The Science behind “Cells at Work!!” Episode 4: “H. Pylori”

In this episode, Neutrophil is called to the stomach when Helicobacter pylori (H. pylori) invades the stomach, taking the Lactic Acid Bacteria from Cell Boy. In the stomach, H. pylori breaks down the lining of the stomach, creating rubble, and splashes gastric acid that melts the other bacteria. While the gastric acid presents a barrier for neutrophils to defeat H. pylori, it also energises one of the Lactic Acid Bacterium, allowing him to grow and beat up H. pylori. H. pylori tries to retreat, but his emergence from the gastric acid allows Neutrophil, accompanied by the Lactic Acid Bacterium, to kill him. Neutrophil realises that the bacteria he brought are good bacteria that help the human body and leaves the Lactic Acid Bacteria alone as he continues his patrol. 

H. pylori is an interesting and important pathogen that causes many gastrointestinal diseases, yet the episode did not look too much into the biology of this bacterium or the numerous problems in the stomach this bacterium produces. This blog post will describe what Helicobacter pylori (H. pylori) are and how it causes disease in the human body. I will then explain how drugs and lactic acid bacteria eradicate H. pylori from the human body, drastically reducing the risk of developing gastrointestinal diseases.  

The microbiology of H. pylori

Schematic	Microscopic	Anime

H. pylori is a spiral-shaped, Gram-negative bacterium that commonly colonises the human stomach, producing various gastrointestinal diseases. Having existed alongside humans for at least 100,000 years, this bacterium was made famous by Barry Marshall’s experiments in 1985 where he ingested some H. pylori to show that this bacterium causes gastrointestinal diseases. Now, H. pylori produces the highest number of chronic infections globally with more than 50% of the world’s population infected with H. pylori. Most people infected with H. pylori do not show any symptoms, but they have a 10-20% chance of developing ulcers and a 1-2% chance of developing gastric cancer. 

Did you know? When the bacterium was first discovered by Barry Marshall and Robin Warren in 1984, it was initially classified as a Campylobacter, being called Campylobacter pylori. The bacterium was subsequently re-classified as Helicobacter pylori due to its vast differences from other Campylobacter bacteria such as Campylobacter coli. 

H. pylori has a variety of features that allow it to colonise the stomach and cause infection. H. pylori adheres to the gastric epithelium via adhesin proteins BabA and SabA on its surface, allowing it to establish colonies in the stomach. The bacterium also possesses multiple flagella that allow it to travel through mucus, a viscous substance, near the gastric epithelium. Contrary to the events of the episode, H. pylori cannot survive in gastric acid, preferring to grow at neutral pH values of 5.5-8.0. Nevertheless, the bacterium is able to grow in the stomach by secreting urease. Urease is an enzyme that converts urea to ammonia and carbon dioxide. Ammonia acts as a base to neutralise the surrounding gastric acid. This raises the pH of the local area, protecting H. pylori from gastric acid so that it can grow near the gastric epithelium. This provides H. pylori an advantage over other gastric bacteria that are unable to adapt to the gastric environment of the stomach. 

H. pylori also has a variety of virulence factors that can cause disease in host cells and protect the bacterium against the immune system. Firstly, CagA (cytotoxin-associated gene A), present in most H. pylori strains, can interact with intracellular proteins in host cells to alter cellular function and morphology. This increases the susceptibility of host cells to becoming cancerous which can contribute to the development of gastric cancer. Secondly, VacA (vacuolating toxin A) can form pores on different membranes in host cells to allow the exchange of ions. VacA pores can be inserted into endosomes to produce empty vacuoles inside the cell, into mitochondria to trigger cell death and into the plasma membrane to leak nutrients from the cell to H. pylori. Lastly, lipopolysaccharide (LPS) is coated on the outer membrane of H. pylori. Unlike LPS from other gram-negative bacteria; however, H. pylori LPS does not promote strong immune and inflammatory responses. Instead, it mimics a self-antigen normally found in host cells that gives H. pylori the ability to evade the immune system, allowing it to grow unchecked. 

How does H. pylori cause disease?

H. pylori stimulates a strong inflammatory response that damages gastric tissue and produces tumour cells, leading to the development of different gastric diseases and gastric cancer. H. pylori infection can produce gastritis, inflammation of the stomach mediated firstly by neutrophils and then by lymphocytes. Gastritis is associated with tissue damage, particularly in the gastric glands which can become altered, damaged and killed. This reduces acid secretion, reducing the capability of the stomach to break down food. This causes dyspepsia or indigestion which is associated with symptoms of stomach pain, heart burn, nausea, vomiting and a sensation of fullness. H. pylori-induced gastritis also leads to the development of gastric ulcers, open, inflamed sores in the lining of the stomach. As acid penetrates through the gastric ulcer, it can eat away the inner layers of the stomach, further damaging the organ. The hole that H. pylori resides in the episode (shown above) is an example of a gastric ulcer. 

H. pylori is also identified as a carcinogen, able to promote cancer by maintaining gastritis over a long period of time. This promotes the transformation and uncontrolled proliferation of different cells in the stomach. Gastric epithelial cells can become cancerous through prolonged H. pylori-induced gastritis, producing a tumour which can contribute to the development of gastric cancer. Gastritis can also affect B cells in the stomach, where it can induce them to slowly but uncontrollably proliferate to form a MALT lymphoma (essentially a cancer of lymphocytes).

How is H. pylori treated?

In the modern age, patients take a combination of drugs to eradicate H. pylori from the body. This eliminates H. pylori from the person’s stomach and the human body which reduces the risk of the person developing gastric ulcers, gastritis, gastric cancer and MALT lymphoma. H. pylori eradication commonly involves a combination of three drugs, known as triple therapy. This consists of two different antibiotics (clarithromycin and amoxicillin) that target and inhibit the growth of H. pylori and a proton pump inhibitor (PPI) that blocks gastric acid production, enhancing the antibacterial actions of antibiotics. Alternatively, in areas where clarithromycin resistance is common, a person takes a combination of four drugs via quadruple therapy. This consists of two different antibiotics (tetracycline and metronidazole), a PPI and bismuth, a chemical that has antibacterial actions against H. pylori. The patient takes either combination of drugs for up to two weeks before a doctor confirms eradication of the bacteria from the body. 

The anime episode is correct in that lactic acid bacteria such as Lactobacillus and Lactococcus can inhibit H. pylori infection. This can occur in a number of ways with different lactic acid bacteria targeting specific areas of H. pylori pathogenesis. Firstly, some lactic acid bacteria can inhibit H. pylori urease. This reduces the production of ammonia of H. pylori which impedes its ability to control its pH, allowing gastric acid to impede its growth. Secondly, Lactococcus lactis and Enterococcus faecalis can suppress IL-8 secretion from gastric cancer cell lines, reducing neutrophil migration to the stomach to weaken inflammation. Lastly, Lactococcus lactis can release lacticin A164, a bacteriocin that can impede the division of different H. pylori strains. Collectively, lactic acid bacteria can play a role in impeding the growth of H. pylori which, in combination with drug therapies, can increase the chances of H. pylori eradication in the person. 

Conclusion

The anime episode underestimates the significance of H. pylori infection in the human body and human society. More than half of the world’s population is estimated to be infected with H. pylori which speaks to its ability to adapt to the gastric environments of different people. Left untreated, H. pylori can promote a chronic inflammation in the stomach called gastritis. It not only leads to the emergence of gastric ulcers associated with H. pylori infection but it can also contribute to the development of indigestion and act as a carcinogen to cause different kinds of cancers, most notably gastric cancer. Thankfully, drug therapy can eradicate H. pylori from the body, drastically reducing the chances of a person in developing gastric ulcers and cancers. Lactic acid bacteria can also play a role in impeding the growth of H. pylori in the bod, offering another potential method of H. pylori eradication from the body.

In the next episode, we will talk in more detail about cytokines and how they are essential in any immune response, particularly influenza. See you then!