The outsiders inside us
Madhavankutty Pillai | 21 Dec, 2017
AROUND 15 years ago, Dr Yogesh Shouche, a scientist with the National Centre for Cell Science,Pune, was on a flight returning from a conference with a friend who was a paediatrician. As they got talking, the discussion turned to probiotic products, food in which good bacteria is added for health. The doctor told Shouche that from first-hand experience, he had observed that commercially available probiotic preparations were not effective in India because they had been developed for the Western population. Moreover, there had been no studies in the country to find out how the micro- organisms that live in the human digestive tract, like bacteria, fungi, viruses, etcetera, were different for Indians. The conversation prompted Shouche to conduct a study comparing the gut microbiome— the total genetic material of these microbes—of babies delivered after vaginal and caesarean deliveries. Inside the womb, a developing baby has no microbes. When born, during the passage to the vagina, the baby acquires them from the mother. However, if the delivery is caesarean, instead of getting them from the mother, it instead picks microbes from the hospital environment. This phenomenon can have an effect on the baby’s health long into the future and that was what Shouche planned to look at.
The researchers started with 100 babies, but he now calls that approach naïve. The yearly follow-ups saw huge dropouts until they finally ended up with a sample of only about 8 to 10. “It became a very small study and was published very late. But then one thing led to another. Another student had developed an interest in obesity (its relation to gut microbes); we did a small work on it. And that is how it started,” the doctor says.
Just how far research has travelled is evident in a study that Shouche is about to helm involving multiple Indian scientific organisations. They have proposed to sample 20,000 individuals across the country to get information about dietary habits and other factors, and correlate that with their microbiome pattern. They are waiting for funding to come through from the Department of Biotechnology in this financial year and begin immediately after that. The study is important and could hold keys to new gateways of health for Indians with microbiome therapy emerging as an alternative and effective tool for ailments like diabetes, Inflammatory Bowel Disease and obesity.
“You should know what is the healthy microbiome in the Indian population because otherwise such a therapy won’t be useful,” says Dr Shouche. Simply getting something developed in the West might not be effective for Indian bodies. An instance of such a difference can be seen in a study of Dr Shouche’s published this September in Nature Scientific Reports. In it, the gut bacterial community of Indian and Finnish children were compared. They found that the composition differed significantly between the two groups. Dr Shouche says, “We studied two factors. One, genetic variation in a particular gene responsible for coding some enzyme which expresses sugar in the blood. We found a mutation in this gene has an effect in both the populations, but the type of [microbial] organisms that increase or decrease is different. We also compared the vaginal born and caesarean born [children]. Both groups had a difference in gut microbiome. But the way the microbiome alters is again different in Indian and Finnish populations.”
Another leading Indian researcher in this field is Dr Mojibur R Khan, now a scientist with the Institute of Advanced Study in Science and Technology, Guwahati. In 2009, he had been an early career researcher in the University College Dublin, when he came across reports on gut microbiota and health in the journals Nature and Science. He realised that the diversity of ethnicities in India, particularly in the Northeast, can be used as a model system for research. In 2011, he returned to India and undertook a project to map the gut microbiota of different ethnicities. In this study, 15 ethnic groups from the states of Assam, Sikkim, Manipur and Telangana of Mongoloid and Proto-Australoid origins were included and their gut microbiomes revealed. ‘When the results were compared with the worldwide data, it was found that the study groups have Prevotella enterotype similar to the population in Mongolia,’ he says over email.
His current studies are focused on connections between rural alcoholism prevalent in the tribes of the Northeast and gut microbiome. Some alcohol, in fact, seemed to have healthy characteristics. ‘The traditional rice beer consumed by the tribes of the Northeast might have several health benefits, many of which could be due to their effect on gut microbiome. A large-scale population based study is underway to characterise the different variants of traditional rice beer and their effect on gut microbiome and health. Our study also includes different brands of commonly used whisky and ‘chulai’ (distilled from fermented jaggery), which are not good for health. Studies are also underway to isolate potential probiotic bacteria from various sources such as dairy products, rice beer, etc,’ he says.
A human being really has a lot of company inside him, he just doesn’t know it. Count all the human cells, the most minute building blocks that make up the body, and there are said to be 38 trillion of them. But count all the cells of microbes inside the human body and it is many times that number. If their material is more than our own, then who exactly does the body belong to? That is a question for another age, but what has become clear in recent times is that these micro-organisms exert tremendous influence over us.
There are many types of them located all over and inside the body, but it is in the gut that they are overwhelmingly concentrated. By some estimates, as many as 100 trillion diverse microbes, mostly bacteria, are located there. Writes Khan, ‘The total number of microbes in the human body is ten times more than our somatic and germline cells and weigh up to 2 kg. The microbiome consists of 3.3 million genes that is 150 times more than human genome. In an individual, 150 to 170 bacterial species predominate and enjoy the warm and nutrient rich environment of the gut.’
Khan calls microbes an inseparable part of the human body, acquired at birth and whose subsequent successions go in parallel with the growth and development of the human body. In the beginning, they help develop the human immune system. Later on, they act as sentinels against germs and pathogens. They digest undigested foods, producing vitamins and nutrients. A disruption of the balance of these microbes has been associated with Crohn’s disease, ulcerative colitis, inflammatory bowel syndrome, obesity, type 2 diabetes, autism, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, lupus, rheumatoid arthritis, and so on. Research now suggests that even our mental condition is influenced by them because they interact with the brain by producing neurotransmitters and hormones that affect mood, and emotions like anxiety and happiness.
Medical science is slowly learning to manipulate gut microbes for health, and a major study published recently showed how the lives of a large number of Indian children could be saved
The degree of association between microbes and humans vary from person to person and population to population, but there are broad generalities that are observed. ‘Overall, the human being is known to possess any one of the three types of gut microbiota (called ‘enterotypes’), i.e. Prevotella or Bacteroides or Ruminococcus dominant. In our study on gut bacterial diversity across 15 ethnic groups from Assam, Sikkim, Manipur and Telangana, it was observed that microbial composition vary across locations and also share a common microbiota across the population. A core microbiota consisting of Prevotella, Fecalibacterium, Balutia, Ruminococcus, Rosiburia, Collinsella, Eubacterium and Clostridium was observed irrespective of ethnicity, geography and diet. The Indian population has Prevotella dominated enterotype. The relative abundance of the bacterial species may vary across populations, e.g. Bifidobacterium and Lactobacillus were more abundant in the people from Sikkim. This is due to their diet which is rich in dairy products. Both Bifidobacteria and Lacto bacilli are considered as probiotic and may have health beneficial effects on the host,’ says Khan.
Medical science is slowly learning to manipulate gut microbes for health, and a major study published recently showed how the lives of a large number of Indian children could be saved. The study was led by Pinaki Panigrahi of the University of Nebraska Medica Center and initiated about a decade ago. Over 4,500 newborns from 149 villages in Orissa were given an oral preparation of good bacteria, ‘Lactobacillus plantarum plus fructooligosaccharide’, and monitored for prevention of sepsis, a condition that kills a million babies worldwide every year.
Pathogenic bacteria is one of the causes of sepsis and the idea behind the study was that good bacteria would prevent the action of the bad to induce infections. They found a radical decrease in sepsis among children who took the oral preparation. The Atlantic, which reported on the study’s findings, wrote, ‘…in Panigrahi’s trial, just 5.4 percent of the infants who took the synbiotic developed sepsis in their first two months of life, compared to 9 percent of those who received a placebo. That’s a reduction of 40 percent. Such estimates always come with a margin of error, but the team calculate that the reduction in risk should still be somewhere between 25 and 50 percent. The effect was twice as large as what the team expected, especially since the infants took daily doses of the synbiotic for just one week. And given the clear evidence of benefits, independent experts who were monitoring the study decided to stop the trial early: It would have been unethical to continue depriving half the newborns of the treatment. Panigrahi originally planned to enroll 8,000 babies into the study. He stopped at 4,557.’
The team tried to first use two probiotics commonly used in India, but they were not effective. They then went on to develop their own strain by studying the faecal matter of healthy babies for locally prevalent beneficiary microbes. The new strain worked even better than their expectations, showing how important it is to indigenise probiotic products for health purposes.
RECENTLY, THE FOOD Safety and Standards Authority of India (FSSAI), came out with guidelines regulating probiotic foods in India which will come into force from January 1st, 2018. It was based on an initiative taken by the Indian Council of Medical Research (ICMR) along with the Department of Biotechnology.
Dr B Sesikeran, a former director of the National Institute of Nutrition, was part of the committee that worked on these guidelines. He says that it is not very clear how effective are the probiotic products that are available in the market today. With the new regulations, consumers will at least know the kind and amount of bacteria present in the product and also the tests which have been done to show its efficacy and shelf life.
“In probiotic regulations, we are in fact much ahead of many countries,” says Sesikeran.
Dr VK Batish, secretary of the Probiotic Association of India, a body comprising scientists, medical professionals and others that seeks to create awareness about probiotics in India, says that probiotic products are effective but not to the same extent as in the Western population and that there is not much Indianising of it by companies at present. “We are trying to promote it. A lot of clinical data needs to be established and developed for that. It is high time we come out with some formulations now. Consumer awareness is growing about probiotics. They don’t want to be dependent on drugs which have side effects and also create drug resistance. Probiotics will always be very effective. There is no possibility of developing resistance in probiotics.”
Even though Dr Shouche’s study will sample a significant population across the country from different ethnic and dietary groups, he believes there might not be a core microbiome common to all Indians because of the vast diversity here. “Maybe we will have region specific or group specific cores. Like, core groups of organisms present in the Northeast population or more pre-dominant in south Indian population. Something like that may emerge. My feeling is that there will be nothing like a core microbiome common to all Indian population,” he says.
Another factor that impacts study is the changing food habits of Indians, leading to changes in the microbes. Even in rural areas, products like instant noodles have become popular. But a way to get around that hurdle is to study tribals who are relatively untouched by modern diets, and that is what Mojibur Khan is doing. And it is important to get to that core. Lifestyle ailments are growing in India and they are also found to be correlated to altered microbiota. He says, ‘Tribal groups are untouched by the modern lifestyle and also have [a lower] incidence of lifestyle diseases. Therefore, it is important to study their microbiota which may harbour clues to find solutions to these problems.’
He says in 2006 there was only one research article from India, whereas in 2017 the number has increased to 25. In India, as always, we have been late starters but there is some momentum now. Abroad, powerful real-world applications are already on the anvil. Says Khan, ‘Recent developments in the field have led to a new regime of next generation probiotics, fecal transplantation, personalised diet, etc, to manage certain diseases. Other promising developments in this field are controlling malnutrition in children, healthy ageing, behavioural transplant, etc.’
We need to know more about own bacteria to make use of these developments. Like Prevotella, a bacteria that is of consequence to Indians. Prevotella is high in healthy Indians and low in diabetics here, but it doesn’t show any such correlation in Western nations.
Prevotella also has an association with a high-fibre diet and both in combination could lead to better control of blood sugar levels in Indians. As a therapy for diabetes, Prevotella could therefore prove very useful. If we find out about how other microbes impact us in this manner, then the benefits would be immense. Like amassing an army of trillions of soldiers in a war against diseases.