Vitamin B12 Deficiency Alters the Gut Microbiota in a Murine Model of Colitis

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Abstract

Purpose: Inflammatory bowel disease (IBD) refers to a spectrum of autoimmune diseases, which result in chronic intestinal inflammation. Previous findings suggest a role for diet, nutrition and dysbiosis of the gut microbiota in both the development and progression of the condition. Vitamin B12 is a key cofactor of methionine synthase and is produced solely by microbes. Previous work links increased levels of homocysteine, a substrate of methionine synthase, MetH, to IBD indicating a potential role for vitamin B12 deficiency in intestinal injury and inflammation. This study assessed the role of vitamin B12 in shaping the gut microbiota and determining responses to intestinal injury using a reproducible murine model of colitis.

Methods: The effects of vitamin B12 supplementation and deficiency were assessed in vivo; 3-week-old post-weanling C57Bl/6 mice were divided into three dietary treatment groups: (1) sufficient vitamin B12 (50 mg/Kg), (2) deficient vitamin B12 (0 mg/Kg) and (3) supplemented vitamin B12 (200 mg/Kg) for a period of 4 weeks. Intestinal injury was induced with 2% dextran sodium sulphate (DSS) via drinking water for 5 days. The impact of varying levels of dietary vitamin B12 on gut microbiota composition was assessed using 16S rRNA gene sequencing from fecal samples collected at day 0 and day 28 of the dietary intervention, and 7 days following induction of colitis on day 38, when blood and colonic tissues were also collected.

Results: No significant alterations were found in the gut microbiota composition of disease-free animals in response to dietary interventions. By contrast, after DSS-induced colitis, >30 genera were significantly altered in vitamin B12 deficient mice. Altered B12 levels produced no significant effect on composite disease-activity scores; however, administration of a B12 deficient diet resulted in reduced DSS-induced epithelial tissue damage.

Conclusions: Vitamin B12 supplementation does not alter the gut microbiota composition under healthy conditions, but does contribute to differential microbial responses and intestinal dysbiosis following the induction of experimental colitis.

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Most cited references 35

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Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis.

Djahida Bouskra, Christophe Brézillon, Marion Bérard … (2008)

Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs). Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and beta-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.

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Is Open Access

The ribosomal database project (RDP-II): introducing myRDP space and quality controlled public data

J. R. Cole, B. Chai, R. J. Farris … (2006)

Substantial new features have been implemented at the Ribosomal Database Project in response to the increased importance of high-throughput rRNA sequence analysis in microbial ecology and related disciplines. The most important changes include quality analysis, including chimera detection, for all available rRNA sequences and the introduction of myRDP Space, a new web component designed to help researchers place their own data in context with the RDP's data. In addition, new video tutorials describe how to use RDP features. Details about RDP data and analytical functions can be found at the RDP-II website ().

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Homocysteine metabolism.

J Selhub (1999)

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.

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Author and article information

Contributors

Rachael G. Horne: URI : http://loop.frontiersin.org/people/585104/overview

Steven R. Botts: URI : http://loop.frontiersin.org/people/925600/overview

Bo Li: URI : http://loop.frontiersin.org/people/925606/overview

Kathene C. Johnson-Henry: URI : http://loop.frontiersin.org/people/925545/overview

Agostino Pierro: URI : http://loop.frontiersin.org/people/93781/overview

Michael G. Surette: URI : http://loop.frontiersin.org/people/65948/overview

Philip M. Sherman: URI : http://loop.frontiersin.org/people/854944/overview

Journal

Journal ID (nlm-ta): Front Nutr

Journal ID (iso-abbrev): Front Nutr

Journal ID (publisher-id): Front. Nutr.

Title: Frontiers in Nutrition

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2296-861X

Publication date (Electronic): 05 June 2020

Publication date Collection: 2020

Volume: 7

Electronic Location Identifier: 83

Affiliations

[1] ¹Cell Biology Program, Research Institute, Hospital for Sick Children , Toronto, ON, Canada

[2] ²Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics , Toronto, ON, Canada

[3] ³Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, ON, Canada

[4] ⁴Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children , Toronto, ON, Canada

[5] ⁵Department of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, ON, Canada

[6] ⁶Division of General and Thoracic Surgery, Hospital for Sick Children , Toronto, ON, Canada

[7] ⁷Farncombe Family Digestive Health Institute, McMaster University , Hamilton, ON, Canada

Author notes

Edited by: Silvia Turroni, University of Bologna, Italy

Reviewed by: Nobuhiko Kamada, University of Michigan, United States; Ravinder Nagpal, Wake Forest School of Medicine, United States

*Correspondence: Philip M. Sherman philip.sherman@ 123456sickkids.ca

This article was submitted to Nutrition and Microbes, a section of the journal Frontiers in Nutrition

†Present address: Eberhard Lurz, Division of Gastroenterology and Hepatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany

†These authors have shared co-first authorship

Article

DOI: 10.3389/fnut.2020.00083

PMC ID: 7291859

PubMed ID: 32582756

SO-VID: dd9b7ec3-7c70-445a-a80c-b83ef4b51d52

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 06 March 2020

Date accepted : 07 May 2020

Page count

Figures: 6, Tables: 1, Equations: 0, References: 50, Pages: 12, Words: 7336

Funding

Funded by: Canadian Institutes of Health Research 10.13039/501100000024

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Vitamin B12 Deficiency Alters the Gut Microbiota in a Murine Model of Colitis

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Karger: Gastroenterology

Most cited references 35

Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis.

The ribosomal database project (RDP-II): introducing myRDP space and quality controlled public data

Homocysteine metabolism.

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Cited by 22

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