The human gut microbiome as the key link between childhood malnutrition and risk of metabolic disorders in later life in south India

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Our research aims to understand how the infant intestinal microbiome affects malnutrition, growth trajectories and the subsequent risk of developing metabolic disorders such as type 2 diabetes and cardiovascular disease, among children and young adults in southern India. India is the second most populous country in the world, and whilst having a huge burden of malnutrition is now also facing a rapidly growing problem of obesity and non-communicable diseases, in particular metabolic disorders. India ranks second in the global diabetes epidemic. Westernisation of diet, increasing affluence and urbanisation are believed to be major causes for this increase in rates of diabetes and cardiovascular diseases. However, this burden is also shifting towards younger people, those less affluent and rural populations. Studies have shown that the first 1000 days of life are key to determining both stunting and obesity. This early period also coincides with development of the infant's intestinal microbiome. Our research puts the gut microbiome as the likely mechanistic link between nutrition in early life and metabolic health in adulthood. There is some strong evidence for this hypothesis. Studies have shown marked differences in the intestinal microbiota composition in malnourished individuals compared to healthy ones. Short chain fatty acids, which are produced by bacterial fermentation from non-digestible sugars in the diet, are major energy sources. Recent studies have shown distinct microbiota profiles in undernourished compared to obese children and that the gut microbiome composition of children at 2 years of age has the potential to identify those that are at risk of obesity. Some of the bacteria that inhabit the intestine are responsible for inflammatory responses, which are linked to risk of metabolic disorders such as diabetes, and gut microbiome alterations are associated with insulin resistance in type 2 diabetes. Gut microbes are also able to produce chemical substances linked to the development of cardiovascular diseases. Our research proposes to investigate the following questions: (1) Are growth trajectories in Indian children linked to their microbiome profiles? (2) Can we identify key changes in the microbiota profiles that correspond with changes between normal and stunted growth states? (3) What is the role of enteric infection on microbiome profiles and on chronic inflammation as a marker of risk of metabolic disease in later life? (4) Can we identify key aspects of the microbiome profiles that translate into changes in metabolic markers of risk of disease leading to a pathway for intervention?To conduct this research, we will make use of an extensive collection of clinical samples and data already collected from a cohort of 300 children recruited at birth in Vellore, Southern India, and followed up into adolescence. We will define the gut microbiome profiles over time using stored stool samples, measure markers of risk of metabolic disease using stored blood, and investigate how the results differ according to their growth trajectories. We will continue to follow up this cohort into adulthood to gather additional information and measurements to assess the onset or risk of obesity and metabolic disorders. Our work aims to provide evidence that malnutrition and associated metabolic disorders are linked to gut microbiome profiles from a very early age. Malnutrition may then be controlled, or its effects modified, by modulating the gut microbiota, and therefore lead to the development of effective therapeutic interventions. Finding solutions to tackle malnutrition will have far-reaching impact; Prevention or correction of malnutrition can lead to improving cognitive development and therefore contribute to breaking the cycle between malnutrition and poverty with far-reaching societal and economic impact in low and middle-income countries.