The human gut microbiome as the key link between childhood malnutrition and risk of metabolic disorders in later life in south India
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Infection and Global Health
Abstract
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.
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.
Technical Summary
We aim to provide further understanding of the role of infant intestinal microbiome establishment on growth trajectories, malnutrition and subsequent risk of developing metabolic disorders, in a birth cohort in southern India. The results will inform type and timing of effective interventions to prevent the growing epidemic of metabolic disorders. We will leverage biological samples and anthropometric data available from a birth cohort in Vellore, Southern India, and extend follow-up into adulthood to answer the following questions: 1) Are growth trajectories in Indian children linked to their microbiome profiles, and do profile changes link with transitions between normal and stunted states? 2) Are enteric infections and changes in microbiota profile linked, and for how long do the profiles stay altered? 3) Do microbiota profiles and enteric infections define chronic inflammation, driving the risk of metabolic disease in later life? 4) Are changes in microbiota profile translated to metabolic alterations and do they indicate pathways for intervention?
We will use archived stool samples to study the microbiome and frequency of infection with pathogens associated with malnutrition, among subjects with distinct growth trajectories. We will use plasma samples to measure markers of nutrition, inflammation, and development of cardiovascular disorders. Prospectively, we will quantify further metabolic markers and body composition parameters, familial, behavioural and life-style risk factors.
In the development phase we will undertake: analysis of enteric infection data against growth trajectories in the cohort; analysis of existing infant microbiome data from a smaller cohort against inflammation and growth; review availability of host genetic control data, and the potential to include a epigenetic study in the prospectively. We will hold an investigators' workshop for joint development of publications arising from these analyses and the full research proposal.
We will use archived stool samples to study the microbiome and frequency of infection with pathogens associated with malnutrition, among subjects with distinct growth trajectories. We will use plasma samples to measure markers of nutrition, inflammation, and development of cardiovascular disorders. Prospectively, we will quantify further metabolic markers and body composition parameters, familial, behavioural and life-style risk factors.
In the development phase we will undertake: analysis of enteric infection data against growth trajectories in the cohort; analysis of existing infant microbiome data from a smaller cohort against inflammation and growth; review availability of host genetic control data, and the potential to include a epigenetic study in the prospectively. We will hold an investigators' workshop for joint development of publications arising from these analyses and the full research proposal.
Planned Impact
We will ensure that this project is an integral part of the long-term goals of the collaborative partnership between the participating institutions. Our activities will be channelled to address the research priorities of the LMIC partner, and to building the capacity to identify and appropriately address questions related to improved nutrition for individual lifelong heath benefit leading to societal and economic change.
Specific areas where impact will be addressed include the following levels:
1. Individuals and teams
Development of investigators through mentoring of young clinician-scientists by the project principal investigators
Development pipelines to integrate complex datasets
2. Institutions
Enhancement of research by establishment of new research area in malnutrition
Development of new investigative capacity by mentored trainees and scientists
3. National level
Provide evidence to support novel interventions for the prevention of malnutrition and associated NCDs
Promote the conduct of in-country evaluations novel interventions
Provide an understanding of the impact of early life events that shape heath in adulthood
4. Populations
Answering questions about the role of a healthy start for a sustained heath and curving the growing epidemic of metabolic disorders
Targeted interventions to improve healthy weight at birth and early infancy for life long impact
Appropriate nutrition leading heathy wright and to improved health resulting in improved productivity contributing towards breaking the poverty cycle
Public engagement to build trust in research and in researchers and advancing public health research impact
In summary, the existing strong collaborations between the UK and India institutions are being leveraged to build a new collaboration expanding the research expertise and scope not just to conduct an important research project but also lay the foundations to contribute significantly to policy development in India with impact on lifelong health and societal outcomes
Specific areas where impact will be addressed include the following levels:
1. Individuals and teams
Development of investigators through mentoring of young clinician-scientists by the project principal investigators
Development pipelines to integrate complex datasets
2. Institutions
Enhancement of research by establishment of new research area in malnutrition
Development of new investigative capacity by mentored trainees and scientists
3. National level
Provide evidence to support novel interventions for the prevention of malnutrition and associated NCDs
Promote the conduct of in-country evaluations novel interventions
Provide an understanding of the impact of early life events that shape heath in adulthood
4. Populations
Answering questions about the role of a healthy start for a sustained heath and curving the growing epidemic of metabolic disorders
Targeted interventions to improve healthy weight at birth and early infancy for life long impact
Appropriate nutrition leading heathy wright and to improved health resulting in improved productivity contributing towards breaking the poverty cycle
Public engagement to build trust in research and in researchers and advancing public health research impact
In summary, the existing strong collaborations between the UK and India institutions are being leveraged to build a new collaboration expanding the research expertise and scope not just to conduct an important research project but also lay the foundations to contribute significantly to policy development in India with impact on lifelong health and societal outcomes
