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Genetic association testing in birth cohorts of Bangladeshi children showed the previously described single nucleotide polymorphisms (SNPs) at the\n                      <jats:italic toggle=\"yes\">CREM<\/jats:italic>\n                      locus associated with\n                      <jats:italic toggle=\"yes\">E. histolytica-<\/jats:italic>\n                      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,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.007; rs58000832: 0.203 reduction in WAZ,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 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\n                      <jats:italic toggle=\"yes\">Crem<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Crem<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Crem<\/jats:italic>\n                      is linked to body weight, plausibly by regulation of mitochondrial gene expression, while\n                      <jats:italic toggle=\"yes\">Crem<\/jats:italic>\n                      expression in other cell types influences the immune response to\n                      <jats:italic toggle=\"yes\">E. histolytica<\/jats:italic>\n                      .\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Undernutrition 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 (\n                        <jats:italic toggle=\"yes\">CREM<\/jats:italic>\n                        ) 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,\n                        <jats:italic toggle=\"yes\">CREM<\/jats:italic>\n                        .\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01390-25","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T09:01:24Z","timestamp":1751014884000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5572-0396","authenticated-orcid":false,"given":"Audrey C.","family":"Brown","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Jashim","family":"Uddin","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca M.","family":"Munday","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farha","family":"Naz","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6032-4320","authenticated-orcid":true,"given":"G. Brett","family":"Moreau","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girija","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.","family":"Rich","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genome Sciences, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashidul","family":"Haque","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04vsvr128","id-type":"ROR","asserted-by":"publisher"}],"name":"International Centre for Diarrheal Disease Research","place":["Dhaka, Bangladesh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve L.","family":"Wojcik","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Duggal","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8193-2771","authenticated-orcid":true,"given":"Chelsea","family":"Marie","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7268-1218","authenticated-orcid":true,"suffix":"Jr.","given":"William A.","family":"Petri","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia School of Medicine","place":["Charlottesville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"United Nations Children\u2019s Fund (\u200eUNICEF)\u200e World Health Organization International Bank for Reconstruction and Development\/The World Bank. 2023. 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