The Effects of Dietary Ferric Iron and Iron Deprivation on the Bacterial Composition of the Mouse Intestine

Tompkins, Geoffrey R.; O’Dell, Norris L.; Bryson, Israel T.; Pennington, Catherine

doi:10.1007/s002840010257

Cited by 67 publications

(59 citation statements)

References 14 publications

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“…Similar diets and feeding periods have been used previously to reduce iron status in rodents (16,17). Males and females were analyzed together, because there was no interaction between the primary variables and sex.…”

Section: Resultsmentioning

confidence: 99%

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Farrow

Summers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

329

324

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Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176 RXXR 179 /S 180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.Online Mendelian Inheritance in Man no. 193100) is characterized by low serum phosphate concentrations due to isolated renal phosphate wasting, inappropriately normal or low serum 1,25(OH) 2 vitamin D (1,25D) concentrations, and rickets/osteomalacia and fracture (1). Heterozygous missense mutations in the fibroblast growth factor-23 (FGF23) gene cause ADHR (2). These mutations replace the arginine (R) residues at positions 176 or 179 with glutamine (Q) or tryptophan (W) within a 176 RXXR 179 / S 180 subtilisin-like proprotein convertase (SPC) site that separates the conserved FGF-like N-terminal domain from the variable Cterminal tail (2-4). Acting through the coreceptor α-Klotho (5) and a fibroblast growth factor receptor (FGFR) (5, 6), FGF23 reduces renal phosphate reabsorption through down-regulation of the sodium phosphate cotransporters NPT2a and NPT2c and suppresses kidney 1,25(OH) 2 vitamin D production by inhibiting and increasing vitamin D 1α-hydroxylase (Cyp27b1) and 24-hydroxylase expression (Cyp24), respectively (7). Compared with WT Fgf23 protein, ADHR-mutant FGF23 shows increased but not complete resistance to SPC proteolytic cleavage (3, 4). When expressed in mammalian cells, the R176Q-, R179Q-, and R179W-FGF23 proteins are secreted primarily as the full-length (32-kDa) polypeptide, in contrast to the full-length and cleavage products (20 and 12 kDa) typically observed for WT FGF23 (3). This proteolytic event inactivates the mature FGF23 polypeptide, as full-length FGF23, but not N-terminal fragments (residues 25-179) or C-terminal fragments (residues 180-251), reduces serum phosphate concentrations when injected into rodents (4).The ADHR...

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Section: Resultsmentioning

confidence: 99%

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Farrow

Summers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

329

324

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“…In adult rodents, iron deprivation increased fecal total anaerobes, Enterococcus spp. as well as lactobacilli (32). ID in rats increased Enterobacteriaceae and Lactobacillus/Leuconostoc/Pediococcus spp.…”

Section: Animal and In Vitro Studiesmentioning

confidence: 87%

The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review

Paganini

Zimmermann

2017

The American Journal of Clinical Nutrition

204

160

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In infants and young children in Sub-Saharan Africa, iron-deficiency anemia (IDA) is common, and many complementary foods are low in bioavailable iron. In-home fortification of complementary foods using iron-containing micronutrient powders (MNPs) and oral iron supplementation are both effective strategies to increase iron intakes and reduce IDA at this age. However, these interventions produce large increases in colonic iron because the absorption of their high iron dose ($12.5 mg) is typically ,20%. We reviewed studies in infants and young children on the effects of iron supplements and iron fortification with MNPs on the gut microbiome and diarrhea. Iron-containing MNPs and iron supplements can modestly increase diarrhea risk, and in vitro and in vivo studies have suggested that this occurs because increases in colonic iron adversely affect the gut microbiome in that they decrease abundances of beneficial barrier commensal gut bacteria (e.g., bifidobacteria and lactobacilli) and increase the abundance of enterobacteria including entropathogenic Escherichia coli. These changes are associated with increased gut inflammation. Therefore, safer formulations of iron-containing supplements and MNPs are needed. To improve MNP safety, the iron dose of these formulations should be reduced while maximizing absorption to retain efficacy. Also, the addition of prebiotics to MNPs is a promising approach to mitigate the adverse effects of iron on the infant gut. Am J Clin Nutr 2017;106(Suppl):1688S-93S.

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“…Furthermore, since it appears that different E. coli strains have different nutritional programs for growth in the intestine (13,17), it seems likely that nonisogenic strains fail to display colonization resistance for nutritional reasons. That is, when the precolonized E. coli strain and the E. coli strain fed at day 10 are strains isolated from different humans, and the strain fed at day 10 grows from low to higher numbers, without eliminating the precolonized strain, we hypothesize that it does so either by using one or more nutrients not being used by the precolonized strain or by outcompeting it for one or more nutrients; however, we fully recognize that E. coli colonization may be impacted by several other factors, including interaction with the indigenous microbiota (21,50), innate immunity (12), and competition for iron (59).…”

Section: Discussionmentioning

confidence: 99%

Precolonized Human Commensal Escherichia coli Strains Serve as a Barrier to E. coli O157:H7 Growth in the Streptomycin-Treated Mouse Intestine

et al. 2009

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Different Escherichia coli strains generally have the same metabolic capacity for growth on sugars in vitro, but they appear to use different sugars in the streptomycin-treated mouse intestine (Fabich et al., Infect. Immun. 76:1143-1152, 2008). Here, mice were precolonized with any of three human commensal strains (E. coli MG1655, E. coli HS, or E. coli Nissle 1917) and 10 days later were fed 10 5 CFU of the same strains. While each precolonized strain nearly eliminated its isogenic strain, confirming that colonization resistance can be modeled in mice, each allowed growth of the other commensal strains to higher numbers, consistent with different commensal E. coli strains using different nutrients in the intestine. Mice were also precolonized with any of five commensal E. coli strains for 10 days and then were fed 10 5 CFU of E. coli EDL933, an O157:H7 pathogen. E. coli Nissle 1917 and E. coli EFC1 limited growth of E. coli EDL933 in the intestine (10 3 to 10 4 CFU/gram of feces), whereas E. coli MG1655, E. coli HS, and E. coli EFC2 allowed growth to higher numbers (10 6 to 10 7 CFU/gram of feces). Importantly, when E. coli EDL933 was fed to mice previously co-colonized with three E. coli strains (MG1655, HS, and Nissle 1917), it was eliminated from the intestine (<10 CFU/gram of feces). These results confirm that commensal E. coli strains can provide a barrier to infection and suggest that it may be possible to construct E. coli probiotic strains that prevent growth of pathogenic E. coli strains in the intestine.

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The Effects of Dietary Ferric Iron and Iron Deprivation on the Bacterial Composition of the Mouse Intestine

Cited by 67 publications

References 14 publications

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review

Precolonized Human Commensal Escherichia coli Strains Serve as a Barrier to E. coli O157:H7 Growth in the Streptomycin-Treated Mouse Intestine

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