The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection

We previously identified genetic polymorphisms associated with <i>Entamoeba histolytica</i>-positive diarrhea at the locus containing the transcription factor, cAMP responsive element modulator (<i>CREM</i>). Genetic association testing in birth cohorts of Bangladeshi children showed the previously described single nucleotide polymorphisms (SNPs) at the <i>CREM</i> locus associated with <i>E. histolytica-</i>positive diarrhea were independently associated with undernutrition at 1 year of age. The reference allele for both tested SNPs was associated with lower weight-for-age z-scores (WAZ) at 1 year of age (rs2148483: 0.161 reduction in WAZ per allele, <i>P</i> = 0.007; rs58000832: 0.203 reduction in WAZ, <i>P</i> = 0.001). Small intestinal transcriptome data from Bangladeshi and American children revealed differentially expressed genes (DEGs) were enriched for cAMP response element-binding sites. DEGs related to mitochondrial function were upregulated in the small intestine of children with the rs2148483 reference allele, while adaptive immune response processes were enriched among downregulated genes. Upregulation of mitochondrial function was mirrored by plasma metabolomics profiles concordant with a shift toward mitochondrial respiration. In mice, global conditional deletion of <i>Crem</i> resulted in reduced body weight, downregulation of genes related to innate immune function, and upregulation of metabolic gene expression in the intestine. Tissue-specific deletion of <i>Crem</i> in intestinal epithelial cells was sufficient to reduce overall body weight and alter intestinal expression of mitochondrial-related metabolic genes but not immune gene transcription. These data indicate that intestinal epithelial expression of <i>Crem</i> is linked to body weight, plausibly by regulation of mitochondrial gene expression, while <i>Crem</i> expression in other cell types influences the immune response to <i>E. histolytica</i>.IMPORTANCEUndernutrition and diarrheal disease are leading causes of global childhood morbidity and mortality. Undernutrition can present as a cause or consequence of diarrheal diseases, leading us to hypothesize these phenotypes share a common genetic basis. Our identification of cAMP responsive element modulator (<i>CREM</i>) as a transcriptional regulator that influences susceptibility to both undernutrition and diarrheal disease in children growing up in an impoverished Bangladeshi community advances our understanding of the interaction of two major causes of childhood illness and offers the potential of therapy targeted to the cAMP-regulated transcription factor, <i>CREM</i>.