Starving for Change: Microbiome Manipulation in the fight against Child Malnutrition

Natacha is a single mother, with three children, a farm, and a modest plot of land. It has been months since the last harvest of millet, and millet is all that grows in her field. Even on the best of days, life was never easy in her village. Natacha was always short on food for her children, with little more than millet to feed them. More nutritious – and more expensive – food is simply not an option. Even Alexis, her six-month old baby, does not seem to grow, despite the meager breast milk she provides. Deprived of nutrients, her children grow increasingly thinner, as her options grow increasingly bleak. Despite her best efforts, Natacha and her children will starve without intervention. Unfortunately, hers is not an uncommon story. Nor is it from the middle ages. This is a story from 2017, in Bowe, Burkina Faso, where – like in many areas of the world – undernutrition still afflicts children like Natacha’s. Due to a lack of essential nutrients, over 236 million children suffer from malnutrition, with symptoms like stunted growth, weakness, and loss of body weight.  In the developing world, many cases of malnutrition are fatal, contributing to 45% of deaths of children under 5 years old. Even with conventional treatment – administering vitamins or a high-nutrient diet – mortality rates remain high for acute cases, especially in youth.  However, could cases like these be prevented?

Scientists now say yes, by harnessing an unlikely ally: bacteria. A community of bacteria, fungi, and other microbes occupy the body, as microscopic guests on our skin, intestines, and other mucosal surfaces. Called the ‘microbiome’, these small inhabitants have a disproportionate effect on our health, with some even causing or combatting human disease. While some ‘bugs’ are harmful –  think Salmonella, the pathogen behind food poisoning; or Clostridium difficile, a diarrhea-causing bacterium – most in the body are benign, or even beneficial. In fact, humans and the microbiome exist in a co-dependent relationship and work to each other’s mutual benefit. For microbes, the human body is an ideal host, providing food and shelter without lease. For humans, microbes can aid in digestion and immunity, metabolising key nutrients, while preventing other, dangerous microbes from taking up residence. In the past, scientists have tried to stress these positive interactions, introducing beneficial microbes while removing harmful species. This has been done with increasing sophistication. Most primitively, probiotics – food with beneficial bacteria, like yogurt – can be ingested, coating the digestive tract with a layer of helpful microbes. When taken with prebiotics like fibre and whole grains, these bacteria are nourished, contributing to a healthy gut flora. More invasively, doctors can add healthy microbes directly to the digestive tract, by transferring healthy faeces to a diseased colon. Through this ‘faecal transplant’, an unhealthy microbiome can be supplanted by a healthy one, provided by new bacteria in the foreign faeces. In recent years, scientists have even altered the genes of certain bacteria, to bestow customised effects on their hosts. Through genetic engineering, bacteria can be made to destroy harmful compounds, kill pathogens, and treat illness, as ‘living medicines’ that shield the body. Now, the potential of the microbiome is being used to treat malnutrition, as well – with remarkable results.

The relationship between malnutrition and the microbiome has been traced with increasing clarity, exemplified by a 2013 study led by Dr. Michelle Smith. Over three years, Dr. Smith and her team studied the microbiomes of twins raised in Malawi, where a form of malnutrition, called kwashiorkor, frequently afflicts local children. Children with kwashiorkor look like images from a ‘FEED THE WORLD’ poster, with bloated bellies, shrunken features, and skin lesions that cover the body. It is a symptom of acute undernourishment, most commonly affecting children in the developing world.  When twins were fed the same, nutrient-poor diet, however, only some developed kwashiorkor, while others were unaffected by the disease. When given nutritious food, sick children only temporarily recovered, relapsing when returned to their former diet. To Dr. Smith, something else seemed at play. After taking faecal samples from both groups, Smith observed that unaffected children had healthier, more diverse microbiomes, carrying a wide range of species in their digestive tract. On the other hand, kwashiorkor-affected children displayed underdeveloped microbiomes, with little species variation. To test this correlation, Smith placed the faecal samples in germ-free mice, which have no pre-existing microbes in their body. When fed the same, low-nutrient diet, mice with the kwashiorkor-associated microbiota demonstrated significant weight loss, whereas those with the healthy microbiome were able to maintain a steady weight. Through the use of a faecal transplant, the microbiome was directly implicated in malnutrition, with undeveloped microbiomes contributing to cases of malnutrition. Since then, studies have further elucidated this relationship in populations from southeast Malawi to Dhaka, Bangladesh. Scientists have even been able to pinpoint the bacteria missing in malnourished microbiomes – for instance, Bifidobacterium longum, a bacterium transmitted in breast milk; or Lactobacillus, which help shield the body from pathogens – and have correlated their absence with increased disease outcomes. The evidence is striking: a decrease in microbe diversity shows a clear increase in malnutrition. But how can this be fixed?

In July 2019, scientists found what may be an answer. Led by Dr. Jeffrey Gordon, a team of researchers with the International Centre for Diarrhoeal Disease Research pioneered a study in Dhaka, Bangladesh. Dr. Gordon studied the faecal samples of children with severe acute malnutrition (SAM), who did not recover after a high-nutrient, ‘therapeutic food’ diet. Rather, these children failed to gain weight, and displayed underdeveloped microbiomes, with little bacterial diversity in their digestive tract. After placing their faecal samples into germ-free mice, the research team administered different, microbiota-directed complementary foods (MDCFs) to the rodents. Unlike therapy foods – high-calorie peanut snacks, for example, or lentil porridge – MDCFs directly target the microbiome, encouraging microbial growth, while helping beneficial bacteria to settle the digestive tract. After feeding test mice twelve possible MDCFs, the research team settled on a winning combination: chickpea, peanuts, soy, and banana. Taken together, these foods provided the greatest growth of microbiome development, increasing the variety of beneficial bacteria in mice. Equally important, all five are widely available in Dhaka, and can be homogenised into an edible paste – known as MDCF-2. Dr. Gordon and his team initiated a clinical trial, giving sixty-seven undernourished, Bangladeshi children MDCF-2 over one month. What came next was remarkable: the recovery of gut microbes, resembling those of healthy children. In turn, the research team observed an increase in key metabolic proteins, linked with bone-growth, neurological development, and greater immune function in test subjects. With a delectable “consistency like chalky peanut butter”, MDCF-2 may not be a crowd-pleaser, but it is a life-saver – bringing young children from the brink of starvation. While there is no single solution to global malnutrition, MDCFs may be our best hope.

MDCF studies are still in their infancy; in fact, Dr. Gordon’s study is the first to examine their effect on malnutrition. Yet, to deny their potential would be rash, especially with such successful results. Going forward, scientists are still to test if MDCFs can bestow health effects in the long run – not just over one-month trials, but over years. Longitudinal studies, following child development before, during, and after MDCF treatment, would be required. Nevertheless, MDCFs could be a simple answer to a complex problem, giving the malnourished a second chance at life.

But administering treatment is not without its challenges. The first challenge is administering treatment in the first place. Many parts of the world – particularly in the developing world – do not have access to primary healthcare centres, where MDCFs could be distributed and malnourished children could receive medical treatment. These are the same countries with high rates of malnutrition, where primary healthcare is needed the most. Without infrastructure at the community level, any intervention is bound to fail. A related, and just as important, challenge is logistical – distributing MDCFs, in a coordinated, efficient manner. Unfortunately, the World Health Organisation (WHO) has not always lived up to this standard. According to Doctors Without Borders, the WHO has failed to deliver vaccines to Ebola-ridden communities, vaccinating 225,000 fewer people than anticipated targets. With a track record like this, the WHO might not be ready for a global anti-malnutrition campaign. At the same time, MDCFs must be culturally-sensitive to permit global outreach. In creating MDCF-2, Dr. Gordon was able to use foods familiar to Bangladeshis, ending with a product palatable for children and trusted by parents. As MDCFs reach greater, global outreach, health organisations must consider the religious and dietary preferences of populations across the world. Are the ingredients Halal? Does this population have a high incidence of lactose-intolerance? Do parents trust this food enough to give it to their children? These are all questions that must be considered, before any global distribution of MDCFs could be implemented.

Ultimately, there is no simple answer to malnutrition. Beyond just science, various inequalities – economic, gendered, geographical – intersect at every level of society, contributing to the nutrition crisis we see today. Malnutrition cannot be solved overnight. But for the 236 million children who go to sleep hungry, for the parents who have to watch their babies starve, for people like Natacha and Alexis, MCDFs might be their best bet. They deserve a chance. And the microbiome might just provide it.

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• Starving for Change: Microbiome Manipulation in the fight against Child Malnutrition - December 23, 2020