The teaching design and implementation of “Helicobacter pylori” in medical microbiology

Development of systematic thinking

In order to foster the development of systematic thinking, it is recommended that educators commence with the pathogens associated with common infections of the digestive system. This approach will enable students to summarize and analyze the similarities and differences between the pathogens of the digestive system, as well as to clarify the characteristics of H. pylori.

Furthermore, the current standard for the treatment of H. pylori is a regimen of proton pump inhibitors, bismuth, and combined antibiotics. However, the long-term use of antibiotics raises concerns about the impact on the human microbiota, particularly the gut microbiota [2]. This is an important area for students to consider in terms of microecosystem balance.

Development of critical thinking

With regard to the development of students’ critical thinking, recent studies have indicated that H. pylori may have a protective effect against a number of diseases, including reflux oesophagitis and multiple sclerosis [3, 4]. Furthermore, children who have been infected with H. pylori in childhood appear to have a reduced incidence of immune-related diseases such as eczema and inflammatory bowel disease (IBD) later in life 5], [6], [7. It is therefore beneficial for students to gain an understanding of pathogens from both positive and negative perspectives, to critically analyze the relationship between pathogens and human health, so as to stimulate the students’ interests in exploring the underlying mechanisms.

Reinforcing the meaning of Koch’s postulates

The discovery of H. pylori is a classic practice of Koch’s postulates in the discovery of pathogenic bacteria [8]. While Koch’s postulates and its application should be studied throughout medical microbiology course, students are expected to equip with the ability to use their knowledge of pre-existing pathogens to identify emerging pathogens in future infectious disease epidemics. Koch’s postulates represent a significant reference point in this context. The scientist’s spirit of truth-seeking and dedication to science, as exemplified by the discovery of H. pylori, helps to cultivate students’ responsibility and commitment in the prevention and control of infectious diseases.

Based on the above principals, following the backward design strategy, we propose the following learning objectives of H. pylori for the comprehensive medical students, viz. at the end of this chapter, the students can:

1. Review the history of H. pylori discovery.

2. Describe the morphology, staining, biochemical properties and culture characteristics of H. pylori.

3. List the diseases caused by H. pylori, along with the laboratory diagnostic methods and treatment of infection.

4. Identify similarities and differences between H. pylori and other gastrointestinal pathogens.

5. Have a comprehensive understanding of the relationship between H. pylori and human health.

Figure 2:

Morphology of Helicobacter pylori. (a) Gram staining of H. pylori (×1,000). H. pylori is Gram negative; (b) transmission electron microscope (TEM) image of H. pylori (×5,000). H. pylori is a curved, elongated bacterium with prominent flagella, facilitating its penetration of the thick mucous layer in the stomach; (c) Histologic manifestations of H. pylori infection (HE staining, ×400). H. pylori is visible as small red rods (arrows) on the epithelial surface and within the glands. The underlying mucosa shows inflammatory cells infiltration.

History of the discovery of H. pylori

In 1984, Australian physicians Barry Marshall and Robin Warren reported a discovery that completely changed the approach to the treatment of gastritis and peptic ulcer disease [8]. Furthermore, their findings established the foundation for understanding the cause of gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas 9], [10], [11. In Barry Marshall and Robin Warren’s study, a histological analysis of gastric biopsy specimens from 100 consecutive patients undergoing gastroscopy was carried out. The researchers demonstrated the presence of curved Gram-negative rods, which they believed to be Campylobacter, in 58 patients. The bacteria were observed in the majority of patients presenting with active gastritis, gastric ulcers, and duodenal ulcers. Although similar organisms had previously been observed in gastric tissues, this report prompted a resurgence in investigations into the role of this “new” organism in gastric diseases. Despite initial skepticism, the significance of their work with Helicobacter was recognized in 2005 when Marshall and Warren received the Nobel Prize in Physiology or Medicine (https://www.nobelprize.org/prizes/medicine/2005/summary/).

The discovery of H. pylori provides a clear illustration of the application of Koch’s postulates in the identification of pathogenic bacteria, thereby establishing a causal relationship between bacteria and disease. Marshall and Warren exemplified the application of Koch’s postulates by observing the bacteria in a patient’s pathological specimen, isolating and culturing the bacteria, and then verifying the presence of the bacteria in their own bodies. Marshall and his assistants encountered difficulties in finding suitable animals to test the bacteria on, they decided to test the bacteria on themselves. This involved swallowing the culture of bacteria, which resulted in acute gastritis. This dedication to the pursuit of truth in science is worthy of respect and learning [12, 13].

In 2006, Barry Marshall published a book called Helicobacter Pioneer. In this publication, Barry Marshall indicates that several medical professionals, including doctors and researchers, had previously observed “small curved and S shaped bacilli” in the stomach. However, they all believed these to be transient bacteria. This was because at that time, prevailing medical opinion considered it impossible for a bacterium to survive and colonize under such a harsh and acidic environment as the stomach. However, Barry Marshall and Robin Warren observed the bacteria and applied Koch’s postulates to demonstrate the presence of bacteria in the stomach, and furthermore, to confirm the causal relationship between this bacterium and chronic digestive disease. Their discovery, therefore, can be considered a true discovery, whereas the previous observations could not be described as such. Consequently, this narrative illustrates that scientists are willing to challenge tradition and pursue the truth, which is an example worthy of emulation by students. Furthermore, it serves to illustrate the value of Koch’s postulates as a guide in the face of unknown pathogens.

The dialectic between H. pylori and human health

H. pylori is the most significant gastric pathogen, with numerous studies confirming a strong association between H. pylori infection and the development of chronic gastritis, duodenal ulcers, gastric ulcers, gastric mucosa-associated lymphomas, and gastric cancer [14]. Furthermore, it is postulated that H. pylori infection is associated with a series of extragastric manifestations, such as halitosis, eosinophilic esophagitis, non-alcoholic fatty liver disease (NAFLD), liver cancer, cholecystitis and cholelithiasis, vitamin B12 deficiency, iron deficiency anemia, ophthalmic manifestations, Alzheimer’s disease, Parkinson’s disease and cardiovascular diseases, etc. [3, 15, 16]. A positive correlation between H. pylori infection and the incidence or symptoms of these diseases has been observed in studies of patients with the aforementioned diseases or in animal models of the diseases.

However, the relationship between H. pylori infection and human health is still subject of debate. In 1997, a study suggested that H. pylori eradication can lead to reflux disease [17]. The majority of studies have demonstrated an inverse association between H. pylori and gastroesophageal reflux disease (GERD) [4, 18]. On the other hand, "the Maastricht V/Florence Consensus Report" claims that H. pylori eradication has little clinical importance in acid production changes [19]. Nevertheless, the presence of H. pylori infection is thought to confer a degree of protection against multiple sclerosis, allergies, some autoimmune diseases, asthma and IBD [3].

The identification of the mechanisms by which H. pylori infection affects human health and the dialectical perspective on the relationship between microbes and host health for the purpose of better disease prevention and treatment should be reflected in the teaching of the content of this chapter.

H. pylori eradication and gut microbiota homeostasis

The eradication of H. pylori infection is a combination of proton pump inhibitors, bismuth and antibiotics, with dosing cycles ranging from seven to fourteen days. A long-term antibiotic combination is an effective method for the clearance of H. pylori; however, it is also important to consider the potential impact of antibiotic application on the gut microbiota homeostasis [2]. The gut microbiota dysbiosis will have adverse consequences. In order to adopt effective clinical diagnostic and therapeutic measures, it is essential to consider the human body as a unified system when we use antibiotics for treatment in bacterial infection. It is imperative that the principles of rational medication use to ensure microbiota homeostasis in the body be taught throughout the medical microbiology curriculum.

Other cutting-edge teaching content

The latest data on the prevalence of H. pylori infection worldwide, recent advances in the pathogenesis mechanism of H. pylori infection, new diagnostic strategies, a review of the current status of medication for the treatment of H. pylori infection, the One Health concept in the prevention and control of the spread of H. pylori resistance will also be included during the teaching process 20], [21], [22], [23], [24.

Case design

In addition to the theoretical content, for the purpose of facilitating the integration of organ-systems thinking within the curriculum and to reinforce the development of clinical thinking, it is recommended that this subject be taught in the form of case-based learning (CBL). It is therefore essential to conduct case design.

Case description:

A 24-year-old male presented to his family physician with a chief complaint of abdominal discomfort that had been progressively worsening over the past three weeks. He stated that the symptoms often abated immediately after meals or the ingestion of antacids. Additionally, he reported occasional heartburn but denied the presence of fevers, nausea or vomiting, diarrhea, or bloody stools.

The patient was a journalist and was accustomed to working in a stressful environment. No other noteworthy prior social or medical history was identified.

1. Physical examination

   Vital signs: temperature (T): 36.8 °C; pulse (P): 80/min; respiration (R): 15/min; blood pressure (BP) 106/75 mmHg.

   A physical examination of the abdomen revealed mild tenderness in the mid-epigastric region, with no rebound. The rectal examination yielded normal results, and no blood was observed on the fecal occult blood test (Hemoccult test).

2. Laboratory diagnosis

   Urea breath test: positive

   Blood: Hematocrit test: 39 %; white blood cell count (WBC): 7,500/μL; Differential: normal; Serum chemistries: normal.

   Endoscopic examination: The image demonstrates a duodenal ulcer with evidence of bleeding (Figure 3a).

   Histologic examination: Endoscopic biopsy specimens were sectioned, stained, and examined microscopically. S-shaped organisms were observed adhering to gastric epithelial cells (Figure 3b).

   Culture: endoscopic biopsy specimens cultured on brain-heart broth medium with blood under microaerophilic environment. After 96 h, colonies appeared and Gram staining was conducted, Gram-negative bacteria were observed under the microscope (Figure 3c).

3. Questions:

   1. What is the diagnosis of this case?

   2. Describe the microbiologic properties of the etiologic agent.

   3. Compare the similarities and differences with other digestive system pathogens.

   4. Whether all patients infected with the pathogen should undergo eradication therapy?

   5. What are the advantages and disadvantages of existing treatment strategies? What is the current state of research into new treatments?

Figure 3:

Teaching materials in case-based learning (CBL). (a) Image of endoscopic examination. Gastric ulcer with active bleeding was observed. (b) Histologic examination of Helicobacter pylori infected tissue (immunohistochemistry, ×40). H. pylori is stained brown in the gastric epithelial layer. (c) H. pylori colonies on culture medium (brain-heart infusion blood agar). Small, transparent colonies appeared on the plate after 96 h of culture.

Pre-class

In this section, students are required to complete a question-led online self-study. Teachers prepare a series of learning materials on the course website, including original massive open online courses (MOOC) videos, a documentary video, and an article from WeChat official account. The MOOC video was teacher filmed lectures on the basic knowledge of H. pylori. While the documentary video is about Barry Marshall telling the story of his discovery of H. pylori with Robin Warren. Together with the article from WeChat, the students can gain an understanding of the whole process of H. pylori discovery.

During self-study, the teacher poses two questions:

1. In the digestive system, why does H. pylori infect the stomach but not the intestines?

2. Given the high prevalence of H. pylori infection, why is it discovered late?

After completing the self-study online, students will draw their own mind maps in relation to the questions and prepare a class presentation on the two questions.

The intention of question design:

These two questions, on the one hand, reinforce students’ organ-system thinking and, on the other hand, inspire their thinking and understanding of the basic characteristics of bacteria through contradictions.

In-class

Students are required to work in small groups to present in class, according to their pre-class preparation. This involves asking questions and interacting with each other in order to deepen their learning, while simultaneously evaluating each other.

Following the presentation by the students, the teacher provides a summary and then poses two questions to facilitate further study and thinking.

1. Who actually discovered H. pylori for the first time and what significant implications does this discovery have for medical students?

2. How to understand the relationship between H. pylori and human health precisely?

The intention of question design:

The first question is designed in the hope that students will learn from the following three aspects: the guiding significance of Koch’s postulates for the understanding of future emerging pathogens; to understand that seeing is not the same as discovering in science, reflecting the spirit of scientists’ courageous challenge and the pursuit of truth; to get touched by the dedication of the discoverer who tested the bacteria on his own.

The second question is designed to lead students to a critical understanding of the relationship between H. pylori and the host, to introduce cutting-edge advances in the protective role that H. pylori plays against some diseases, and also to stimulate students’ interest in science through the paradox between pathogenicity and protection.

After-class

After the class, the teacher presents two cutting-edge questions as below, based on these two questions, students complete micro-lecture recording assignments, make a mechanism figure, and students who have interest in H. pylori related studies can participate in scientific research training in the second classroom.

1. What effect will antibiotic treatment of H. pylori have on the gastrointestinal microbiota?

2. Explaining the spread of antimicrobial resistance of H. pylori from the One Health perspective.

The intention of question design:

These two questions are designed to incorporate the concepts of rational drug use, the impact of antibiotics on gut microbiota homeostasis, and the concept of One Health in the prevention and control of antimicrobial resistance. “One Health” approach emphasizes the harmony between humans, animals, and the environment, and encourages interdisciplinary communication and multi-sectoral collaboration which plays an important role in promoting the health of people, animals, and ecosystems.

CBL teaching

Discussion and flipped classroom are used in the CBL teaching. The application of online instant interactive system in the classroom, such as Chaoxing platform, Rain classroom, and Wenjuanxing, etc., can make the whole process of learning more active. Depending on the size of the class, students will be divided into groups of four to five, and the case content will be discussed and interacted with step by step based on the questions until the whole case is completed.