Turns Out, The Purpose of Diarrhoea Is Way More Complicated Than We Thought


For centuries, scientists have been confounded by one of the messiest aspects of the human experience – diarrhoea, and why exactly we have to endure it.

While it makes sense that its purpose would be to flush out infections as quickly as possible, there’s been a surprising lack of biological evidence to back up this assumption. And now researchers have waded into the science of diarrhoea to find that we might be doing more harm than good by trying to prevent it.

 

“The hypothesis that diarrhoea clears intestinal pathogens has been debated for centuries,” says one of the team, Jerrold Turner from the Brigham and Women’s Hospital in Boston.

“Its impact on the progression of intestinal infections remains poorly understood. We sought to define the role of diarrhoea, and to see if preventing it might actually delay pathogen clearance and prolong disease.”

Turner and his team were interested in one key aspect of the diarrhoea experience – how does all that water get past the intestinal wall and into the final product?

Working with mouse models of ‘traveller’s diarrhoea‘ – the type caused by bacterial infections – the researchers examined the animals’ intestinal lining to figure out how large amounts of water are able to pass through to facilitate diarrhoea.

The mice were infected with Citrobacter rodentium, the mouse equivalent of an E. coliinfection.

The team discovered that in response to the infection, immune cells started gravitating towards the intestinal wall, and triggered the production of a protein called interleukin-22.

Interleukin-22 fused with cells in the intestinal lining, and prompted them to produce a second protein, called claudin-2.

This protein’s job is to coordinate with the cells to form large openings in the intestinal wall, so more water than usual can start flushing through.

This all happened within just two days of the bacterial infection – well before inflammation and tissue damage start to make the infection more obvious.

The activity of claudin-2 has been noted in humans before, but these are the first signs of the interplay between it and interleukin-22 in the event of a bacterial infection.

And it suggests that while having diarrhoea might be a nightmare, not having it could be an even worse fate.

Below you can see the interaction between interleukin-22 (blue sphere) and claudin-2 to fight the C rodentium bacteria:

bacteria june newPei-Yun Tsai et. al/Cell Host and Microbe

It’s not just the mechanism by which diarrhoea is more complicated than we’ve assumed – we’ve been misjudging how it interacts with the bacteria to fight the infection too.

The team figured this out by observing three types of mice – one that was engineered to overproduce claudin-2, one whose ability to produce claudin-2 was blocked (called claudin-2 knockout mice), and a control group.

As expected, the control group got diarrhoea in response to the infection, and the claudin-2 over-producer had diarrhoea all the time.

But none suffered as much as the claudin-2 knockout mice.

Despite the fact that they were the only ones to avoid a messy bout of runny poop, they experienced symptoms of the infection far more severely than the others, and it took much longer for their immune systems to clear out the bacteria.

“Their immune system went crazy trying to clear this infection [but] it couldn’t,” Turner told Ryan F. Mandelbaum at Gizmodo.

In the early stages of the infection, the claudin-2 knockout mice experienced far greater tissue damage than the other two groups, and greater proliferation of the harmful bacteria.

And here’s the kicker – they ended up getting terrible diarrhoea anyway.

By day 11 of the infection, the diarrhoea finally set in, and remained “significantly greater” than the other two groups up to day 21.

The researchers suggest that if the body isn’t able to produce diarrhoea to flush the infection out – facilitated by the activity of both interleukin-22 and claudin-2 – it will start breaking down its own intestinal lining to force the water through and bring on the flow itself.

It’s important to note that the experiment has so far only been carried out in mice, so until we observe it in humans, it’s too soon to say that the same process occurs in our bodies.

But humans do produce the protein interleukin-22, so it might well be responsible for triggering the production of diarrhoea in us too.

And what this research shows is that any medications designed to block its or claudin-2’s activity could be doing more harm than good – we’ve been underestimating just how important it could be in preventing more serious and prolonged infections.

“People are working on drugs to prevent diarrhoea. But this tells us that … you have to be careful about it,” Turner told Gizmodo.

“In the case of this pathogen, if you block it, you make the infection much worse.”

UNICEF study reveals two-thirds of rural Indian children who die below the age of five are lost to treatable conditions like premature birth, infection, and diarrhoea


Despite the government’s efforts to curb child mortality, children under the age of five continue to die due to medical negligence and lack of timely medical aid.

A study, funded by the Ministry of Health and Family Welfare, USAID and UNICEF, conducted in rural areas of 16 districts from eight states across India, revealed that even today newborns suffer from infections, acute respiratory infection (ARI) and diarrhoea, which accounts for approximately 63 per cent of deaths in children under the age of five.

The study conducted by the Department of Biostatistics, All India Institutes of Medical Sciences (AIIMS), along with the INCLEN Trust International, was published in the latest issue of Indian Journal of Community Medicine.

Children under the age of five continue to die of diseases such as acute respiratory infection and diarrhoea

Children under the age of five continue to die of diseases such as acute respiratory infection and diarrhoea

The survey conducted in around 216,794 households revealed that more than 1,656 children under the age of five die due to various reasons.

The autopsies were analysed to learn the specific causes of deaths. In newborns, these were shown to be birth asphyxia, premature birth, and infection.

All this contributed to more than 67.5 per cent of the neonatal deaths, while in children aged 29 days to 59 months, ARI and diarrhea accounted for 54.3 per cent of deaths.

Shockingly, the families of 52.6 per cent of newborns and 21.7 per cent of infants and children under the age of five, did not seek any medical care.

The study said that substantial delays in seeking medical attention led to deaths either at home or during transit.

Little girls continue to be ignored in the Indian households, as the study revealed that baby girls born at home, or born in a health center run by unskilled health workers and caregivers with less than primary education were at a higher risk.

States such as Bihar, Madhya Pradesh, Rajasthan, Uttar Pradesh and Andhra Pradesh have recorded high mortality rates in children below five, and these were dubbed high-burden states in India.

Low birth weight and premature birth were the leading causes of neonatal mortality in Karnataka, Maharashtra, and Odisha. In Uttar Pradesh and Haryana, children largely died in the post-neonatal period due to diarrhoea.

“The majority of these deaths could have been prevented with the interventions offered in primary and secondary care,” the study revealed.

The study has indicated that arranging for transportation and social support for accompanying and deciding health care needs are interlinked and these were reported to be the major difficulties faced by families living in remote villages.

A contrary report was released by the National Family Health Survey (NFHS).

This survey was conducted in four of the 15 states and union territories, and it concluded that fewer children were dying in infancy and early childhood.

The Health Ministry recently said after the last round of NFHS in 2005-06, the infant mortality has declined in all the states/union territories.

The Ministry also said that all the 15 states/union territories have low death which is 51 deaths per 1,000 children born each day. It also added that there is a considerable variation among the states and the union territories.

 

India unveils first indigenous rotavirus vaccine.


VIJAY_RAGHAVAN_PRE_1457427f

Rotavirus responsible for approximately 4,53,000 child deaths due to diarrhoea globally each year

The Phase-III clinical trial of low cost Indian-made rotavirus vaccine Rotavac has demonstrated strong efficacy and excellent safety profile and if approved by the Drugs Controller General of India, it would be available at Rs. 54 per dose.

This vaccine, developed under a public-private partnership, will be the third to hit the Indian market, but will be more affordable than the two vaccines now available costing more than Rs. 1,000 per dose.

The clinical study has demonstrated for the first time that Rotavac is efficacious in preventing severe rotavirus diarrhoea in low-resource settings in India, and developing countries in Asia and Africa. Strain diversity, too, has not apparently affected its efficacy.

Rotavirus is responsible for approximately 4,53,000 child deaths due to diarrhoea globally each year. It is particularly threatening in India where — according to a recent study — around 1,00,000 children die each year from severe diarrhoea and dehydration caused by rotavirus.

India accounts for 22 per cent of the estimated global deaths from diarrhoea-causing rotavirus.

Rotavac is an oral vaccine and is administered to infants in a three-dose course at the ages of 6, 10 and 14 weeks.

It is given alongside routine immunisations in the Universal Immunisation Programme (UIP) vaccines recommended at these ages.

“Once sanitation and drinking water supply in the country improves, the efficacy of the vaccine is bound to go up. Rotavirus is also associated with gut infection and the vaccine is known to give ‘herd immunity.’ Even if 25 per cent infection is prevented, it will mean a substantial public health gain,” said M.K. Bhan, former Secretary, Department of Biotechnology.

“This is an important scientific breakthrough against rotavirus infections. Clinical results indicate that the vaccine, if licensed, could save the lives of thousands of children each year in India,” K. Vijay Raghavan, Secretary, Department of Biotechnology, said.

The randomised, double-blind, placebo-controlled phase-III clinical trial enrolled 6,799 infants in India (aged six to seven weeks at the time of enrolment) at three sites — the Centre for Health Research and Development, Society for Applied Sciences, in New Delhi; Shirdi Sai Baba Rural Hospital, KEM Hospital Research centre in Vadu; and Christian Medical College in Vellore.

Infants received Rotavac and the UIP vaccines, including the oral polio vaccine (OPV).

Result showed that infants receiving OPV at the same time as Rotavac generated comparable immune responses to all three polio serotypes as the infants receiving OPV without Rotavac, supporting the concurrent administration of OPV and Rotavac.


Source: The Hindu

Probiotics for treating acute infectious diarrhoea


Episodes of acute infectious diarrhoea remain a major disease burden throughout the world, especially in developing countries. They are due to infection by many different organisms. Most episodes are self-limiting and usually investigations are not done to identify the infectious agent. The main risk to health is dehydration and management aims to improve and maintain hydration status. However, rehydration fluids do not reduce the stool volume or shorten the episode of diarrhoea. Probiotics are “friendly” bacteria that improve health and are not harmful in themselves. A number of randomized controlled trials have been done to see whether probiotics are beneficial in acute infectious diarrhoea. We have searched for as many of these trials as possible and collected together the data in a systematic way to try to discover whether or not probiotics are beneficial in acute diarrhoea. We identified 63 trials, which included a total of 8014 people – mainly infants and children. Probiotics were not associated with any adverse effects. Nearly all studies reported a shortened duration of diarrhoea and reduced stool frequency in people who received probiotics compared to the controls. Overall, probiotics reduced the duration of diarrhoea by around 25 hours, the risk of diarrhoea lasting four or more days by 59% and resulted in about one fewer diarrhoeal stool on day 2 after the intervention. However, there was very marked variability in the study findings and so these estimates are approximate. We concluded that these results were very encouraging but more research is needed to identify exactly which probiotics should be used for which groups of people, and also to assess the cost effectiveness of this treatment.