Membrane transport of cobalamin

Nijland, Mark; Felices, Jose M Martínez; Slotboom, Dirk Jan; Thangaratnarajah, Chancievan

doi:10.1016/bs.vh.2022.01.008

Cited by 11 publications

(7 citation statements)

References 90 publications

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“…Different cobamides uptake systems have been identified in Gram-positive and Gram-negative bacteria, such as Bacteroides spp. that have up to four cobamides uptake systems ( 43 , 44 ). However, it is not yet known how intracellularly synthesized cobamides are released into the gut environment to enable exchange between producers and consumers ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

“…that have up to four cobamides uptake systems ( 43 , 44 ). However, it is not yet known how intracellularly synthesized cobamides are released into the gut environment to enable exchange between producers and consumers ( 44 ). Our data suggest that fecal communities can function without exogenous B12, and that the presence of prototrophic bacteria could supply enough B12 for the community.…”

Section: Discussionmentioning

confidence: 99%

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Healthy adult gut microbiota sustains its own vitamin B12 requirement in an in vitro batch fermentation model

et al. 2022

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Vitamin B12 (cobalamin) is present in the human lower gastrointestinal tract either coming from the unabsorbed dietary fraction or from in situ production of the gut microbiota. However, it is unclear whether the gut microbial communities need exogenous B12 for growth and metabolism, or whether B12 in low and high levels could affect gut community composition and metabolite production. Here, we investigated in vitro B12 production of human fecal microbiota and the effects of different levels of B12 (as cyanocobalamin) on composition and activity. Eight fecal communities from healthy human adults distributed over three enterotypes, dominated by Firmicutes (n = 5), Bacteroides (n = 1) or Prevotella (n = 2) were used to perform batch fermentations in Macfarlane medium supplemented with low B12 medium (Control, 5 ng/ml, within the tested fecal range), no B12 addition (NB12), and high B12 addition (ExtraB12, 2500 ng/ml). The microbiota community composition (qPCR, 16S rRNA metabarcoding), metabolic activity (HPLC-RI), and B12 levels (UHPLC-DAD) were measured after 24 h incubation at 37°C under strict anaerobic conditions. All fecal microbial communities produced B12 in the NB12 condition after 24 h, in the range from 152 ± 4 to 564 ± 25 ng/ml. None of the B12 treatments had an impact on total bacterial growth, community richness, diversity and total metabolite production, compared to the low B12 control. However, a significant increase of propionate was measured in ExtraB12 compared to NB12. Most taxonomic and metabolite changes compared to control incubations were donor-dependent, implying donor-microbiota-specific changes upon B12 treatments. Our in vitro data suggest that healthy human adult gut microbial communities have the capacity to produce B12 at levels fulfilling their own requirements, independently of the initial B12 content tested in the donor’s feces. Further, supplementation of exogenous dietary B12 may have limited impact on the healthy human gut microbial community composition and function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Healthy adult gut microbiota sustains its own vitamin B12 requirement in an in vitro batch fermentation model

et al. 2022

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“…Cobalamin is often shared between cobalamin producers and consumers within microbial communities 53 , 54 . While multiple membrane transport systems have been identified that are used to import cobalamin 55 , it has remained elusive how synthesised cobalamin is released into the environment 54 . It is likely that cobalamin producing microbes live in symbiosis with cobalamin auxotrophic organisms and therefore share the vitamin via the export through membrane transporters 54 , 56 .…”

Section: Discussionmentioning

confidence: 99%

Bidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA

Nijland,

Lefebvre,

Thangaratnarajah

et al. 2024

Nat Commun

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BacA is a mycobacterial ATP-binding cassette (ABC) transporter involved in the translocation of water-soluble compounds across the lipid bilayer. Whole-cell-based assays have shown that BacA imports cobalamin as well as unrelated hydrophilic compounds such as the antibiotic bleomycin and the antimicrobial peptide Bac7 into the cytoplasm. Surprisingly, there are indications that BacA also mediates the export of different antibacterial compounds, which is difficult to reconcile with the notion that ABC transporters generally operate in a strictly unidirectional manner. Here we resolve this conundrum by developing a fluorescence-based transport assay to monitor the transport of cobalamin across liposomal membranes. We find that BacA transports cobalamin in both the import and export direction. This highly unusual bidirectionality suggests that BacA is mechanistically distinct from other ABC transporters and facilitates ATP-driven diffusion, a function that may be important for the evolvability of specific transporters, and may bring competitive advantages to microbial communities.

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“…An alternative reason could be a decreased ileal uptake of cobalamin due to intestinal dysbiosis and increased abundances of Bacteroides spp. carrying a competitive advantage of high-affinity cobalamin binding [ 57 ]. Receptor dysfunction or a reduction in total ileal epithelial mass resulting from the inflammatory lesions and/or epithelial damage are also possible causes.…”

Section: Discussionmentioning

confidence: 99%

Expression of the cobalamin transporters cubam and MRP1 in the canine ileum–Upregulation in chronic inflammatory enteropathy

Kather,

Kacza,

Pfannkuche

et al. 2024

PLoS ONE

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Chronic inflammatory enteropathy (CIE) in dogs, a spontaneous model of human inflammatory bowel disease (IBD), is associated with a high rate of cobalamin deficiency. The etiology of hypocobalaminemia in human IBD and canine CIE remains unknown, and compromised intestinal uptake of cobalamin resulting from ileal cobalamin receptor deficiency has been proposed as a possible cause. Here, we evaluated the intestinal expression of the cobalamin receptor subunits, amnionless (AMN) and cubilin (CUBN), and the basolateral efflux transporter multi-drug resistance protein 1 (MRP1) in 22 dogs with CIE in comparison to healthy dogs. Epithelial CUBN and AMN levels were quantified by confocal laser scanning microscopy using immunohistochemistry in endoscopic ileal biopsies from dogs with (i) CIE and normocobalaminemia, (ii) CIE and suboptimal serum cobalamin status, (iii) CIE and severe hypocobalaminemia, and (iv) healthy controls. CUBN and MRP1 expression was quantified by RT-qPCR. Receptor expression was evaluated for correlation with clinical patient data. Ileal mucosal protein levels of AMN and CUBN as well as mRNA levels of CUBN and MRP1 were significantly increased in dogs with CIE compared to healthy controls. Ileal cobalamin receptor expression was positively correlated with age, clinical disease activity index (CCECAI) score, and lacteal dilation in the ileum, inversely correlated with serum folate concentrations, but was not associated with serum cobalamin concentrations. Cobalamin receptor downregulation does not appear to be the primary cause of hypocobalaminemia in canine CIE. In dogs of older age with severe clinical signs and/or microscopic intestinal lesions, intestinal cobalamin receptor upregulation is proposed as a mechanism to compensate for CIE-associated hypocobalaminemia. These results support oral supplementation strategies in hypocobalaminemic CIE patients.

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Membrane transport of cobalamin

Cited by 11 publications

References 90 publications

Healthy adult gut microbiota sustains its own vitamin B12 requirement in an in vitro batch fermentation model

Healthy adult gut microbiota sustains its own vitamin B12 requirement in an in vitro batch fermentation model

Bidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA

Expression of the cobalamin transporters cubam and MRP1 in the canine ileum–Upregulation in chronic inflammatory enteropathy

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