Tag: Hong Kong

A research study led by scientists from the School of Chinese Medicine (SCM) at Hong Kong Baptist University (HKBU) has shown for the first time that the human gut bacterium Ruminococcus gnavus is a major trigger factor of diarrhoea-predominant irritable bowel syndrome (IBS-D). Based on this discovery, a new therapeutic target for the disease’s treatment was identified. The study also found that low-protein food items such as fresh fruits, vegetables and bread may help reduce the gut motility in IBS-D. The research findings have been published in the internationally renowned scientific journal Cell Host & Microbe.

Curative treatment for IBS-D needed

Irritable bowel syndrome (IBS) is a common functional bowel disorder characterised by stool irregularities, abdominal discomfort and bloating. It has been estimated that about 7% of adults in Hong Kong are affected by IBS. IBS-D is the most common type of IBS and there is no known cure for the disease. Most clinical treatments for IBS-D focus on relieving symptoms.

Previous research has demonstrated that the increased production of serotonin, a key neurotransmitter involved in the regulation of gut motility, contributes to the gastrointestinal symptoms displayed in IBS-D. It has also been shown that gut microbiota play a role in regulating the levels of serotonin. However, the bacterial species concerned and the molecular mechanism by which the gut microbiota modulate serotonin production remain unclear.

Phenethylamine and tryptamine produced by Ruminococcus gnavus trigger IBS-D

To explore curative treatment options for IBS-D, a research team co-led by Professor Bian Zhaoxiang, Director of the Clinical Division and Tsang Shiu Tim Endowed Professor in Chinese Medicine Clinical Studies; Dr Xavier Wong Hoi-leong, Assistant Professor of the Teaching and Research Division; and Dr Zhai Lixiang, Post-Doctoral Research Fellow of SCM at HKBU, screened
thousands of food components and their breakdown products in the fecal samples of 290 patients with IBS-D. They found that phenethylamine and tryptamine, two aromatic trace amines produced by the microbial digestion of dietary proteins, are highly enriched in IBS-D faeces, and they are associated with the severity of diarrheal symptoms in patients with IBS-D.

Probing further, the researchers found that mice which had been fed with either phenethylamine or tryptamine experienced increased stool frequencies and colonic secretions, which are major symptoms of IBS-D.

On the other hand, the team found that the gut bacterium Ruminococcus gnavus, which is enriched in IBS-D faecal samples, is a primary producer of phenethylamine and tryptamine. Furthermore, mice with this bacterium transplanted into their guts go on to develop IBS-D diarrheal symptoms. These results suggest that phenethylamine and tryptamine produced by Ruminococcus gnavus trigger IBS-D in mammals without the involvement of other risk factors of IBS-D.

Phenethylamine and tryptamine stimulate serotonin production

The research team further conducted a series of experiments to understand the mechanism by which phenethylamine and tryptamine lead to IBS-D. The results showed that phenethylamine and tryptamine directly stimulate the production of serotonin from the enterochromaffin cells in the gut through the activation of a trace amine-associated receptor (TAAR1), thereby stimulating gut motility and secretion disorders in IBS-D.

The team then explored the therapeutic potential of targeting the phenethylamine/tryptamine/TAAR1 pathway for the treatment of IBS-D. It was discovered that inhibition of TAAR1 activation through the use of a specific inhibitor effectively alleviated the diarrheal symptoms in mice which had been transplanted with IBS-D faecal samples.

Prospects for new therapeutic options

“With a full outline of the mechanism of how gut microbiota associate with gut motility disorders, our research results suggest that the phenethylamine/tryptamine-mediated TAAR1 pathway
is a new therapeutic target for IBS-D,” said Dr Zhai Lixiang.

“IBS-D patients experience frequent episodes of diarrhea with accompanying abdominal pain, which reduce the quality of life. The research discoveries offer promising potential for the development of therapies for IBS-D based on the inhibition of the pathway,” said Professor Bian Zhaoxiang.

The research team also found that a diet low in phenylalanine, an amino acid and a dietary precursor of phenethylamine, suppresses gut motility in mice by reducing the microbial production of phenethylamine and tryptamine. Low-protein food items such as fresh fruits, vegetables and bread have relatively low levels of phenylalanine.

“Developing strategies to reduce the microbial transformation of dietary amino acids into phenethylamine and tryptamine, such as dietary intervention with reduced consumption of high-protein food items which usually have high phenylalanine levels, may represent a feasible approach for the management of IBS-D,” said Dr Xavier Wong.

A study led by scientists from Hong Kong Baptist University (HKBU) has identified a protease called MT1-MMP that is a major host factor behind the infectivity of the SARS-CoV-2 virus in the human body, which leads to the infection of COVID-19 and multi-organ failure. By applying a humanised antibody called 3A2 that can inhibit the activity of MT1-MMP, the viral load of infected mice was reduced by almost 90%. The research team also demonstrated that the protease is a potential therapeutic target for COVID-19.

The research findings have been published in the internationally renowned scientific journal Nature Communications.

ACE2 as a receptor for SARS-CoV-2 cell entry 

Vaccination can protect people against COVID-19 and its potential complications, but it is not always effective in individuals with weak immune systems, or against some COVID-19 variants of concern. Thus, the development of a more effective treatment for COVID-19 remains a huge challenge in the post-vaccine era. Understanding the cell entry mechanism of SARS-CoV-2 is vital to curb the spread of the virus, and it will also aid the search for new COVID-19 treatments.

SARS-CoV-2 requires angiotensin-converting enzyme 2 (ACE2), a protein found on the membrane of human cells, as its receptor for cellular entry. Despite the lungs being the major organ affected by SARS-CoV-2 infection, only a small proportion of lung cells express ACE2.

Previous studies found that the infection of organs with low levels of ACE2 expression by SARS-CoV-2 is made possible by a soluble form of ACE2. The soluble ACE2 binds with SARS-CoV-2, carries the virus to cells with low levels of ACE2 expression, and facilitates its entry into the cells.

MT1-MMP mediates cell entry of SARS-CoV-2 

A research team led by Dr Xavier Wong Hoi-leong, Assistant Professor of the Teaching and Research Division of the School of Chinese Medicine at HKBU, in collaboration with Dr Yuan Shuofeng, Assistant Professor of the Department of Microbiology at The University of Hong Kong, further studied how the physiological regulation of soluble ACE2 shedding contributes to the aetiology of COVID-19.

The team found that SARS-CoV-2 infection leads to the increased activation of MT1-MMP, a protease crucial for many physiological processes. MT1-MMP mediates the release of soluble ACE2 from ACE2-expressing cells. This soluble ACE2 in turn binds to the spike proteins of SARS-CoV-2 and carries it to the uninfected cells with low levels of ACE2 expression.

Notably, the team demonstrated that the introduction of human-soluble ACE2 enables SARS-CoV-2 to infect the lungs of a laboratory mouse strain (C57BL/6 mice) that is naturally insusceptible to SARS-CoV-2 infection due to the incompatibility of its mouse ACE2 and the viral spike proteins. The findings unveil the mechanism by which the virus hijacks host enzymes to enhance its infectivity, triggering multi-organ infections.

Antibody 3A2 blocks MT1-MMP activity 

To study MT1-MMP’s functions and how it affects viral infection, the researchers used human cells to create organoids, a 3D tissue structure grown in vitro to resemble and model different organs in the laboratory.

They discovered that blocking MT1-MMP activity with the monoclonal antibody 3A2 effectively depleted soluble ACE2 levels and reduced the degree of infection of SARS-CoV-2 in human lung, heart and liver organoids by 60-80%. Consistent results were obtained using the original strain of SARS-CoV-2, as well as variants of concern, such as Delta and Omicron. The

results demonstrate that MT1-MMP is a major host factor that mediates the cell entry of SARS-CoV-2, and that it is also a potential therapeutic target for COVID-19 drugs.

The researchers further tested the effects of applying 3A2 in a mouse COVID-19 model. A group of 11 mice were treated with either 3A2 or vehicle controls. Older mice were used in the experiment as old age is a major risk factor for severe symptoms and mortality for COVID-19. The results show that 3A2 reduced the viral load of SARS-CoV-2 by almost 90% and dramatically alleviated lung tissue damage resulting from infection.

MT1-MMP as a therapeutic target 

Dr Wong said: “Two major challenges when it comes to developing COVID-19 drugs are how to enhance treatment results for patients with weakened immune systems, and how to maintain the drugs’ effectiveness across different viral strains. 3A2 has good potential to become an effective drug for curing COVID-19 because it antagonises the activity of MT1-MMP, instead of boosting the immunity of patients or acting directly on the virus.

“Our previous studies have demonstrated that 3A2 also offers protection against obesity and diabetes, two major risk factors for severe symptoms and mortality for COVID-19. Therefore, 3A2 could be particularly suitable for high-risk groups, including older adults and people with metabolic disorders. It could also be effective against emerging coronaviruses in the future, because ACE2 is a doorway for many such viruses with similar cell entry mechanisms. Further research and experiments on 3A2 are required before it can be applied in humans.”