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Gut Feelings: Dissecting the molecular basis of chronic non-infectious diarrhoea

A healthy gut is a prerequisite for a healthy life. However, when things go wrong in the bowels, diarrhoea or leaky bowels are often the result – with the condition ranging from being merely irritating or embarrassing to life-threatening. Recently, novel mutations have been discovered to be responsible for causing distinct gastro-intestinal disorders of hitherto unknown causes. The work was carried out by scientists at the Indian Institute of Science, Bangalore in collaboration with international teams from Austria and Norway.

Congenital sodium diarrhoea (CSD) and familial diarrhoea syndrome (FDS) are two rare, conditions where patients suffer from chronic diarrhoea that inevitably means high susceptibility to dehydration, irritable bowel syndrome and inflammatory bowel diseases. These two syndromes are caused by mutations in a protein receptor called guanylate cyclase C (GC-C). This receptor is an important part of the network of ‘second messengers’ that are crucial for cell signalling.

Second messengers are key molecules that help in carrying signals from the outside of the cell to the inside, ensuring that signals are perceived and responded to. Prof. Sandhya Visweswariah’s lab at the Indian Institute of Science has been studying second messenger cell signaling, and she along with her former students Dr. Najla Arshad and Ms. Insha Rasool, have uncovered the role of receptor GC-C in causing these two forms of gastro-intestinal disorders. . GC-C produces cyclic guanosine monophosphate (cGMP), a critical second messenger involved in the absorption and secretion of water and electrolytes in the human gut. “This is the first ever report that links GC-Cs to these human intestinal disorders” says Prof. Sandhya.

The revelation that mutations in the GC-C receptor could potentially cause intestinal diarrhoea has not failed to capture the attention of clinicians abroad. “Doctors at the Medical University of Innsbruck, Austria (working on CSD patients) approached us based on our previous discovery of GC-C mutations that caused FDS in a Norwegian family” said Prof. Sandhya while describing her international collaborations.

Prof. Sandhya’s group has been working on the basic science behind GC-C signalling for two decades, mainly by generating and characterizing mutations in different regions of the receptor. “It was fortuitous. We just happened to be at the right place in our research at the right time. The Norwegian group (from Haukeland University Hospital and the University of Bergen, Norway) contacted us regarding a mutation that they found in a family. The discovery of GC-C mutations linked to FDS was published in the prestigious New England Journal of Medicine, and was voted ‘best paper’ in the medical sciences division at the University of Bergen. Following this publication, clinicians approached Prof. Sandhya after identifying mutations in children with secretory diarrhea. One of the mutations was the same that we had described years ago while studying receptor structure and activation!”, she says. The discovery of GC-C mutations linked to FDS was published in the prestigious New England Journal of Medicine, and was voted ‘best paper’ in the medical sciences division at the University of Bergen. This collaborative work with clinicians in Europe has now led to the discovery of not just one, but two novel links between intestinal diseases and GC-Cs.

Prof. Sandhya is hopeful that this breakthrough will provide an answer to other non-infectious chronic diarrhoea syndromes that have no known cause. “If such patients are there (suffering from diarrhoea of unknown origin), it would be worthwhile to look at the sequence of their GC-Cs”. While clinicians abroad have been most active in reaching out to her with their cases, Prof. Sandhya was disappointed that there were no such collaborations with Indian clinicians. “More and more people in India need to be aware of high impact science” she said, underscoring the need for a greater partnership between basic science and clinical diagnosis in India.

The discoveries may help in future treatments of these diseases for which there is no cure at the moment. “Now that we know the involvement of the receptor in these syndromes, chemical inhibitors of their signalling, such as CFTR or PKG2 inhibitors may be beneficial for patients battling this chronic disease”. The future of GC-C research in Prof. Sandhya’s lab promises to be exciting, as she has recently received a grant from the Bill and Melinda Gates Foundation to further investigate the involvement of GC-Cs in regulating intestinal health.

With the discovery of novel mutations that followed close on the heels of the first ever report of GC-C involvement with disease, Prof. Sandhya Visweswariah has been able to orchestrate the union of classical biochemistry with the classical genetics approach of clinical diagnosis perfectly. With 24% of post neonatal deaths in India caused by diarrheal diseases (according to WHO), her work promises to make an impact closer to home. It is said that knowing why a disease occurs is halfway to finding a cure – the cutting edge research from Prof. Sandhya’s lab has certainly given science a push along that arduous road.

About the papers:

The papers appeared in the New England Journal of Medicine, 2012 and Gut, 2015.

About the author:

Sandhya S. Visweswariah is a pPofessor at the Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore.