Glucagon-like Peptide 2 Concentrations Vary in Zambian Children During Diarrhoea, in Malnutrition and Seasonally.

OBJECTIVES: Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide hormone released from enteroendocrine L-cells following nutrient ingestion. It has been shown to exert trophic effects on the gut. We set out to measure GLP-2 concentrations in blood in children with diarrhoea and malnutrition. METHODS: GLP-2 levels were measured in blood samples collected from 5 different groups of children (n = 324) at different time points: those with acute diarrhoea, during illness and 3 weeks after recovery; persistent diarrhoea and severe acute malnutrition; controls contemporaneous for diarrhoea; stunted children from the community; and controls contemporaneous for the stunted children. Stool biomarkers and pathogen analysis were carried out on the children with stunting. RESULTS: GLP-2 concentrations were higher during acute diarrhoea (median 3.1 ng/mL, interquartile range 2.1, 4.4) than on recovery (median 1.8, interquartile range 1.4, 3.1; P = 0.001), but were not elevated in children with persistent diarrhoea and severe acute malnutrition. In stunted children, there was a progressive decline in GLP-2 levels from 3.2 ng/mL (1.9, 4.9) to 1.0 (0.0, 2.0; P < 0.001) as the children became more stunted. Measures of seasonality (rainfall, temperature,Food Price Index, and Shiga toxin-producing Escherichia coli) were found to be significantly associated with GLP-2 concentrations in multivariable analysis. We also found a correlation between stool inflammatory biomarkers and GLP-2. CONCLUSIONS: In diarrhoea, GLP-2 levels increased in acute but not persistent diarrhoea. Malnutrition was associated with reduced concentrations. GLP-2 displayed seasonal variation consistent with variations in nutrient availability.

Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines.

All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4ß7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4ß7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/ß signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.