Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease

Abstract

More than one-fifth of the world's population live in extreme poverty, where a lack of safe water and adequate sanitation enables high rates of enteric infections and diarrhoea to continue unabated. Although oral rehydration therapy has greatly reduced diarrhoea-associated mortality, enteric infections still persist, disrupting intestinal absorptive and barrier functions and resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Diarrhoea in children from impoverished areas during their first 2 years might cause, on average, an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7–9 years old. A child's height at their second birthday is therefore the best predictor of cognitive development or 'human capital'. To this 'double burden' of diarrhoea and malnutrition, data now suggest that children with stunted growth and repeated gut infections are also at increased risk of developing obesity and its associated comorbidities, resulting in a 'triple burden' of the impoverished gut. Here, we Review the growing evidence for this triple burden and potential mechanisms and interventions that must be understood and applied to prevent the loss of human potential and unaffordable societal costs caused by these vicious cycles of poverty.

Key Points

  • High diarrhoea rates continue unabated in developing countries, despite benefits from oral rehydration therapy in reducing mortality

  • One-fifth (178 million) children worldwide have stunted growth; early childhood enteric infections, with or without overt diarrhoea, are predicted to account for 25–43% of this burden

  • Malnutrition severe enough to cause stunting contributes to more than half of global mortality in children >5 years old, as well as to impaired cognitive development

  • Enteric infections and undernutrition each increase the risk of the other in a vicious cycle

  • Increasing data show that early childhood infections and stunting are associated with obesity and its comorbidities in later life, forming a triple burden of poverty

  • Enteric infections, malnutrition and noncommunicable diseases form vicious cycles with poverty that are best reduced using multiple approaches including improved water purity and availability, sanitation, vaccines and supplementary nutrients

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The vicious cycles of diseases of poverty.
Figure 2: Catch-up growth in malnourished children and its eradication by recurring diarrhoea.
Figure 3: Chronic consequences of early childhood enteric infections and stunting.

References

  1. Ravallioin, M., Chen, S. & Sangraula, P. Dollar a day revisited. Policy Research Working Paper No. 4620 (Washington DC, USA) (2008).

  2. The World Bank Poverty Overview. The World Bank [online], (2012).

  3. Kosek, M., Bern, C. & Guerrant, R. L. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull. World Health Organ. 81, 197–204 (2003).

    PubMed  PubMed Central  Google Scholar 

  4. Scrimshaw, N. S., Taylor, C. E. & Gordon, J. E. Interactions of nutrition and infection. Monogr. Ser. World Health Organ. 57, 3–329 (1968).

    CAS  PubMed  Google Scholar 

  5. Mata Leonardo, J. (Ed.). The children of Santa Maria Cauque: a prospective field study of health and growth. (MIT Press, Cambridge, USA) (1978).

  6. Victora, C. G. et al. Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371, 340–357 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guerrant, R. L., Oria, R. B., Moore, S. R., Oria, M. O. & Lima, A. A. Malnutrition as an enteric infectious disease with long-term effects on child development. Nutr. Rev. 66, 487–505 (2008).

    Article  PubMed  Google Scholar 

  8. Schorling, J. B. & Guerrant, R. L. Diarrhoea and catch-up growth. Lancet 335, 599–600 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Stoger, R. The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? Bioessays 30, 156–166 (2008).

    Article  PubMed  Google Scholar 

  10. Gerson, C. D., Kent, T. H., Saha, J. R., Siddiqi, N. & Lindenbaum, J. Recovery of small-intestinal structure and function after residence in the tropics. II. Studies in Indians and Pakistanis living in New York City. Ann. Intern. Med. 75, 41–48 (1971).

    Article  CAS  PubMed  Google Scholar 

  11. Lindenbaum, J., Kent, T. H. & Sprinz, H. Malabsorption and jejunitis in American Peace Corps volunteers in Pakistan. Ann. Intern. Med. 65, 1201–1209 (1966).

    Article  CAS  PubMed  Google Scholar 

  12. Lindenbaum, J., Gerson, C. D. & Kent, T. H. Recovery of small-intestinal structure and function after residence in the tropics. I. Studies in Peace Corps volunteers. Ann. Intern. Med. 74, 218–222 (1971).

    Article  CAS  PubMed  Google Scholar 

  13. Goto, R., Mascie-Taylor, C. G. & Lunn, P. G. Impact of intestinal permeability, inflammation status and parasitic infections on infant growth faltering in rural Bangladesh. Br. J. Nutr. 101, 1509–1516 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Goto, R., Mascie-Taylor, C. G. & Lunn, P. G. Impact of anti-Giardia and anthelminthic treatment on infant growth and intestinal permeability in rural Bangladesh: a randomised double-blind controlled study. Trans. R. Soc. Trop. Med. Hyg. 103, 520–529 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Lunn, P. G., Northrop-Clewes, C. A. & Downes, R. M. Intestinal permeability, mucosal injury, and growth faltering in Gambian infants. Lancet 338, 907–910 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Lunn, P. G. Growth retardation and stunting of children in developing countries. Br. J. Nutr. 88, 109–110 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Humphrey, J. H. Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet 374, 1032–1035 (2009).

    Article  PubMed  Google Scholar 

  18. Campbell, D. I., Elia, M. & Lunn, P. G. Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation. J. Nutr. 133, 1332–1338 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Costa, L. B. et al. Novel in vitro and in vivo models and potential new therapeutics to break the vicious cycle of cryptosporidium infection and malnutrition. J. Infect. Dis. 205, 1464–1471 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Coutinho, B. P. et al. Cryptosporidium infection causes undernutrition and, conversely, weanling undernutrition intensifies infection. J. Parasitol. 94, 1225–1232 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Roche, J. K., Cabel, A., Sevilleja, J., Nataro, J. & Guerrant, R. L. Enteroaggregative Escherichia coli (EAEC) impairs growth while malnutrition worsens EAEC infection: a novel murine model of the infection malnutrition cycle. J. Infect. Dis. 202, 506–514 (2010).

    Article  PubMed  Google Scholar 

  22. Ueno, P. M. et al. Alanyl-glutamine promotes intestinal epithelial cell homeostasis in vitro and in a murine model of weanling undernutrition. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G612–G622 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Checkley, W. et al. Multi-country analysis of the effects of diarrhoea on childhood stunting. Int. J. Epidemiol. 37, 816–830 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Eppig, C., Fincher, C. L. & Thornhill, R. Parasite prevalence and the worldwide distribution of cognitive ability. Proc. Biol. Sci. 277, 3801–3808 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bhutta, Z. A. et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 371, 417–440 (2008).

    Article  PubMed  Google Scholar 

  26. Black, R. E. et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 371, 243–260 (2008).

    Article  PubMed  Google Scholar 

  27. Black, R. E. et al. Global, regional, and national causes of child mortality in 2008, a systematic analysis. Lancet 375, 1969–1987 (2010).

    Article  PubMed  Google Scholar 

  28. Bryce, J., Boschi-Pinto, C., Shibuya, K. & Black, R. E. WHO estimates of the causes of death in children. Lancet 365, 1147–1152 (2005).

    Article  PubMed  Google Scholar 

  29. Guerrant, R. L., Kosek, M., Lima, A. A., Lorntz, B. & Guyatt, H. L. Updating the DALYs for diarrhoeal disease. Trends Parasitol. 18, 191–193 (2002).

    Article  PubMed  Google Scholar 

  30. Kosek, M. et al. Directing diarrhoeal disease research towards disease-burden reduction. J. Health Popul. Nutr. 27, 319–331 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lopez, A. D., Mathers, C. D., Ezzati, M., Jamison, D. T. & Murray, C. J. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757 (2006).

    Article  PubMed  Google Scholar 

  32. Murray, C. J. & Lopez, A. D. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349, 1436–1442 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Mata, L. J., Kronmal, R. A., Urrutia, J. J. & Garcia, B. Antenatal events and postnatal growth and survival of children in a rural Guatemalan village. Ann. Hum. Biol. 3, 303–315 (1976).

    Article  CAS  PubMed  Google Scholar 

  34. Schlaudecker, E. P., Steinhoff, M. C. & Moore, S. R. Interactions of diarrhea, pneumonia, and malnutrition in childhood: recent evidence from developing countries. Curr. Opin. Infect. Dis. 24, 496–502 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shrimpton, R., Victora C. G., de, O. M., Lima, R. C., Blossner, M. & Clugston, G. Worldwide timing of growth faltering: implications for nutritional interventions. Pediatrics 107, E75 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Victora C. G., de, O. M., Hallal, P. C., Blossner, M. & Shrimpton, R. Worldwide timing of growth faltering: revisiting implications for interventions. Pediatrics 125, e473–e480 (2010).

    Article  PubMed  Google Scholar 

  37. Black, R. E., Brown, K. H. & Becker, S. Effects of diarrhea associated with specific enteropathogens on the growth of children in rural Bangladesh. Pediatrics 73, 799–805 (1984).

    CAS  PubMed  Google Scholar 

  38. Guerrant, R. L. et al. Prospective study of diarrheal illnesses in northeastern Brazil: patterns of disease, nutritional impact, etiologies, and risk factors. J. Infect. Dis. 148, 986–997 (1983).

    Article  CAS  PubMed  Google Scholar 

  39. Lima, A. A. et al. Persistent diarrhea signals a critical period of increased diarrhea burdens and nutritional shortfalls: a prospective cohort study among children in northeastern Brazil. J. Infect. Dis. 181, 1643–1651 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Moore, S. R. et al. Early childhood diarrhoea and helminthiases associate with long-term linear growth faltering. Int. J. Epidemiol. 30, 1457–1464 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Moore, S. R., Lima, A. A. & Guerrant, R. L. Infection: Preventing 5 million child deaths from diarrhea in the next 5 years. Nat. Rev. Gastroenterol. Hepatol. 8, 363–364 (2011).

    Article  PubMed  Google Scholar 

  42. Guerrant, R. L., Schorling, J. B., McAuliffe J. F. & de Souza, M. A. Diarrhea as a cause and an effect of malnutrition: diarrhea prevents catch-up growth and malnutrition increases diarrhea frequency and duration. Am. J. Trop. Med. Hyg. 47, 28–35 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Mata, L. Diarrheal disease as a cause of malnutrition. Am. J. Trop. Med. Hyg. 47, 16–27 (1992).

    Article  CAS  PubMed  Google Scholar 

  44. Schorling, J. B., McAuliffe, J. F., de Souza, M. A. & Guerrant, R. L. Malnutrition is associated with increased diarrhoea incidence and duration among children in an urban Brazilian slum. Int. J. Epidemiol. 19, 728–735 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Costa, L. B. et al. Cryptosporidium-malnutrition interactions: mucosal disruption, cytokines, and TLR signaling in a weaned murine model. J. Parasitol. 97, 1113–1120 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Fischer Walker, C. L. et al. Does childhood diarrhea influence cognition beyond the diarrhea-stunting pathway? PLoS ONE 7, e7908 (2012).

    Google Scholar 

  47. Adair, L. S. et al. Cohort profile: the Cebu longitudinal health and nutrition survey. Int. J. Epidemiol. 40, 619–625 (2011).

    Article  PubMed  Google Scholar 

  48. Berkman, D. S., Lescano, A. G., Gilman, R. H., Lopez, S. L. & Black, M. M. Effects of stunting, diarrhoeal disease, and parasitic infection during infancy on cognition in late childhood: a follow-up study. Lancet 359, 564–571 (2002).

    Article  PubMed  Google Scholar 

  49. Chang, S. M., Walker, S. P., Grantham-McGregor, S. & Powell, C. A. Early childhood stunting and later behaviour and school achievement. J. Child. Psychol. Psychiatry 43, 775–783 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Cusick, S. E. & Georgieff, M. K. Nutrient supplementation and neurodevelopment: timing is the key. Arch. Pediatr. Adolesc. Med. 166, 481–482 (2012).

    Article  PubMed  Google Scholar 

  51. Martorell, R., Habicht, J. P. & Rivera, J. A. History and design of the INCAP longitudinal study (1969–77) and its follow-up (1988–1989). J. Nutr. 125 (Suppl.), 1027S–1041S (1995).

    CAS  PubMed  Google Scholar 

  52. Mendez, M. A. & Adair, L. S. Severity and timing of stunting in the first two years of life affect performance on cognitive tests in late childhood. J. Nutr. 129, 1555–1562 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Niehaus, M. D. et al. Early childhood diarrhea is associated with diminished cognitive function 4 to 7 years later in children in a northeast Brazilian shantytown. Am. J. Trop. Med. Hyg. 66, 590–593 (2002).

    Article  PubMed  Google Scholar 

  54. Patrick, P. D. et al. Limitations in verbal fluency following heavy burdens of early childhood diarrhea in Brazilian shantytown children. Child. Neuropsychol. 11, 233–244 (2005).

    Article  PubMed  Google Scholar 

  55. Pollitt, E., Gorman, K. S., Engle, P. L., Martorell, R. & Rivera, J. Early supplementary feeding and cognition: effects over two decades. Monogr. Soc. Res. Child. Dev. 58, 1–99 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Pongcharoen, T. et al. Influence of prenatal and postnatal growth on intellectual functioning in school-aged children. Arch. Pediatr. Adolesc. Med. 166, 411–416 (2012).

    Article  PubMed  Google Scholar 

  57. Popkin, B. M. et al. Breast-feeding and diarrheal morbidity. Pediatrics 86, 874–882 (1990).

    CAS  PubMed  Google Scholar 

  58. Tarleton, J. L. et al. Cognitive effects of diarrhea, malnutrition, and Entamoeba histolytica infection on school age children in Dhaka, Bangladesh. Am. J. Trop. Med. Hyg. 74, 475–481 (2006).

    Article  PubMed  Google Scholar 

  59. Walker, S. P., Grantham-McGregor, S. M., Powell, C. A. & Chang, S. M. Effects of growth restriction in early childhood on growth, IQ, and cognition at age 11 to 12 years and the benefits of nutritional supplementation and psychosocial stimulation. J. Pediatr. 137, 36–41 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Hoddinott, J., Maluccio, J. A., Behrman, J. R., Flores, R. & Martorell, R. Effect of a nutrition intervention during early childhood on economic productivity in Guatemalan adults. Lancet 371, 411–416 (2008).

    Article  PubMed  Google Scholar 

  61. Stein, A. D. et al. Nutritional supplementation in early childhood, schooling, and intellectual functioning in adulthood: a prospective study in Guatemala. Arch. Pediatr. Adolesc. Med. 162, 612–618 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ajjampur, S. S. et al. Effect of cryptosporidial and giardial diarrhoea on social maturity, intelligence and physical growth in children in a semi-urban slum in south India. Ann. Trop. Paediatr. 31, 205–212 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Guerrant, D. I. et al. Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four-seven years later in a poor urban community in northeast Brazil. Am. J. Trop. Med. Hyg. 61, 707–713 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Nokes, C., Grantham-McGregor, S. M., Sawyer, A. W., Cooper, E. S. & Bundy, D. A. Parasitic helminth infection and cognitive function in school children. Proc. Biol. Sci. 247, 77–81 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Partovi, F., Khalili, G., Kariminia, A. & Mahmoudzadeh-Niknam, H. Effect of Giardia lamblia infection on the cognitive function of school children. Iranian J. Publ. Health 36, 73–78 (2007).

    Google Scholar 

  66. Petri, W. A. Jr et al. Enteric infections, diarrhea, and their impact on function and development. J. Clin. Invest. 118, 1277–1290 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fischer Walker, C. L. et al. Does childhood diarrhea influence cognition beyond the diarrhea-stunting pathway? PLoS ONE 7, e47908 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Misra, A. & Khurana, L. Obesity and the metabolic syndrome in developing countries. J. Clin. Endocrinol. Metab. 93 (Suppl. 1), S9–S30 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Yach, D., Hawkes, C., Gould, C. L. & Hofman, K. J. The global burden of chronic diseases: overcoming impediments to prevention and control. JAMA 291, 2616–2622 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Godfrey, K. M., Gluckman, P. D. & Hanson, M. A. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol. Metab. 21, 199–205 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Barker, D. J. Fetal programming of coronary heart disease. Trends Endocrinol. Metab. 13, 364–368 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Barker, D. J. et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 62–67 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Barker, D. J., Osmond, C., Golding, J., Kuh, D. & Wadsworth, M. E. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298, 564–567 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Veening, M. A., Van Weissenbruch, M. M. & Delemarre-Van De Waal, H. A. Glucose tolerance, insulin sensitivity, and insulin secretion in children born small for gestational age. J. Clin. Endocrinol. Metab. 87, 4657–4661 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Williams, S., St. George, I. M. & Silva, P. A. Intrauterine growth retardation and blood pressure at age seven and eighteen. J. Clin. Epidemiol. 45, 1257–1263 (1992).

    Article  CAS  PubMed  Google Scholar 

  77. Ravelli, G. P., Stein, Z. A. & Susser, M. W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353 (1976).

    Article  CAS  PubMed  Google Scholar 

  78. Roseboom T. J. et al. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol. Cell Endocrinol. 185, 93–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Nilsson, P. M. Elevated blood pressure predicts type 2 diabetes, but why? J. Hypertens. 26, 1740–1741 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Tobi, E. W. et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum. Mol. Genet. 18, 4046–4053 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Barker, D. J., Osmond, C., Forsen, T. J., Kajantie, E. & Eriksson, J. G. Trajectories of growth among children who have coronary events as adults. N. Engl. J. Med. 353, 1802–1809 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Bhargava, S. K. et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N. Engl. J. Med. 350, 865–875 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Deboer, M. D. et al. Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome? Nutr. Rev. 70, 642–653 (2012).

    Article  PubMed  Google Scholar 

  84. Ferreira, H. S. et al. Short stature of mothers from an area endemic for undernutrition is associated with obesity, hypertension and stunted children: a population-based study in the semi-arid region of Alagoas, Northeast Brazil. Br. J. Nutr. 101, 1239–1245 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Florencio, T. T., Ferreira, H. S., Cavalcante, J. C., Stux, G. R. & Sawaya, A. L. Short stature, abdominal obesity, insulin resistance and alterations in lipid profile in very low-income women living in Maceio, north-eastern Brazil. Eur. J. Cardiovasc. Prev. Rehabil. 14, 346–348 (2007).

    Article  PubMed  Google Scholar 

  86. Florencio, T. T., Ferreira, H. S., Cavalcante, J. C. & Sawaya, A. L. Short stature, obesity and arterial hypertension in a very low income population in North-eastern Brazil. Nutr. Metab. Cardiovasc. Dis. 14, 26–33 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Schroeder, D. G., Martorell, R. & Flores, R. Infant and child growth and fatness and fat distribution in Guatemalan adults. Am. J. Epidemiol. 149, 177–185 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Sesso, R., Barreto, G. P., Neves, J. & Sawaya, A. L. Malnutrition is associated with increased blood pressure in childhood. Nephron Clin. Pract. 97, c61–c66 (2004).

    Article  PubMed  Google Scholar 

  89. Grillol, L. P. et al. Lower resting metabolic rate and higher velocity of weight gain in a prospective study of stunted vs nonstunted girls living in the shantytowns of Sao Paulo, Brazil. Eur. J. Clin. Nutr. 59, 835–842 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Walker, S. P., Chang, S. M. & Powell, C. A. The association between early childhood stunting and weight status in late adolescence. Int. J. Obes. 31, 347–352 (2007).

    Article  CAS  Google Scholar 

  91. Timaeus, I. M. Stunting and obesity in childhood: a reassessment using longitudinal data from South Africa. Int. J. Epidemiol. 41, 764–772 (2012).

    Article  PubMed  Google Scholar 

  92. Martins, V. J., Martins, P. A., Neves, J. & Sawaya, A. L. Children recovered from malnutrition exhibit normal insulin production and sensitivity. Br. J. Nutr. 99, 297–302 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Fall, C. H. et al. Adult metabolic syndrome and impaired glucose tolerance are associated with different patterns of BMI gain during infancy: Data from the New Delhi Birth Cohort. Diabetes Care 31, 2349–2356 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Margolis, R. Childhood Morbidity and Health in Early Adulthood: life course linkages in a high morbidity context. Adv. Life Course Res. 15, 132–146 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Margolis, R. The effects of early childhood diseases on young adult health in Guatemala. University of Pennsylvania ScholarlyCommons: Repository [online], (2008).

  96. Brenchley, J. M. & Douek, D. C. Microbial translocation across the GI tract. Annu. Rev. Immunol. 30, 149–173 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jiang, W. et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J. Infect. Dis. 199, 1177–1185 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Moore, S. R. et al. Prolonged episodes of acute diarrhea reduce growth and increase risk of persistent diarrhea in children. Gastroenterology 139, 1156–1164 (2010).

    Article  PubMed  Google Scholar 

  99. Camilleri, M. et al. Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion. Neurogastroenterol. Motil. 22, e15–e26 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Lima, A. A. et al. Intestinal barrier function and weight gain in malnourished children taking glutamine supplemented enteral formula. J. Pediatr. Gastroenterol. Nutr. 40, 28–35 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Barboza Junior, M. S., Silva, T. M., Guerrant, R. L. & Lima, A. A. Measurement of intestinal permeability using mannitol and lactulose in children with diarrheal diseases. Braz. J. Med. Biol. Res. 32, 1499–1504 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Rahaman, M. M. & Wahed, M. A. in Diarrhea and Malnutrition: Interactions, Mechanisms and Interventions. (eds Chen, L. C. & Sears, C. L.) 155–160 (Plenum Press, New York and London, 1983).

    Book  Google Scholar 

  103. Steiner, T. S., Lima, A. A., Nataro, J. P. & Guerrant, R. L. Enteroaggregative Escherichia coli produce intestinal inflammation and growth impairment and cause interleukin-8 release from intestinal epithelial cells. J. Infect. Dis. 177, 88–96 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Peterson, K. M. et al. The expression of REG 1A and REG 1B is increased during acute amebic colitis. Parasitol. Int. 60, 296–300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sandler, N. G. et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J. Infect. Dis. 203, 780–790 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Swann, J. R. et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4523–4530 (2011).

    Article  PubMed  Google Scholar 

  107. Saric, J. et al. Integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents. J. Proteome Res. 9, 2255–2264 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Masoodi, I. et al. Fecal lactoferrin, myeloperoxidase and serum C-reactive are effective biomarkers in the assessment of disease activity and severity in patients with idiopathic ulcerative colitis. J. Gastroenterol. Hepatol. 24, 1768–1774 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Campbell, D. I., McPhail, G., Lunn, P. G., Elia, M. & Jeffries, D. J. Intestinal inflammation measured by fecal neopterin in Gambian children with enteropathy: association with growth failure, Giardia lamblia, and intestinal permeability. J. Pediatr. Gastroenterol. Nutr. 39, 153–157 (2004).

    Article  PubMed  Google Scholar 

  110. Langhorst, J. et al. Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity in ulcerative colitis. Inflamm. Bowel Dis. 11, 1085–1091 (2005).

    Article  PubMed  Google Scholar 

  111. Reigstad, C. S., Lunden, G. O., Felin, J. & Backhed, F. Regulation of serum amyloid A3 (SAA3) in mouse colonic epithelium and adipose tissue by the intestinal microbiota. PLoS ONE 4, e5842 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fasano, A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin. Gastroenterol. Hepatol. 10, 1096–1100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tripathi, A. et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc. Natl Acad. Sci. USA 106, 16799–16804 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  114. George, N. S., Sankineni, A. & Parkman, H. P. Small intestinal bacterial overgrowth in gastroparesis. Dig. Dis. Sci. http://doi:10.1007/s10620-012-2426-7.

  115. Esposito, I. et al. Breath test for differential diagnosis between small intestinal bacterial overgrowth and irritable bowel disease: an observation on non-absorbable antibiotics. World J. Gastroenterol. 13, 6016–6021 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Papadia, C. et al. Plasma citrulline as a quantitative biomarker of HIV-associated villous atrophy in a tropical enteropathy population. Clin. Nutr. 29, 795–800 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Lima, N. L. et al. Wasting and intestinal barrier function in children taking alanyl-glutamine-supplemented enteral formula. J. Pediatr. Gastroenterol. Nutr. 44, 365–374 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Stephenson, L. S., Latham, M. C., Kurz, K. M., Kinoti, S. N. & Brigham, H. Treatment with a single dose of albendazole improves growth of Kenyan schoolchildren with hookworm, Trichuris trichiura, and Ascaris lumbricoides infections. Am. J. Trop. Med. Hyg. 41, 78–87 (1989).

    Article  CAS  PubMed  Google Scholar 

  119. Wardlaw, T., Salama, P., Brocklehurst, C. & Mason, E. Diarrhoea: why children are still dying and what can be done. Lancet 13, 870–872 (2010).

    Article  Google Scholar 

  120. Moore, S. R. Update on prolonged and persistent diarrhea in children. Curr. Opin. Gastroenterol. 27, 19–23 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Ladd, F. V. et al. Zinc and glutamine improve brain development in suckling mice subjected to early postnatal malnutrition. Nutrition 26, 662–670 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mitter, S. S. et al. Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil. Clinics (Sao Paulo) 67, 11–18 (2012).

    Article  Google Scholar 

  123. Taniuchi, M. et al. Development of a multiplex polymerase chain reaction assay for diarrheagenic Escherichia coli and Shigella spp. and its evaluation on colonies, culture broths, and stool. Diagn. Microbiol. Infect. Dis. 73, 121–128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Platts-Mills, J. A., Operario, D. J. & Houpt, E. R. Molecular diagnosis of diarrhea: current status and future potential. Curr. Infect. Dis. Rep. 14, 41–46 (2012).

    Article  PubMed  Google Scholar 

  125. Stroup, S. et al. Dual probe DNA capture for sensitive real-time PCR detection of Cryptosporidium and Giardia. Mol. Cell Probes 26, 104–106 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Oberhelman, R. A. et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J. Pediatr. 134, 15–20 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Preidis, G. A. et al. Probiotics, enteric and diarrheal diseases, and global health. Gastroenterology 140, 8–14 (2011).

    Article  PubMed  Google Scholar 

  128. Guandalini, S. Probiotics for prevention and treatment of diarrhea. J. Clin. Gastroenterol. 45 (Suppl.), S149–S153 (2011).

    Article  PubMed  Google Scholar 

  129. Videlock, E. J. & Cremonini, F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment. Pharmacol. Ther. 35, 1355–1369 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Passaro, D. J. et al. Acute Helicobacter pylori infection is followed by an increase in diarrheal disease among Peruvian children. Pediatrics 108, E87 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Shmuely, H. et al. Association of Helicobacter pylori infection with Shigella gastroenteritis in young children. Am. J. Gastroenterol. 99, 2041–2045 (2004).

    Article  PubMed  Google Scholar 

  132. Cohen, D., Shoham, O., Orr, N. & Muhsen, K. An inverse and independent association between Helicobacter pylori infection and the incidence of shigellosis and other diarrheal diseases. Clin. Infect. Dis. 54, e35–e42 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Serazin, A. C., Shackelton, L. A., Wilson, C. & Bhan, M. K. Improving the performance of enteric vaccines in the developing world. Nat. Immunol. 11, 769–773 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' collaborative work in this area is supported in part by NIH (ICIDR-UO1AI026512, FIC GIDRT D43TW006578) and the MAL-ED study, funded by an award from the Bill and Melinda Gates Foundation to the Foundation for the National Institutes of Health (FNIH). S. Moore is supported by an Independent Scientist in Global Health Award K02-TW008767 from the Fogarty International Center at NIH.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to all aspects of producing this article.

Corresponding author

Correspondence to Richard L. Guerrant.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guerrant, R., DeBoer, M., Moore, S. et al. The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease. Nat Rev Gastroenterol Hepatol 10, 220–229 (2013). https://doi.org/10.1038/nrgastro.2012.239

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2012.239

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing