New therapeutic target for irritable bowel syndrome
A research study led by scientists from the School of Chinese Medicine at Hong Kong Baptist University has shown for the first time that the human gut bacterium Ruminococcus gnavus is a major trigger factor of diarrhoea-predominant irritable bowel syndrome.
Irritable bowel syndrome is a common functional bowel disorder characterised by stool irregularities, abdominal discomfort and bloating. It has been estimated that around 7% of adults in Hong Kong are affected by irritable bowel syndrome. The most common type, diarrhoea-predominant irritable bowel syndrome, has no known cure and most clinical treatments focus solely on relieving symptoms.
Previous research has demonstrated that increased production of serotonin, a neurotransmitter involved in the regulation of gut motility, contributes to the gastrointestinal symptoms displayed in the disease. Gut microbiota play a role in regulating the levels of serotonin, however, the bacterial species concerned and the molecular mechanism for serotonin production have remained unclear.
To explore curative treatment options, a research team co-led by Professor Zhaoxiang Bian, Dr Xavier Wong, and Dr Lixiang Zhai at Hong Kong Baptist University screened thousands of food components and their breakdown products in the faecal samples of 290 patients with diarrhoea-predominant irritable bowel syndrome. They found that phenethylamine and tryptamine, two aromatic trace amines produced by the microbial digestion of dietary proteins, are highly enriched in the faeces and are associated with the severity of diarrheal symptoms.
Mice which had been fed with either phenethylamine or tryptamine experienced increased stool frequencies and colonic secretions, which are major symptoms of diarrhoea-predominant irritable bowel syndrome. The gut bacterium Ruminococcus gnavus, which is enriched in faecal samples of those suffering from the disease, is a primary producer of phenethylamine and tryptamine, and mice with this bacterium transplanted into their guts developed diarrhoea. These results suggest that phenethylamine and tryptamine produced by Ruminococcus gnavus trigger diarrhoea-predominant irritable bowel syndrome in mammals without the involvement of other risk factors.
The research team conducted tests which 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, thereby stimulating gut motility and secretion disorders. The team then explored the therapeutic potential of targeting the this pathway for treatment. It was discovered that inhibition of the receptor activation through the use of a specific inhibitor effectively alleviated related diarrheal symptoms in mice.
“IBS-D patients experience frequent episodes of diarrhoea 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 this pathway,” said Bian.
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 Wong.
Their research findings have been published in Cell Host & Microbe.