in Cdx2 induction and in the resulting activation of intestinal genes in stomach cells. dCas9-conjugated KRAB repression mapped this activity to the shadow enhancer's HNF4A binding site. Altogether, we show extensive but selective recruitment of intestinal enhancers by CDX2 in gastric cells and that HNF4A-mediated ectopic CDX2 expression in the stomach occurs through a conserved shadow cis-element. These findings identify mechanisms for TF-driven intestinal metaplasia and a likely pathogenic TF hierarchy.

In vitro Prebiotic Properties of Garlic Polysaccharides and Its Oligosaccharide Mixtures Obtained by Acid Hydrolysis

Fructans and oligofructose are usually used as prebiotics without any limitation in functional food or food ingredients. The degree of polymerization (DP) of polysaccharides affects the utilization of probiotics. Garlic is rich in fructans. The objective of this study was to extract and purify polysaccharides from garlic, analyze its composition, hydrolyze them using HCl, and then evaluate the prebiotic potential of the garlic neutral polysaccharides (GPs) before and after hydrolysis. GPs were 6.57 × 103 Da with a composition of fructose and glucose at a ratio of 4:1. After acid hydrolysis, low molecular weight fraction in garlic oligofructose (GOs) may be eliminated through ultrafiltration. The content of oligosaccharides with an average DP < 10 increased from 15 to 75%. GPs and GOS had a stronger resistance to acid conditions in human stomach than fructooligosaccharide, and GOs showed better prebiotic properties on the growth of lactobacilli than GPs. This study evaluates the prebiotic potential of the garlic frutctans and oligosaccharides mixtures obtained by acid hydrolysis, which may be used as an ingredient in functional food and nutraceutical products.

Metagenomic and single-cell RNA-seq survey of the H. pylori-infected stomach in asymptomatic individuals

ABSTRACTObjectiveHelicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. Although latent H. pylori infection can progress to cancer, a detailed survey of the microbiome and immune composition in the chronically infected stomach is still lacking.DesignWe collected human gastric tissues and performed metagenomic sequencing, single-cell RNA sequencing (scRNA-seq), flow cytometry and fluorescent microscopy to deeply characterize the host-microbiota environment in H. pylori-infected (HPI) stomachs.ResultsHPI asymptomatic individuals showed dramatic changes in the composition of gastric microbiome and immune cells compared to non-infected individuals. With metagenomic data, we also demonstrated antibiotic resistant genes, enzymes and pathway alterations related to metabolism and immune response. scRNA-seq and flow cytometry data revealed that in contrast to murine stomachs, ILC2 are virtually absent in the human gastric mucosa, whereas ILC3 are the dominant population in asymptomatic HPI individuals. Specifically, NKp44+ ILC3s were highly increased in the gastric mucosa of asymptomatic HPI individuals, and their proportions correlated with the abundance of selected microbial taxa found to be enriched in the infected mucosa. In addition, CD11c+ myeloid cells, activated CD4 T cells and B cells were expanded in HPI individuals. In HPI individuals, B cells acquired an activated phenotype and progressed into a highly proliferating germinal center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria.ConclusionOur study provides a comprehensive atlas of the gastric mucosa-associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.SIGNIFICANCE OF THE STUDYWhat is already known on this subject? Previous studies on the gastric microbiome were performed via 16S rRNA gene sequencing.Acute Helicobacter spp. infection in murine models and symptomatic H. pylori-driven pathology in humans result in remodeling of the stomach immune cell compartment.ILC2 is the dominant ILC population in the murine stomach.What are the new findings? We described the effect of chronic asymptomatic H. pylori infection on the gastric microbiome via whole-genome sequencing.Single cell census of the gastric mucosa reveals ILC3 to be the dominant ILC population in the human stomach, whereas ILC2 were virtually absent.scRNA-seq reveals the gastric immune cell programs in asymptomatic H. pylori-infected individuals, which is characterized by the formation of tertiary lymphoid structures.How might it impact on clinical practice in the foreseeable future? Whole genome sequencing of uninfected and H. pylori-infected gastric mucosa bolsters collective knowledge of stomach physiology with respect to the gastric microbiome and microbiota function.We present a comprehensive immune cellular landscape of the human stomach, which will be a valuable resource to interrogate pathology of gastric diseases.

Follow the Metaplasia: Characteristics and Oncogenic Implications of Metaplasia’s Pattern of Spread Throughout the Stomach

The human stomach functions as both a digestive and innate immune organ. Its main product, acid, rapidly breaks down ingested products and equally serves as a highly effective microbial filter. The gastric epithelium has evolved mechanisms to appropriately handle the myriad of injurious substances, both exogenous and endogenous, to maintain the epithelial barrier and restore homeostasis. The most significant chronic insult that the stomach must face is Helicobacter pylori (Hp), a stomach-adapted bacterium that can colonize the stomach and induce chronic inflammatory and pre-neoplastic changes. The progression from chronic inflammation to dysplasia relies on the decades-long interplay between this oncobacterium and its gastric host. This review summarizes the functional and molecular regionalization of the stomach at homeostasis and details how chronic inflammation can lead to characteristic alterations in these developmental demarcations, both at the topographic and glandular levels. More importantly, this review illustrates our current understanding of the epithelial mechanisms that underlie the pre-malignant gastric landscape, how Hp adapts to and exploits these changes, and the clinical implications of identifying these changes in order to stratify patients at risk of developing gastric cancer, a leading cause of cancer-related deaths worldwide.

Gastric Microbiota beyond H. pylori: An Emerging Critical Character in Gastric Carcinogenesis

Gastric cancer (GC) is one of the global leading causes of cancer death. The association between Helicobacter pylori, which is a predominant risk factor for GC, with GC development has been well-studied. Recently, accumulating evidence has demonstrated the presence of a large population of microorganisms other than H. pylori in the human stomach. Existing sequencing studies have revealed microbial compositional and functional alterations in patients with GC and highlighted a progressive shift in the gastric microbiota in gastric carcinogenesis with marked enrichments of oral or intestinal commensals. Moreover, using a combination of gastric bacterial signatures, GC patients could be significantly distinguished from patients with gastritis. These findings, therefore, emphasize the importance of a collective microbial community in gastric carcinogenesis. Here, we provide an overview of non-H. pylori gastric microbes in gastric carcinogenesis. The molecular mechanisms of gastric microbes-related carcinogenesis and potential clinical applications of gastric microbiota as biomarkers of GC are also explored.

Role of Helicobacter pylori and Other Environmental Factors in the Development of Gastric Dysbiosis

Microbiomes are defined as complex microbial communities, which are mainly composed of bacteria, fungi, and viruses residing in diverse regions of the human body. The human stomach consists of a unique and heterogeneous habitat of microbial communities owing to its anatomical and functional characteristics, that allow the optimal growth of characteristic bacteria in this environment. Gastric dysbiosis, which is defined as compositional and functional alterations of the gastric microbiota, can be induced by multiple environmental factors, such as age, diet, multiple antibiotic therapies, proton pump inhibitor abuse, H. pylori status, among others. Although H. pylori colonization has been reported across the world, chronic H. pylori infection may lead to serious consequences; therefore, the infection must be treated. Multiple antibiotic therapy improvements are not always successful because of the lack of adherence to the prescribed antibiotic treatment. However, the abuse of eradication treatments can generate gastric dysbiotic states. Dysbiosis of the gastric microenvironment induces microbial resilience, due to the loss of relevant commensal bacteria and simultaneous colonization by other pathobiont bacteria, which can generate metabolic and physiological changes or even initiate and develop other gastric disorders by non-H. pylori bacteria. This systematic review opens a discussion on the effects of multiple environmental factors on gastric microbial communities.