Microbiome-driven IBS metabotypes influence response to the low FODMAP diet: insights from the faecal volatome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common and debilitating disorder manifesting with abdominal pain and bowel dysfunction. A mainstay of treatment is dietary modification, including restriction of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). A greater response to a low FODMAP diet has been reported in those with a distinct IBS microbiome termed IBS-P. We investigated whether this is linked to specific changes in the metabolome in IBS-P. METHODS: Solid phase microextraction gas chromatography-mass spectrometry was used to examine the faecal headspace of 56 IBS cases (each paired with a non-IBS household control) at baseline, and after four-weeks of a low FODMAP diet (39 pairs). 50% cases had the IBS-P microbial subtype, while the others had a microbiome that more resembled healthy controls (termed IBS-H). Clinical response to restriction of FODMAPs was measured with the IBS-symptom severity scale, from which a pain sub score was calculated. FINDINGS: Two distinct metabotypes were identified and mapped onto the microbial subtypes. IBS-P was characterised by a fermentative metabolic profile rich in short chain fatty acids (SCFAs). After FODMAP restriction significant reductions in SCFAs were observed in IBS-P. SCFA levels did not change significantly in the IBS-H group. The magnitude of pain and overall symptom improvement were significantly greater in IBS-P compared to IBS-H (p = 0.016 and p = 0.026, respectively). Using just five metabolites, a biomarker model could predict microbial subtype with accuracy (AUROC 0.797, sensitivity 78.6% (95% CI: 0.78-0.94), specificity 71.4% (95% CI: 0.55-0.88). INTERPRETATION: A metabotype high in SCFAs can be manipulated by restricting fermentable carbohydrate, and is associated with an enhanced clinical response to this dietary restriction. This implies that SCFAs harbour pro-nociceptive potential when produced in a specific IBS niche. By ascertaining metabotype, microbial subtype can be predicted with accuracy. This could allow targeted FODMAP restriction in those seemingly primed to respond best. FUNDING: This research was co-funded by Addenbrooke's Charitable Trust, Cambridge University Hospitals and the Wellcome Sanger Institute, and supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).

Differential association of dietary scores with the risk of type 2 diabetes by metabotype.

PURPOSE: We aimed to examine the association between dietary patterns and type 2 diabetes mellitus (T2DM) while considering the potential effect modification by metabolic phenotypes (metabotypes). Additionally, we aimed to explore the association between dietary scores and prediabetes. METHODS: A total of 1460 participants (11.8% with T2DM) from the cross-sectional population-based KORA FF4 study were included. Participants, classified into three metabotype subgroups, had both their FSAm-NPS dietary index (underpinning the Nutri-Score) and ultra-processed foods (UPF) intake (using NOVA classification) calculated. Glucose tolerance status was assessed via oral glucose tolerance tests (OGTT) in non-diabetic participants and was classified according to the American Diabetes Association criteria. Logistic regression models were used for both the overall and metabotype-stratified analyses of dietary scores' association with T2DM, and multinomial probit models for their association with prediabetes. RESULTS: Participants who had a diet with a higher FSAm-NPS dietary index (i.e., a lower diet quality) or a greater percentage of UPF consumption showed a positive association with T2DM. Stratified analyses demonstrated a strengthened association between UPF consumption and T2DM specifically in the metabolically most unfavorable metabotype (Odds Ratio, OR 1.92; 95% Confidence Interval, CI 1.35, 2.73). A diet with a higher FSAm-NPS dietary index was also positively associated with prediabetes (OR 1.19; 95% CI 1.04, 1.35). CONCLUSION: Our study suggests different associations between poorer diet quality and T2DM across individuals exhibiting diverse metabotypes, pointing to the option for stratified dietary interventions in diabetes prevention.

Association of the habitual dietary intake with the fatty liver index and effect modification by metabotypes in the population-based KORA-Fit study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an emerging threat for public health with diet being a major risk factor in disease development and progression. However, the effects of habitual food consumption on fatty liver are still inconclusive as well as the proposed role of the individuals' metabolic profiles. Therefore, the aim of our study is to examine the associations between diet and NAFLD with an emphasis on the influence of specific metabotypes in the general population. METHODS: A total of 689 participants (304 men and 385 women) of the KORA-Fit (S4) survey, a follow-up study of the population-based KORA cohort study running in the Region of Augsburg, Germany, were included in this analysis. Dietary information was derived from repeated 24-h food lists and a food frequency questionnaire. The intake of energy and energy-providing nutrients were calculated using the national food composition database. The presence of fatty liver was quantified by the fatty liver index (FLI), and metabotypes were calculated using K-means clustering. Multivariable linear regression models were used for the analysis of habitual food groups and FLI; for the evaluation of macronutrients, energy substitution models were applied. RESULTS: A higher consumption of nuts and whole grains, and a better diet quality (according to Alternate Healthy Eating Index and Mediterranean Diet Score) were associated with lower FLI values, while the intake of soft drinks, meat, fish and eggs were associated with a higher FLI. The isocaloric substitution of carbohydrates with polyunsaturated fatty acids was associated with a decreased FLI, while substitution with monounsaturated fatty acids and protein showed increased FLI. Statistically significant interactions with the metabotype were observed for most food groups. CONCLUSION: The consumption of plant-based food groups, including nuts and whole grains, and diet quality, were associated with lower FLI values, whereas the intake of soft drinks and products of animal origin (meat, fish, eggs) were associated with a higher FLI. The observed statistically significant interactions with the metabotype for most food groups could help to develop targeted prevention strategies on a population-based level if confirmed in independent prospective studies.

Nutritional and Lifestyle Features in a Mediterranean Cohort: An Epidemiological Instrument for Categorizing Metabotypes Based on a Computational Algorithm.

Background and Objectives: Modern classification and categorization of individuals' health requires personalized variables such as nutrition, physical activity, lifestyle, and medical data through advanced analysis and clustering methods involving machine learning tools. The objective of this project was to categorize Mediterranean dwellers' health factors and design metabotypes to provide personalized well-being in order to develop professional implementation tools in addition to characterizing nutritional and lifestyle features in such populations. Materials and Methods: A two-phase observational study was conducted by the Pharmacists Council to identify Spanish nutritional and lifestyle characteristics. Adults over 18 years of age completed questionnaires on general lifestyle habits, dietary patterns (FFQ, MEDAS-17 p), physical activity (IPAQ), quality of life (SF-12), and validated well-being indices (LS7, MEDLIFE, HHS, MHL). Subsequently, exploratory factor, clustering, and random forest analysis methods were conducted to objectively define the metabotypes considering population determinants. Results: A total of 46.4% of the sample (n = 5496) had moderate-to-high adherence to the Mediterranean diet (>8 points), while 71% of the participants declared that they had moderate physical activity. Almost half of the volunteers had a good self-perception of health (49.9%). Regarding lifestyle index, population LS7 showed a fair cardiovascular health status (7.9 ± 1.7), as well as moderate quality of life by MEDLIFE (9.3 ± 2.6) and MHL scores (2.4 ± 0.8). In addition, five metabotype models were developed based on 26 variables: Westernized Millennial (28.6%), healthy (25.1%), active Mediterranean (16.5%), dysmetabolic/pre-morbid (11.5%), and metabolically vulnerable/pro-morbid (18.3%). Conclusions: The support of tools related to precision nutrition and lifestyle integrates well-being characteristics and contributes to reducing the impact of unhealthy lifestyle habits with practical implications for primary care. Combining lifestyle, metabolic, and quality of life traits will facilitate personalized precision interventions and the implementation of targeted public health policies.

Factors driving the inter-individual variability in the metabolism and bioavailability of (poly)phenolic metabolites: A systematic review of human studies.

This systematic review provides an overview of the available evidence on the inter-individual variability (IIV) in the absorption, distribution, metabolism, and excretion (ADME) of phenolic metabolites and its determinants. Human studies were included investigating the metabolism and bioavailability of (poly)phenols and reporting IIV. One hundred fifty-three studies met the inclusion criteria. Inter-individual differences were mainly related to gut microbiota composition and activity but also to genetic polymorphisms, age, sex, ethnicity, BMI, (patho)physiological status, and physical activity, depending on the (poly)phenol sub-class considered. Most of the IIV has been poorly characterised. Two major types of IIV were observed. One resulted in metabolite gradients that can be further classified into high and low excretors, as seen for all flavonoids, phenolic acids, prenylflavonoids, alkylresorcinols, and hydroxytyrosol. The other type of IIV is based on clusters of individuals defined by qualitative differences (producers vs. non-producers), as for ellagitannins (urolithins), isoflavones (equol and O-DMA), resveratrol (lunularin), and preliminarily for avenanthramides (dihydro-avenanthramides), or by quali-quantitative metabotypes characterized by different proportions of specific metabolites, as for flavan-3-ols, flavanones, and even isoflavones. Future works are needed to shed light on current open issues limiting our understanding of this phenomenon that likely conditions the health effects of dietary (poly)phenols.

Characterization of the Interindividual Variability Associated with the Microbial Metabolism of (-)-Epicatechin.

Although the relationship between gut microbiota and flavan-3-ol metabolism differs greatly between individuals, the specific metabolic profiles, known as metabotypes, have not yet been clearly defined. In this study, fecal batch fermentations of 34 healthy donors inoculated with (-)-epicatechin were stratified into groups based on their conversion rate of (-)-epicatechin and their quali-quantitative metabolic profile. Fast and slow converters of (-)-epicatechin, high producers of 1-(3'-hydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol (3-HPP-2-ol) and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (3,4-DHPVL) were identified. Fecal microbiota analysis revealed that fast conversion of (-)-epicatechin was associated with short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibacterium spp. and Bacteroides spp., and higher levels of acetate, propionate, butyrate, and valerate were observed for fast converters. Other bacteria were associated with the conversion of 1-(3',4'-dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol into 3-HPP-2-ol (Lachnospiraceae UCG-010 spp.) and 3,4-DHPVL (Adlercreutzia equolifaciens). Such stratification sheds light on the mechanisms of action underlying the high interindividual variability associated with the health benefits of flavan-3-ols.

Metabolic phenotyping in people living with obesity: Implications for dietary prevention.

Given the increasing number of people living with obesity and related chronic metabolic disease, precision nutrition approaches are required to increase the effectiveness of prevention strategies. This review addresses these approaches in different metabolic phenotypes (metabotypes) in obesity. Although obesity is typically associated with an increased cardiometabolic disease risk, some people with obesity are relatively protected against the detrimental effects of excess adiposity on cardiometabolic health, also referred to as 'metabolically healthy obesity' (MHO). Underlying mechanisms, the extent to which MHO is a transient state as well as lifestyle strategies to counteract the transition from MHO to metabolically unhealthy obesity (MUO) are discussed. Based on the limited resources that are available for dietary lifestyle interventions, it may be reasonable to prioritize interventions for people with MUO, since targeting high-risk patients for specific nutritional, lifestyle or weight-loss strategies may enhance the cost-effectiveness of these interventions. Additionally, the concept of tissue insulin resistant (IR) metabotypes is discussed, representing distinct etiologies towards type 2 diabetes (T2D) as well as cardiovascular disease (CVD). Recent evidence indicates that these tissue IR metabotypes, already present in individuals with obesity with a normal glucose homeostasis, respond differentially to diet. Modulation of dietary macronutrient composition according to these metabotypes may considerably improve cardiometabolic health benefits. Thus, nutritional or lifestyle intervention may improve cardiometabolic health, even with only minor or no weight loss, which stresses the importance of focusing on a healthy lifestyle and not on weight loss only. Targeting different metabotypes towards T2D and cardiometabolic diseases may lead to more effective lifestyle prevention and treatment strategies. Age and sex-related differences in tissue metabotypes and related microbial composition and functionality (fermentation), as important drivers and/or mediators of dietary intervention response, have to be taken into account. For the implementation of these approaches, more prospective trials are required to provide the knowledge base for precision nutrition in the prevention of chronic metabolic diseases.

Main Determinants Affecting the Antiproliferative Activity of Stilbenes and Their Gut Microbiota Metabolites in Colon Cancer Cells: A Structure-Activity Relationship Study.

trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4'-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure-antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4'-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 µM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 µM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 µM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 µM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4'-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.

Optimized Metabotype Definition Based on a Limited Number of Standard Clinical Parameters in the Population-Based KORA Study.

The aim of metabotyping is to categorize individuals into metabolically similar groups. Earlier studies that explored metabotyping used numerous parameters, which made it less transferable to apply. Therefore, this study aimed to identify metabotypes based on a set of standard laboratory parameters that are regularly determined in clinical practice. K-means cluster analysis was used to group 3001 adults from the KORA F4 cohort into three clusters. We identified the clustering parameters through variable importance methods, without including any specific disease endpoint. Several unique combinations of selected parameters were used to create different metabotype models. Metabotype models were then described and evaluated, based on various metabolic parameters and on the incidence of cardiometabolic diseases. As a result, two optimal models were identified: a model composed of five parameters, which were fasting glucose, HDLc, non-HDLc, uric acid, and BMI (the metabolic disease model) for clustering; and a model that included four parameters, which were fasting glucose, HDLc, non-HDLc, and triglycerides (the cardiovascular disease model). These identified metabotypes are based on a few common parameters that are measured in everyday clinical practice. These metabotypes are cost-effective, and can be easily applied on a large scale in order to identify specific risk groups that can benefit most from measures to prevent cardiometabolic diseases, such as dietary recommendations and lifestyle interventions.

Lunularin Producers versus Non-producers: Novel Human Metabotypes Associated with the Metabolism of Resveratrol by the Gut Microbiota.

We describe here for the first time the consistent observation of two metabotypes associated with resveratrol metabolism by the human gut microbiota, that is, lunularin (LUNU)-producers and LUNU non-producers. In healthy volunteers (n = 195), resveratrol was reduced to dihydroresveratrol, which only in the LUNU-producer metabotype was sequentially dehydroxylated at the 5-position to yield LUNU and the 3-position to produce 4-hydroxydibenzyl. These metabolites (also 3,4'-dihydroxy-trans-stilbene in some LUNU-producers) were detected in the urine and (or) feces of 74% of volunteers after consuming resveratrol, while 26% lacked these dehydroxylase activities. The LUNU non-producer metabotype was more prevalent in females (P < 0.05) but independent of individuals' BMI and age. A 4-styrylphenol reductase in both metabotypes converted stilbenes to their corresponding dibenzyls, while no 4-dehydroxylation in stilbenes or dibenzyls was observed. 4-Hydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 3-hydroxydibenzyl, and 3-hydroxy-trans-stilbene were not detected in vivo or in vitro. Further research on LUNU metabotypes, their associated gut microbiota, and their impact on health is worthwhile.

Association between Usual Dietary Intake of Food Groups and DNA Methylation and Effect Modification by Metabotype in the KORA FF4 Cohort.

Associations between diet and DNA methylation may vary among subjects with different metabolic states, which can be captured by clustering populations in metabolically homogenous subgroups, called metabotypes. Our aim was to examine the relationship between habitual consumption of various food groups and DNA methylation as well as to test for effect modification by metabotype. A cross-sectional analysis of participants (median age 58 years) of the population-based prospective KORA FF4 study, habitual dietary intake was modeled based on repeated 24-h diet recalls and a food frequency questionnaire. DNA methylation was measured using the Infinium MethylationEPIC BeadChip providing data on >850,000 sites in this epigenome-wide association study (EWAS). Three metabotype clusters were identified using four standard clinical parameters and BMI. Regression models were used to associate diet and DNA methylation, and to test for effect modification. Few significant signals were identified in the basic analysis while many significant signals were observed in models including food group-metabotype interaction terms. Most findings refer to interactions of food intake with metabotype 3, which is the metabotype with the most unfavorable metabolic profile. This research highlights the importance of the metabolic characteristics of subjects when identifying associations between diet and white blood cell DNA methylation in EWAS.

Evaluation of the metabotype concept after intervention with oral glucose tolerance test and dietary fiber-enriched food: An enable study.

BACKGROUND AND AIMS: Evidence suggests that people react differently to the same diet due to inter-individual differences. However, few studies have investigated variation in response to dietary interventions based on individuals' baseline metabolic characteristics. This study aims to examine the differential reaction of metabotype subgroups to an OGTT and a dietary fiber intervention. METHODS AND RESULTS: We assigned 356 healthy participants of an OGTT sub-study and a 12-week dietary fiber intervention sub-study within the enable cluster to three metabotype subgroups previously identified in the KORA F4 study population. To explore the association between plasma glucose level and metabotype subgroups, we used linear mixed models adjusted for age, sex, and physical activity. Individuals in different metabotype subgroups showed differential responses to OGTT. Compared to the healthy metabotype (metabotype 1), participants in intermediate metabotype (metabotype 2) and unfavorable metabotype (metabotype 3) had significantly higher plasma glucose concentrations at 120 min after glucose bolus (ß = 7.881, p = 0.005; ß = 32.79, p < 0.001, respectively). Additionally, the linear regression model showed that the Area under the curve (AUC) of plasma glucose concentrations was significantly different across the metabotype subgroups. The associations between metabotype subgroups and metabolic parameters among fiber intervention participants remained insignificant in the multivariate-adjusted linear model. However, the metabotype 3 had the highest mean reduction in insulin, cholesterol parameters (TC, LDLc, and non-HDLc), and systolic and diastolic blood pressure at the end of the intervention period. CONCLUSION: This study supports the use of the metabotype concept to identify metabolically similar subgroups and to develop targeted dietary interventions at the metabotype subgroup level for the primary prevention of diet-related diseases.

Variability in the Beneficial Effects of Phenolic Compounds: A Review.

When analysing the beneficial effects of phenolic compounds, several factors that exert a clear influence should be taken into account. The content of phenolic compounds in foods is highly variable, directly affecting individual dietary intake. Once ingested, these compounds have a greater or lesser bioaccessibility, defined as the amount available for absorption in the intestine after digestion, and a certain bioavailability, defined as the proportion of the molecule that is available after digestion, absorption and metabolism. Among the external factors that modify the content of phenolic compounds in food are the variety, the cultivation technique and the climate. Regarding functional foods, it is important to take into account the role of the selected food matrix, such as dairy matrices, liquid or solid matrices. It is also essential to consider the interactions between phenolic compounds as well as the interplay that occurs between these and several other components of the diet (macro- and micronutrients) at absorption, metabolism and mechanism of action levels. Furthermore, there is a great inter-individual variability in terms of phase II metabolism of these compounds, composition of the microbiota, and metabolic state or metabotype to which the subject belongs. All these factors introduce variability in the responses observed after ingestion of foods or nutraceuticals containing phenolic compounds.

Human Milk Metabolomics Are Related to Maternal Adiposity, Infant Growth Rate and Allergies: The Chinese Human Milk Project.

The metabolomic profiles of Chinese human milk have been poorly documented. The objective of the study was to explore associations between human milk metabotypes, maternal adiposity, infant growth patterns, and risk of allergies. Two hundred mother−infant dyads from seven cities were randomly selected from the Chinese Human Milk Project (CHMP). Untargeted human milk metabolomic profiles were determined using HPLC-MS/MS. Two human milk metabotypes were identified using principal component analysis. Principal component (PC) 1 was characterized by high linoleic acid metabolites with low purine nucleosides and metabolites of glutamate and glutathione metabolism. PC 2 was characterized by high glycerophospholipids and sphingomyelins content. Higher PC1 scores were associated with slower infant growth rate and higher ambient temperature (p < 0.05). Higher PC 2 scores were related to higher maternal BMI and increased risk of infant allergies (p < 0.05). Future work is needed to understand the biologic mechanisms of these human milk metabotypes.

Chemical phenotype as important and dynamic niche dimension of plants.

Niche theory considering the traits of species and individuals provides a powerful tool to integrate ecology and evolution of species. In plant ecology, morphological and physiological traits are commonly considered as niche dimensions, whereas phytochemical traits are mostly neglected in this context despite their pivotal functions in plant responses to their environment and in mediating interactions. The diversity of plant phytochemicals can thus mediate three key processes: niche choice, conformance and construction. Here, we integrate frameworks from niche theory with chemical ecology and argue that plants use their individual-specific diversity in phytochemicals (chemodiversity) for different niche realization processes. Our concept has important implications for ecosystem processes and stability and increases the predictive ability of chemical ecology.

Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota.

Urolithins, metabolites produced by the gut microbiota from the polyphenols ellagitannins and ellagic acid, are discovered by the research group in humans almost 20 years ago. Pioneering research suggests urolithins as pleiotropic bioactive contributors to explain the health benefits after consuming ellagitannin-rich sources (pomegranates, walnuts, strawberries, etc.). Here, this study comprehensively updates the knowledge on urolithins, emphasizing the review of the literature published during the last 5 years. To date, 13 urolithins and their corresponding conjugated metabolites (glucuronides, sulfates, etc.) have been described and, depending on the urolithin, detected in different human fluids and tissues (urine, blood, feces, breastmilk, prostate, colon, and breast tissues). There has been a substantial advance in the research on microorganisms involved in urolithin production, along with the compositional and functional characterization of the gut microbiota associated with urolithins metabolism that gives rise to the so-called urolithin metabotypes (UM-A, UM-B, and UM-0), relevant in human health. The design of in vitro studies using physiologically relevant assay conditions (molecular forms and concentrations) is still a pending subject, making some reported urolithin activities questionable. In contrast, remarkable progress has been made in the research on the safety, bioactivity, and associated mechanisms of urolithin A, including the first human interventions.

(Poly)phenolic compounds and gut microbiome: new opportunities for personalized nutrition.

For decades, (poly)phenols have been linked to cardiometabolic health, but population heterogeneity limits their apparent efficacy and the development of tailored, practical protocols in dietary interventions. This heterogeneity is likely determined by the existence of different metabotypes, sub-populations of individuals metabolizing some classes of (poly)phenols differently. The gut microbiota plays a major role in this process. The impact of microbiota-related phenolic metabotypes on cardiometabolic health is becoming evident, although the picture is still incomplete, and data are absent for some classes of (poly)phenols. The lack of a complete understanding of the main microbial actors involved in the process complicates the picture. Elucidation of the mechanisms behind phenolic metabotypes requires novel experimental designs that can dissect the inter-individual variability. This paper, in addition to providing an overview on the current state-of-the-art, proposes wider metabotyping approaches as a means of paving the way towards effective personalized nutrition with dietary (poly)phenols.

Genetic and environmental influences on covariation in reproducible diet-metabolite associations.

BACKGROUND: Early applications of metabolomics in nutrition and health research identified associations between dietary patterns and metabolomic profiles. Twin studies show that diet-related phenotypes and diet-associated metabolites are influenced by genes. However, studies have not examined whether diet-metabolite associations are explained by genetic or environmental factors and whether these associations are reproducible over multiple time points. OBJECTIVE: This research aims to examine the genetic and environmental factors influencing covariation in diet-metabolite associations that are reproducible over time in healthy twins. METHODS: The UCD Twin Study is a semi-longitudinal classic twin study that collected repeated dietary, anthropometric, and urinary data over 2 months. Correlation analysis identified associations between diet quality measured using the Healthy Eating Index (HEI) and urinary metabolomic profiles at 3 time points. Diet-associated metabolites were examined using linear regression to identify those significantly influenced by familial factors between twins and those significantly influenced by unique factors. Cholesky decomposition modeling quantified the genetic and environmental path coefficients through associated dietary components onto the metabolites. RESULTS: The HEI was associated with 14 urinary metabolites across 3 metabolomic profiles (r: ±0.15-0.49). For 8 diet-metabolite associations, genetic or shared environmental factors influencing HEI component scores significantly influenced variation in metabolites (ß: 0.40-0.52). A significant relation was observed between dietary intakes of whole grain and acetoacetate (ß: -0.50, P < 0.001) and ß-hydroxybutyrate (ß: -0.46, P < 0.001), as well as intakes of saturated fat and acetoacetate (ß: 0.47, P < 0.001) and ß-hydroxybutyrate (ß: 0.52, P < 0.001). For these diet-metabolite associations a common shared environmental factor explained 66-69% of variance in the metabolites. CONCLUSIONS: This study shows that diet-metabolite associations are reproducible in 3 urinary metabolomic profiles. Components of the HEI covary with metabolites, and covariation is largely due to the shared environment.

Avenanthramide Metabotype from Whole-Grain Oat Intake is Influenced by Faecalibacterium prausnitzii in Healthy Adults.

BACKGROUND: Oat has been widely accepted as a key food for human health. It is becoming increasingly evident that individual differences in metabolism determine how different individuals benefit from diet. Both host genetics and the gut microbiota play important roles on the metabolism and function of dietary compounds. OBJECTIVES: To investigate the mechanism of individual variations in response to whole-grain (WG) oat intake. METHODS: We used the combination of in vitro incubation assays with human gut microbiota, mouse and human S9 fractions, chemical analyses, germ-free (GF) mice, 16S rRNA sequencing, gnotobiotic techniques, and a human feeding study. RESULTS: Avenanthramides (AVAs), the signature bioactive polyphenols of WG oat, were not metabolized into their dihydro forms, dihydro-AVAs (DH-AVAs), by both human and mouse S9 fractions. DH-AVAs were detected in the colon and the distal regions but not in the proximal and middle regions of the perfused mouse intestine, and were in specific pathogen-free (SPF) mice but not in GF mice. A kinetic study of humans fed oat bran showed that DH-AVAs reached their maximal concentrations at much later time points than their corresponding AVAs (10.0-15.0 hours vs. 4.0-4.5 hours, respectively). We observed interindividual variations in the metabolism of AVAs to DH-AVAs in humans. Faecalibacterium prausnitzii was identified as the individual bacterium to metabolize AVAs to DH-AVAs by 16S rRNA sequencing analysis. Moreover, as opposed to GF mice, F. prausnitzii-monocolonized mice were able to metabolize AVAs to DH-AVAs. CONCLUSIONS: These findings demonstrate that the presence of intestinal F. prausnitzii is indispensable for proper metabolism of AVAs in both humans and mice. We propose that the abundance of F. prausnitzii can be used to subcategorize individuals into AVA metabolizers and nonmetabolizers after WG oat intake. This study was registered at clinicaltrials.gov as NCT04335435.

Sulfur amino acid metabolism and related metabotypes of autism spectrum disorder: A review of biochemical evidence for a hypothesis.

There are multiple lines of evidence for an impaired sulfur amino acid (SAA) metabolism in autism spectrum disorder (ASD). For instance, the concentrations of methionine, cysteine and S-adenosylmethionine (SAM) in body fluids of individuals with ASD is significantly lower while the concentration of S-adenosylhomocysteine (SAH) is significantly higher as compared to healthy individuals. Reduced methionine and SAM may reflect impaired remethylation pathway whereas increased SAH may reflect reduced S-adenosylhomocysteine hydrolase activity in the catabolic direction. Reduced SAM/SAH ratio reflects an impaired methylation capacity. We hypothesize multiple mechanisms to explain how the interplay of oxidative stress, neuroinflammation, mercury exposure, maternal use of valproate, altered gut microbiome and certain genetic variants may lead to these SAA metabotypes. Furthermore, we also propose a number of mechanisms to explain the metabolic consequences of abnormal SAA metabotypes. For instance in the brain, reduced SAM/SAH ratio will result in melatonin deficiency and hypomethylation of a number of biomolecules such as DNA, RNA and histones. In addition to previously proposed mechanisms, we propose that impaired activity of "radical SAM" enzymes will result in reduced endogenous lipoic acid synthesis, reduced molybdenum cofactor synthesis and impaired porphyrin metabolism leading to mitochondrial dysfunction, porphyrinuria and impaired sulfation capacity. Furthermore depletion of SAM may also lead to the disturbed mTOR signaling pathway in a subgroup of ASD. The proposed "SAM-depletion hypothesis" is an inclusive model to explain the relationship between heterogeneous risk factors and metabotypes observed in a subset of children with ASD.