Malnutrition and diarrheal disease are leading causes of global childhood morbidity and mortality. Malnutrition can present as a cause or consequence of diarrheal diseases leading us to hypothesize these phenotypes share a common genetic basis. We previously identified genetic polymorphisms associated with E. histolytica-positive diarrhea at the locus containing the transcription factor, cAMP Responsive Element Modulator (CREM). Genetic association testing in birth cohorts of Bangladeshi children showed the previously described single nucleotide polymorphisms (SNPs) at the CREM locus associated with E. histolytica-positive diarrhea were independently associated with malnutrition at 1 year of age. The reference allele for both tested SNPs was associated with lower weight-for-age z-scores (WAZ) at one year of age (rs2148483: 0.161 reduction in WAZ per allele, P=0.007; rs58000832: 0.203 reduction in WAZ, P=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. Upregulation of mitochondrial function was mirrored by plasma metabolomics profiles concordant with a shift toward mitochondrial respiration. Conversely, adaptive immune response processes were enriched among down regulated genes. Concordantly, the lamina propria of the small intestine contained significantly fewer Th17 cells in children with the rs2148483 reference allele. Future studies will delineate if altered metabolism and immunity are causally linked or if these phenotypes are independently driven by CREM genetic variation. Our identification of CREM as a transcriptional regulator that influences susceptibility to both malnutrition 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, CREM.