The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection
ABSTRACT We previously identified genetic polymorphisms associated with Entamoeba 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 descr...
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American Society for Microbiology
2025-08-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01390-25 |
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| author | Audrey C. Brown Md. Jashim Uddin Rebecca M. Munday Farha Naz G. Brett Moreau Girija Ramakrishnan Stephen S. Rich Rashidul Haque Genevieve L. Wojcik Priya Duggal Chelsea Marie William A. Petri |
| author_facet | Audrey C. Brown Md. Jashim Uddin Rebecca M. Munday Farha Naz G. Brett Moreau Girija Ramakrishnan Stephen S. Rich Rashidul Haque Genevieve L. Wojcik Priya Duggal Chelsea Marie William A. Petri |
| author_sort | Audrey C. Brown |
| collection | DOAJ |
| description | ABSTRACT We previously identified genetic polymorphisms associated with Entamoeba 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 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, 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, 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 Crem 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 Crem 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 Crem is linked to body weight, plausibly by regulation of mitochondrial gene expression, while Crem expression in other cell types influences the immune response to E. histolytica.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 (CREM) 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, CREM. |
| format | Article |
| id | doaj-art-e7ce49843d1e43a492e8504c2d5f41b8 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | American Society for Microbiology |
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| series | mBio |
| spelling | doaj-art-e7ce49843d1e43a492e8504c2d5f41b82025-08-20T04:00:50ZengAmerican Society for MicrobiologymBio2150-75112025-08-0116810.1128/mbio.01390-25The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infectionAudrey C. Brown0Md. Jashim Uddin1Rebecca M. Munday2Farha Naz3G. Brett Moreau4Girija Ramakrishnan5Stephen S. Rich6Rashidul Haque7Genevieve L. Wojcik8Priya Duggal9Chelsea Marie10William A. Petri11Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USADivision of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USADepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USADivision of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USADivision of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USADivision of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USADepartment of Genome Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USAInternational Centre for Diarrheal Disease Research, Dhaka, BangladeshDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USADepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USADivision of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USADivision of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USAABSTRACT We previously identified genetic polymorphisms associated with Entamoeba 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 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, 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, 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 Crem 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 Crem 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 Crem is linked to body weight, plausibly by regulation of mitochondrial gene expression, while Crem expression in other cell types influences the immune response to E. histolytica.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 (CREM) 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, CREM.https://journals.asm.org/doi/10.1128/mbio.01390-25undernutritionmalnutritiongenetic susceptibilityamebiasistranscriptomicsmetabolomics |
| spellingShingle | Audrey C. Brown Md. Jashim Uddin Rebecca M. Munday Farha Naz G. Brett Moreau Girija Ramakrishnan Stephen S. Rich Rashidul Haque Genevieve L. Wojcik Priya Duggal Chelsea Marie William A. Petri The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection mBio undernutrition malnutrition genetic susceptibility amebiasis transcriptomics metabolomics |
| title | The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection |
| title_full | The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection |
| title_fullStr | The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection |
| title_full_unstemmed | The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection |
| title_short | The cAMP responsive element modulator (CREM) transcription factor influences susceptibility to undernutrition and infection |
| title_sort | camp responsive element modulator crem transcription factor influences susceptibility to undernutrition and infection |
| topic | undernutrition malnutrition genetic susceptibility amebiasis transcriptomics metabolomics |
| url | https://journals.asm.org/doi/10.1128/mbio.01390-25 |
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