Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease

Haikonen, Retu; Kärkkäinen, Olli; Koistinen, Ville; Hanhineva, Kati

doi:10.1016/j.tem.2022.04.004

Cited by 27 publications

(17 citation statements)

References 107 publications

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“…Recent advances in small metabolites have opened novel avenues in the metabolic route of betaines, metabolites with a quaternary ammonium group involved in the regulation of metabolic homeostasis such as protection against osmotic stress. One such compound, δVB, has been associated with positive health effects (fetal brain development, insulin secretion, and reduced cancer risk) and some negative health outcomes associated with a high-fat diet (cardiovascular disease and fatty liver disease) [ 44 ], suggesting that investigations into the metabolic route and role of this novel betaine are still necessary. δVB, at least partially synthesized by gut microbes, has been reported to be present in certain food sources, including milk and meat, and the kinds of marine algae used as foodstuffs [ 25 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

et al. 2022

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Emerging evidence indicates that defects in sirtuin signaling contribute to impaired glucose and lipid metabolism, resulting in insulin resistance (IR) and endothelial dysfunction. Here, we examined the effects of palmitic acid (PA) treatment on mitochondrial sirtuins (SIRT2, SIRT3, SIRT4, and SIRT5) and oxidative homeostasis in human endothelial cells (TeloHAEC). Results showed that treatment for 48 h with PA (0.5 mM) impaired cell viability, induced loss of insulin signaling, imbalanced the oxidative status (p < 0.001), and caused negative modulation of sirtuin protein and mRNA expression, with a predominant effect on SIRT3 (p < 0.001). Restoration of SIRT3 levels by mimic transfection (SIRT3+) suppressed the PA-induced autophagy (mimic NC+PA) (p < 0.01), inflammation, and pyroptosis (p < 0.01) mediated by the NLRP3/caspase-1 axis. Moreover, the unbalanced endothelial redox state induced by PA was counteracted by the antioxidant δ-valerobetaine (δVB), which was able to upregulate protein and mRNA expression of sirtuins, reduce reactive oxygen species (ROS) accumulation, and decrease cell death. Overall, results support the central role of SIRT3 in maintaining the endothelial redox homeostasis under IR and unveil the potential of the antioxidant δVB in enhancing the defense against IR-related injuries.

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Section: Discussionmentioning

confidence: 99%

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

et al. 2022

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“…Moreover, lower levels of 5-aminovalerate were observed in the HFD group, and 5-Aminovalerate can be generated either endogenously or through bacterial activity. Lower levels of this metabolite may thus reflect alterations in gut microbiome metabolism, as discussed below [ 48 ]. The HFD-fed group displayed elevated levels of all three branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine ( Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

Metabolic and Transcriptomic Changes in the Mouse Brain in Response to Short-Term High-Fat Metabolic Stress

et al. 2023

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The chronic consumption of diets rich in saturated fats leads to obesity and associated metabolic disorders including diabetes and atherosclerosis. Intake of a high-fat diet (HFD) is also recognized to dysregulate neural functions such as cognition, mood, and behavior. However, the effects of short-term high-fat diets on the brain are elusive. Here, we investigated molecular changes in the mouse brain following an acute HFD for 10 days by employing RNA sequencing and metabolomics profiling. Aberrant expressions of 92 genes were detected in the brain tissues of acute HFD-exposed mice. The differentially expressed genes were enriched for various pathways and processes such as superoxide metabolism. In our global metabolomic profiling, a total of 59 metabolites were significantly altered by the acute HFD. Metabolic pathways upregulated from HFD-exposed brain tissues relative to control samples included oxidative stress, oxidized polyunsaturated fatty acids, amino acid metabolism (e.g., branched-chain amino acid catabolism, and lysine metabolism), and the gut microbiome. Acute HFD also elevated levels of N-acetylated amino acids, urea cycle metabolites, and uracil metabolites, further suggesting complex changes in nitrogen metabolism. The observed molecular events in the present study provide a valuable resource that can help us better understand how acute HFD stress impacts brain homeostasis.

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“…Although the gut microbiota is likely an important source of human circulating 5-AVAB, the exact microbial pathways to produce 5-AVAB are unknown. It has been shown that 5-AVAB can be produced from TML by gut microbes in mice 29 , but is unknown to what extent TML is the source of microbially produced 5-AVAB in humans and other pathways have been proposed 45 . In recent years, the gut microbiome has increasingly been implicated in autism, as children with autism experience increased prevalence of gastrointestinal issues 6 , have altered gut microbiome 7,8 compared to typically developing children.…”

Section: Discussionmentioning

confidence: 99%

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

Ottosson,

Russo,

Abrahamsson

et al. 2023

Preprint

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The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental and prenatal factors, the molecular etiology of autism is largely unknown. Metabolomics has emerged as a tool to measure small molecules that reflect genetic, gut microbiome and dietary intake variations. Here, we apply untargeted metabolomics to over 1400 neonatal dried bloods spots, including neonates who later are diagnosed with autism and matching controls. Overall, we detect underlying molecular perturbations that precede autism related to metabolism of amino acids, acylcarnitines and peptides. In particular the cyclic dipeptide cyclo-leucine-proline and the carnitine-related 5-aminovaleric acid betaine (5-AVAB), were associated with an increased probability for autism. Analysis of genetic and dietary data in over 7000 adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy and with variantsSLC22A5, coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. We identify 5-AVAB as a novel and potentially modifiable early biomarker for autism that may influence carnitine homeostasis.

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Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease

Cited by 27 publications

References 107 publications

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

Metabolic and Transcriptomic Changes in the Mouse Brain in Response to Short-Term High-Fat Metabolic Stress

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

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