Conceptualization and Assessment of 24-H Timing of Eating and Energy Intake: A Methodological Systematic Review of the Chronic Disease Literature.

Timing of eating (TOE) and energy intake (TOEI) has important implications for chronic disease risk beyond diet quality. The 2020 Dietary Guidelines Advisory Committee recommended developing consistent terminology to address the lack of TOE/TOEI standardization. The primary objective of this methodological systematic review was to characterize the conceptualization and assessment of TOE/TOEI within the chronic disease literature (International Prospective Register of Systematic Reviews registration number: CRD42021236621). Literature searches in Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, Embase, PubMed, and Scopus were limited to English language publications from 2000 to August 2022. Eligible studies reported the association between TOE/TOEI and obesity, cardiovascular disease, type 2 diabetes mellitus, cancer, or a related clinical risk factor among adults (≥19 y) in observational and intervention studies. A qualitative synthesis described and compared TOE/TOEI conceptualization, definitions, and assessment methods across studies. Of the 7579 unique publications identified, 259 studies (observational [51.4 %], intervention [47.5 %], or both [1.2 %]) were eligible for inclusion. Key findings indicated that most studies (49.6 %) were conducted in the context of obesity and body weight. TOE/TOEI variables or assigned conditions conceptualized interrelated aspects of time and eating or energy intake in varying ways. Common TOE/TOEI conceptualizations included the following: 1) timepoint (specific time to represent when intake occurs, such as time of breakfast [74.8 %]); 2) duration (length of time or interval when intake does/does not occur, such as "eating window" [56.5 %]); 3) distribution (proportion of daily intake at a given time interval, such as "percentage of energy before noon" [29.8 %]); and 4) cluster (grouping individuals based on temporal ingestive characteristics [5.0 %]). Assessment, definition, and operationalization of 24-h TOE/TOEI variables varied widely across studies. Observational studies most often used surveys or questionnaires (28.9 %), whereas interventions used virtual or in-person meetings (23.8 %) to assess TOE/TOEI adherence. Overall, the diversity of terminology and methods solidifies the need for standardization to guide future research in chrononutrition and to facilitate inter-study comparisons.

Bioavailable Microbial Metabolites of Flavanols Demonstrate Highly Individualized Bioactivity on In Vitro ß-Cell Functions Critical for Metabolic Health.

Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, we investigated their effects on INS-1 832/13 ß-cell glucose stimulated insulin secretion (GSIS) capacity. We measured insulin secretion under non-stimulatory (low) and stimulatory (high) glucose levels, insulin secretion fold induction, and total insulin content. We conducted treatment-level comparisons, individual-level dose responses, and a responder vs. non-responder predictive analysis of metabolite composition. While the first two analyses did not elucidate treatment effects, metabolites from 9 of the 28 animals demonstrated significant dose responses, regardless of treatment. Differentiation of responders vs. non-responder revealed that levels of native flavanols and valerolactones approached significance for predicting enhanced GSIS, regardless of treatment. Although treatment-level patterns were not discernable, we conclude that the high inter-individual variability shows that metabolite bioactivity on GSIS capacity is less related to flavanol supplementation or antibiotic treatment and may be more associated with the unique microbiome or metabolome of each animal. These findings suggest flavanol metabolite activities are individualized and point to the need for personalized nutrition practices.

Potential of Phenolic Compounds and Their Gut Microbiota-Derived Metabolites to Reduce TMA Formation: Application of an In Vitro Fermentation High-Throughput Screening Model.

Trimethylamine N-oxide (TMAO) is a pro-atherosclerotic product of dietary choline metabolism generated by a microbiome-host axis. The first step in this pathway is the enzymatic metabolism of choline to trimethylamine (TMA) by the gut microbiota. This reaction could be targeted to reduce atherosclerosis risk. We aimed to evaluate potential inhibitory effects of select dietary phenolics and their relevant gut microbial metabolites on TMA production via a human ex vivo-in vitro fermentation model. Various phenolics inhibited choline use and TMA production. The most bioactive compounds tested (caffeic acid, catechin, and epicatechin) reduced TMA-d9 formation (compared to control) by 57.5 ± 1.3 to 72.5 ± 0.4% at 8 h and preserved remaining choline-d9 concentrations by 194.1 ± 6.4 to 256.1 ± 6.3% at 8 h. These inhibitory effects were achieved without altering cell respiration or cell growth. However, inhibitory effects decreased at late fermentation times, which suggested that these compounds delay choline metabolism rather than completely inhibiting TMA formation. Overall, caffeic acid, catechin, and epicatechin were the most effective noncytotoxic inhibitors of choline use and TMA production. Thus, these compounds are proposed as lead bioactives to test in vivo.

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It's Not All Bad.

Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic ß-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 ß-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions.

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic ß-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional ß-cell mass. We hypothesized that TMAO may damage functional ß-cell mass by inhibiting ß-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 ß-cells and primary rat islets with physiological TMAO concentrations and compared functional ß-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded ß-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in ß-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects ß-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.