Boccellato Group Research Overview

The stomach mucosa is a barrier whose main function is to secrete acid and digestive enzymes and absorb nutrients from food. This barrier also has a fundamental protective role: it senses and reacts to bacterial infection. Helicobacter pylori is the only bacterium that can infect the stomach and its extraordinary ability to colonise the mucosa despite the strongly acidic environment has been associated with gastritis, stomach ulcers and with the onset of stomach cancer.

The World Health Organization (WHO) considers Helicobacter pylori a class 1 carcinogen and stomach cancer causes more than 700,000 deaths per year worldwide. Thanks to higher hygiene standards that reduce the risk of bacterial transmission and to more efficient diagnosis and treatment with antibiotics, the number of cases is diminishing, especially in the UK. Unfortunately, after 20 years of standard antibiotic therapies, the WHO has recognised that there is an alarming increase in the number of antibiotic-resistant cases.

The most external part of the stomach mucosa is the epithelium, which forms a continuous layer of cells that faces the lumen of the stomach. The mucosa is organised in narrow cavities called gastric glands. The glands are where H. pylori survives lifelong if not eradicated. In recent years, an increased understanding of stem cell biology has driven the development of organoid cultures as a way of maintaining adult stem cells in vitro, including those obtained by isolating glands from gastric tissue samples.

Following the infection route of H. pylori, the pathogen would first cope with the mucus and then contact the apical side of the epithelium. We have developed a primary culture system that enables routine infection while maintaining the epithelial architecture characterised by polarised cells and tight junctions, as well as an intact mucus layer. This system support large-scale experiments, longer-term infection, and analysis of the mucus (Boccellato et al., GUT, 2018). We named these in vitro models “mucosoid cultures”. The apical surface of the mucosoids is protected by secreted mucus, enabling chronic in vitro infection.

These features represent key advantages over existing culture methods and permit advanced studies on the mechanisms of chronic inflammation, the role of mucus in epithelial defence, and the factors that control epithelial homeostasis during infection. As such, mucosoids represent an important and unique new tool for illuminating the mechanisms underlying gastrointestinal immunity and carcinogenesis.

Research aims

Our aims are

• To further develop complex tissue culture systems to mimic chronic infection in vitro.
• To understand the molecular basis of the regenerative programme initiated by the infection.
• To understand the genetic consequences of chronic infection.

A cross-sectional microscope image of a mucosoid culture of the stomach epithelium infected with Helicobactor pylori. A layer of stomach cells with the stained H. pylori occupying the space above.