EED, Gut Health and Intestinal Function

Parasites and Childhood Growth Retardation: Biochemical Evidence

• Childhood growth retardation is characterized by global prevalence of stunting, wasting, and underweight.
• A significant number of children under the age of 5 (149.2 million in 2020) experience growth retardation.
• Potential key pathways linking parasitic infection to childhood growth retardation include appetite suppression, undernutrition, diarrhea, environmental enteric dysfunction (EED), systemic inflammation, anemia, and epigenetic regulation.

Important Definitions

• Crypt hypertrophy is the elongation of intestinal crypts compared to normal, short crypts.
• The intestinal crypt is a sterile invagination of the intestines containing goblet, stem, and Paneth cells that secrete mucus and antimicrobial peptides (cryptdins).
• DNA methylation is a biological process where methyl groups are added to the DNA molecule, potentially altering gene activity without altering the DNA sequence.
• Environmental enteric dysfunction (EED) is an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine, often associated with parasitic infection.
• Immune activation is the appropriate response to invading pathogens.
• Growth retardation is the stunting, wasting, and underweight of a child.

Childhood Growth Retardation

• Human height results from a combination of genetic and environmental factors that influence phenotype expression.
• Growth retardation signals an environment lacking sufficient, nutritious foods for both maternal and child post-natal, contributing to the observable retardation.

Global Prevalence of Stunting, Wasting, and Underweight

• In 2020, 149.2 million children under the age of 5 globally were stunted.
• 45.4 million children under the age of 5 were wasted globally in 2020
• 12.6% of children under 5 globally in 2020 were underweight
• 24.4% of children under the age of 5 suffered from malnutrition in 2019

Potential Key Pathways Linking Parasitic Infection to Childhood Growth Retardation

• Parasitic infections can negatively impact the host by suppressing appetite & leading to undernutrition.
• Parasites can cause diarrhea, EED, and systemic inflammatory response.
• Anemia and other nutrient deficiencies are also triggered by parasitic infections.
• Parasitic infections lead to epigenetic changes directly impacting growth and development.

Parasites Reduce Host Nutrient Intake

• Chronic/repeated lack of sufficient nutrition during prenatal and postnatal periods is a key factor contributing to growth retardation.
• Parasitic infections can cause reduced appetite and food withdrawal, leading to decreased nutrient intake.
• Parasites may influence neuroendocrine control of appetite and induce cytokine expansion.

Parasites Reduce Host Nutrient Intake

• Leptin, a satiety hormone, is elevated in children infected with certain parasites like Entamoeba histolytica, Strongyloides spp., and Giardia lamblia.
• These infections can cause reduced protein, calorie, iron and riboflavin intake in children.

Parasites Causing Diarrhea

• Protozoan and helminthic parasites cause diarrheal illness (including bloody diarrhea) in children.
• Prolonged or severe diarrhea negatively impacts the absorption, digestion and reserves of macronutrients and micronutrients.
• Diarrhea decreases levels of important growth hormone Insulin-like growth factor (IGF-1).

Parasitic Cause of Environmental Enteric Dysfunction (EED)

• Parasitic infections are implicated in the etiology of EED, a subclinical enteropathy in the small intestine that potentially leads to growth retardation.
• Villous atrophy (reduction in the surface area of the small intestine), and reduced absorption of nutrients are characteristics of EED.
• EED exacerbates undernutrition and micronutrient deficiencies.

Parasites Cause Environmental Enteric Dysfunction (EED) - Further

• Direct evidence in humans about villous atrophy and growth retardation associated with Giardia lamblia infection is limited, but data from murine models provides some association.
• EED can deplete active brush-border enzymes and nutrient transporters, creating an ideal environment for parasite to compromise nutrient absorption.
• Parasites can increase gut permeability, as seen with the proteins produced by E. histolytica.
• Parasitic protozoa damage the epithelium by attaching and invading cells.
• Nutritional deficiencies hinder mucosal repair and thus exacerbate the impact of EED.
• Microbial translocation into the lamina propria triggers inflammation, perpetuating the EED cycle and further impacting nutritional status.

Progression of EED and Microbiome Changes in Response to Parasitic Infection

• Parasitic feeding and invasion can damage intestinal epithelial tissue.
• Chronic exposure to parasites can result in increased intestinal permeability, inflammation, and crypt damage. This creates an environment where bacteria can enter the lamina propria.
• This causes a cycle of infiltration of immune cells, leading to inflammation and further worsening of EED.
• Damage compromises micronutrient and macronutrient absorption, worsening malnutrition.
• Parasite infections disrupt the healthy gut microbiome which can cause nutritional deficiencies.

Parasitic Cause of Systemic Inflammation

• Parasitic infections directly or via EED, trigger systemic inflammation and immune activation, leading to growth retardation.
• Immune activation diverts crucial calories and nutrients away from processes like growth.
• Growth retardation is linked to higher antiparasite adaptive immune response (measured by total IgE levels in children)

Parasitic Cause of Systemic Inflammation - Further

• Parasites consume amino acids, which are vital for nucleic acids production and hormone synthesis including IGF-1, causing reduced growth.
• Parasites might directly utilize host amino acids (e.g. Giardia intestinalis consuming Arginine).
• Deficient amino acids hinder intestinal repair and exacerbates EED further.
• Low serum glutamine and arginine levels are associated with impaired intestinal barrier function and slowed linear growth.

Parasitic Cause of Systemic Inflammation - further

• Parasitic infections can dysregulate growth factors and affect prenatal and postnatal growth.
• Immune activation triggers acute-phase protein production inhibiting IGF-1.
• Inhibition of IGF-1 reduces growth hormone (GH) resistance and impairs longitudinal bone growth.
• For example; Cryptosporidium infection is linked to lower length for age, increased systemic inflammation, and reduced plasma IGF-1 concentration in infants

Parasitic Causes of Anemia

• Several parasites, including malaria, leishmaniasis, babesiosis, cause anemia due to reduced red blood cell production, compromised lifespan, and increased destruction due to hypersplenism.
• Parasites can consume host blood directly or indirectly, by damaging blood vessels, leading to anemia and potentially hindering growth.
• Certain parasites, like hookworms, cause blood loss through extracorporeal mechanisms.
• Schistosoma eggs migrate to various organs, rupturing blood vessels - causing extracorporeal blood loss
• Bloody diarrhea as a result of parasite infection can also cause blood loss due to mucosal damage and inflammation.
• Parasites can induce a proinflammatory cytokine response that may increase iron sequestration and reduce iron absorption from the intestine.

Parasites can cause Anemia, which contributes to Growth Retardation

• Anemia and growth retardation often coexist, but causal linkage can be difficult for observational study design.
• Anemia directly diminishes oxygen-dependent cellular energy production by reducing the ability to metabolize energy.
• Hypoxic conditions caused by anemia impair growth and development via negative impacts on the IGF-1 system.
• Malaria, leishmaniasis, babesiosis are risk factors for anemia from parasitic infections

Parasitic Alteration of Epigenetic Regulation

• Evidence suggests that DNA methylation can influence childhood growth.
• Birth weight and other epigenetic signatures are correlated with parasite exposure.
• Malnutrition during gestation, may impact the host's epigenetic programming and effect long-term metabolic health through DNA methylation changes.
• Parasite infections can change epigenetic expression relating to inflammation and immune response in children.
• Various parasite infections, including Schistosoma haematobium and Ascaris lumbricoides, elicit a specific DNA methylation signature in human primary immune cells.

Test your knowledge of gut health. This quiz covers intestinal crypts, DNA methylation, environmental enteric dysfunction (EED), immune activation, gut microbiota, and parasitic infections like Entamoeba histolytica. Also includes questions on child development indicators.