Methionine restriction fundamentally supports health by tightening epithelial barriers

Mullin, James M.; Skrovanek, Sonja M.; Ramalingam, Arivudainambi; DiGuilio, Katherine M; Valenzano, Mary Carmen

doi:10.1111/nyas.12955

Cited by 8 publications

(7 citation statements)

References 53 publications

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“…Shifts in intestinal microbiota profiles may cause intestinal inflammation and affect the expression of tight junction-related proteins leading to increased intestinal permeability [ 18 , 33 , 69 ]. Furthermore, modulation of the methionine dietary intake has recently been reported to affect the expression of the intestinal tight junction-related proteins [ 56 ]. Gene expression analysis revealed a non-significant trend towards increase (2.6-fold, p < 0.2) in the expression of Tnfα in the proximal jejunum of mice fed MSD, compared to MAD-fed mice on day 6.…”

Section: Resultsmentioning

confidence: 99%

Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology

et al. 2017

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BackgroundMethionine, a central molecule in one-carbon metabolism, is an essential amino acid required for normal growth and development. Despite its importance to biological systems, methionine is toxic when administered at supra-physiological levels. The aim of this study was to investigate the effects of short-term methionine dietary modulation on the proximal jejunum, the section of the gut specifically responsible for amino acid absorption, in a mouse model. Eight-week-old CBA/J male mice were fed methionine-adequate (MAD; 6.5 g/kg) or methionine-supplemented (MSD; 19.5 g/kg) diets for 3.5 or 6 days (average food intake 100 g/kg body weight). The study design was developed in order to address the short-term effects of the methionine supplementation that corresponds to methionine dietary intake in Western populations. Biochemical indices in the blood as well as metabolic, epigenetic, transcriptomic, metagenomic, and histomorphological parameters in the gut were evaluated.ResultsBy day 6, feeding mice with MSD (protein intake <10% different from MAD) resulted in increased plasma (2.3-fold; p < 0.054), but decreased proximal jejunum methionine concentrations (2.2-fold; p < 0.05) independently of the expression of neutral amino acid transporters. MSD has also caused small bowel bacteria colonization, increased the abundance of pathogenic bacterial species Burkholderiales and decreased the gene expression of the intestinal transmembrane proteins—Cldn8 (0.18-fold, p < 0.05), Cldn9 (0.24-fold, p < 0.01) and Cldn10 (0.05-fold, p < 0.05). Feeding MSD led to substantial histomorphological alterations in the proximal jejunum exhibited as a trend towards decreased plasma citrulline concentrations (1.8-fold, p < 0.07), as well as loss of crypt depth (by 28%, p < 0.05) and mucosal surface (by 20%, p < 0.001).ConclusionsTogether, these changes indicate that short-term feeding of MSD substantially alters the normal gut physiology. These effects may contribute to the pathogenesis of intestinal inflammatory diseases and/or sensitize the gut to exposure to other stressors.Electronic supplementary materialThe online version of this article (10.1186/s12263-017-0576-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology

et al. 2017

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“…Another role of AMPK in TJ formation and maintenance could be hypothetically linked to dietary methionine restriction (MR). MR has been found to modify the protein composition of TJ complexes in epithelial cells [ 125 ]. In addition, the stimulation of S- adenosyl-l-methionine, a key intermediate of methionine metabolism, led to the consumption of both Met and ATP [ 126 ] and AMPK activation [ 127 ].…”

Section: Ampk Effectorsmentioning

confidence: 99%

Implications of AMPK in the Formation of Epithelial Tight Junctions

Rowart

Caplan

et al. 2018

IJMS

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Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of membrane components; and (ii) TJ regulate the selective paracellular permeability. Disruption of TJ is regarded as one of the earliest hallmarks of epithelial injury, leading to the loss of cell polarity and tissue disorganization. Many factors have been identified as modulators of TJ assembly/disassembly. More specifically, in addition to its role as an energy sensor, adenosine monophosphate-activated protein kinase (AMPK) participates in TJ regulation. AMPK is a ubiquitous serine/threonine kinase composed of a catalytic α-subunit complexed with regulatory β-and γ-subunits. AMPK activation promotes the early stages of epithelial TJ assembly. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the TJ-associated protein zonula occludens (ZO)-1, thereby facilitating ZO-1 distribution to the plasma membrane. In the present review, we detail the signaling pathways up-and down-stream of AMPK activation at the time of Ca2+-induced TJ assembly.

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“…However, methionine restriction to a level of 0.12-0.15% in rodent diets (compared to 0.60-0.86% in a standard diet, and similar to a plant-based diet [12]) is consistently associated with an increase in lifespan in animal models [13][14][15][16][17]. It is also associated with many health benefits, such as improvements in insulin and lipid regulation and barrier function [18]. Furthermore, methionine restriction significantly impairs tumor growth and metastasis in preclinical models [10,19].…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Effects of Dietary Methionine Restriction on the Intestinal Microbiome

2020

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Dietary methionine restriction is associated with improved health outcomes and an increase in lifespan in animal models. We have previously shown that an increase in dietary methionine induces alteration in the intestinal microbiome. The composition of the intestinal microbiota is a determinant of health and we, therefore, hypothesized that dietary methionine restriction would also induce changes in the murine microbiome. After one month on a methionine-restricted diet, five-month-old male and female C57BL/6 mice had decreased levels of serum methionine, without changes in body weight. We identified a decrease in the hepatic methylation status of animals fed a methionine-restricted diet compared to controls. This decrease was not associated with changes in DNA or protein methylation in the liver. In males, we saw an increase in families Bacteroidaceae and Verrucoccaceae (mostly A. mucinophila) and a decrease in Rumminococcaceae in animals fed a methionine-restricted diet compared to controls. In females, Bacteroidales family S24-7 was increased two-fold, while families Bacteroidaceae, Verrucoccaceae, Rumminococcaceae, and Rikenellaceae were decreased compared to controls. In summary, feeding a methionine-restricted diet for one month was associated with significant and sex-specific changes in the intestinal microbiome.

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Methionine restriction fundamentally supports health by tightening epithelial barriers

Cited by 8 publications

References 53 publications

Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology

Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology

Implications of AMPK in the Formation of Epithelial Tight Junctions

Sex-Specific Effects of Dietary Methionine Restriction on the Intestinal Microbiome

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