Lignans are polyphenolic compounds abundant in plant-based foods such as seeds, whole grains, and certain fruits and vegetables and may lead to favorable metabolic health. It remains to be elucidated regarding the role of lignan consumption in the etiology of premature deaths among individuals with diabetes.

To prospectively examine the association between postdiagnosis lignan intake and mortality among individuals with type 2 diabetes (T2D).

We analyzed data from 2 prospective United States cohorts, the Nurses' Health Study (1984-2020) and Health Professionals Follow-up Study (1986-2022). Mean daily consumption of total and individual lignans was calculated, and postdiagnosis lignan intakes were cumulatively averaged. Multivariable-adjusted Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between lignan intake and mortality.

Among 8465 incident T2D cases contributing 116,026 person-years of follow-up, 4372 deaths were documented, including 1318 from cardiovascular disease (CVD) and 752 from cancer. The pooled multivariable-adjusted HRs (95% CIs) of all-cause mortality comparing the highest compared with the lowest quintiles of postdiagnosis lignan intake were 0.83 (0.74, 0.94) for total lignans, 0.89 (0.80, 0.99) for matairesinol (MAT), 0.78 (0.69, 0.87) for secoisolariciresinol (SECO), 0.91 (0.81, 1.01) for pinoresinol (PINO), and 0.92 (0.82, 1.03) for lariciresinol (LARIC). Higher postdiagnosis SECO intake was also significantly associated with lower CVD and cancer mortality. Changes in lignan intake from pre- to postdiagnosis showed similar favorable associations: 0.83 (0.75, 0.93) for total lignans, 0.86 (0.77, 0.96) for MAT, and 0.81 (0.72, 0.90) for SECO. The associations of lignan intake were significantly stronger among nonwhite individuals.

Among individuals with T2D, a higher intake of lignans, particularly SECO, was significantly associated with reduced overall CVD and cancer mortality. Minority groups may particularly benefit from lignan intake, although further studies are warranted to substantiate this observation.

Type 2 diabetes mellitus (T2DM), a serious metabolic disorder, is a worldwide health problem due to the alarming rise in prevalence and elevated morbidity and mortality. Chronic hyperglycemia, insulin resistance, and ineffective insulin effect and secretion are hallmarks of T2DM, leading to many serious secondary complications. These include, in particular, cardiovascular disorders, diabetic neuropathy, nephropathy and retinopathy, diabetic foot, osteoporosis, liver damage, susceptibility to infections and some cancers. Polyphenols such as flavonoids, phenolic acids, stilbenes, tannins, and lignans constitute an extensive and heterogeneous group of phytochemicals in fresh fruits, vegetables and their products. Various in vitro studies, animal model studies and available clinical trials revealed that flavonoids (e.g., quercetin, kaempferol, rutin, epicatechin, genistein, daidzein, anthocyanins), phenolic acids (e.g., chlorogenic, caffeic, ellagic, gallic acids, curcumin), stilbenes (e.g., resveratrol), tannins (e.g., procyanidin B2, seaweed phlorotannins), lignans (e.g., pinoresinol) have the ability to lower hyperglycemia, enhance insulin sensitivity and improve insulin secretion, scavenge reactive oxygen species, reduce chronic inflammation, modulate gut microbiota, and alleviate secondary complications of T2DM. The interaction between polyphenols and conventional antidiabetic drugs offers a promising strategy in the management and treatment of T2DM, especially in advanced disease stages. Synergistic effects of polyphenols with antidiabetic drugs have been documented, but also antagonistic interactions that may impair drug efficacy. Therefore, additional research is required to clarify mutual interactions in order to use the knowledge in clinical applications. Nevertheless, dietary polyphenols can be successfully applied as part of supportive treatment for T2DM, as they reduce both obvious clinical symptoms and secondary complications.

The rising prevalence of metabolic diseases, such as diabetes and obesity, presents a significant global health challenge. Dietary interventions, with their minimal side effects, hold great promise as effective strategies for blood sugar management. Highland barley (HB) boasts a comprehensive and unique nutritional composition, characterized by high protein, high fiber, high vitamins, low fat, low sugar, and diverse bioactive components. These attributes make it a promising candidate for alleviating high blood sugar. This review explores the mechanisms underlying the glucose-lowering properties of HB, emphasizing its nutritional profile and bioactive constituents. Additionally, it examines the impact of common HB processing techniques on its nutrient composition and highlights its applications in food products. By advancing the understanding of HB's value and mechanisms in diabetes prevention, this review aims to facilitate the development of HB-based foods suitable for diabetic patients.

Lignans are phytoestrogens abundant in Western diets and may be associated with type 2 diabetes (T2D) risk.

To prospectively investigate associations between lignan intake and T2D incidence.

Population-based cohort study of US men and women enrolled in the Nurses' Health Study (NHS, 1984-2018), NHSII (1991-2019), and Health Professionals Follow-Up Study (HPFS, 1986-2020), as well as 496 participants from the Men's Lifestyle Validation Study (MLVS). Participants were free of T2D, cardiovascular disease, and cancer at baseline. Data were analyzed from November 2022 to July 2023.

Total and individual lignans were assessed using a validated food frequency questionnaire, which was updated every 2 to 4 years. In the MLVS, lignan intake was measured using 2 sets of 7-day diet records (7DDRs).

Incident T2D cases were confirmed using American Diabetes Association diagnostic criteria. Cox proportional hazards models were used to assess multivariable-adjusted associations.

The current study included 201 111 participants (mean [SD] age, 44.7 [10.1] years; 161 169 female participants [80.2%]; 2614 African American participants [1.3%], 1609 Asian participants [0.8%], 2414 Hispanic and other race or ethnicity participants [1.2%], and 194 474 White participants [96.7%]) from the HPFS, NHS, and NHSII studies. The median (IQR) total lignan intake of the highest quintile ranged from 355.1 (330.2-396.9) μg/d in NHS to 459.9 (422.2-519.5) μg/d in HPFS at the median follow-up time. Over 5 068 689 person-years, 20 291 incident cases of T2D were identified. Higher lignan intake was inversely associated with T2D incidence, except for lariciresinol. The multivariable-adjusted pooled hazard ratios (HRs) for the highest vs lowest quintiles were 0.87 (95% CI, 0.83-0.91) for total lignans, 0.72 (95% CI, 0.69-0.76) for secoisolariciresinol, 0.92 (95% CI, 0.87-0.96) for pinoresinol, 0.93 (95% CI, 0.89-0.98) for matairesinol, and 0.99 (95% CI, 0.94-1.04) for lariciresinol. Secoisolariciresinol intake exhibited a significant inverse association with T2D risk among individuals with obesity (HR, 0.75 for body mass index [BMI] ≥30; 95% CI, 0.71-0.79 vs HR, 0.82 for BMI <25; 95% CI, 0.81-0.83; P < .001 for interaction) and premenopausal women (HR, 0.67 for premenopausal women; 95% CI, 0.65-0.69 vs HR, 0.82 for the past use of hormones; 95% CI, 0.76-0.88; P = .003 for interaction). Dietary lignan assessed with 7DDRs was associated with lower HbA1c levels (percentage change range from -0.92% to 1.50%), as well as lower C-reactive protein levels and better lipid profiles.

This cohort study found that long-term lignan consumption was associated with a lower T2D risk, particularly among individuals with obesity and premenopausal women.

Estrogens are classically considered essential hormonal signals, but they exert profound effects in a number of physiological and pathological states, including glucose homeostasis and insulin resistance. Estrogen deficiency after menopause in most women leads to increased androgenicity and changes in body composition, and it is recommended to manipulate the β-cell function of the pancreas, insulin-induced glucose transport, and hepatic glucose output, hence, the increasing incidence of type 2 diabetes mellitus. Recently, studies have reported that gut biota alteration due to estrogen deficiency contributes to altered energy metabolism and, hence, accentuates the pathology of diabetes mellitus. Emerging research suggests estrogen deficiency via genetic disposition or failure of ovaries to function in old age modulates the insulin resistance and glucose secretion workload on pancreatic beta cells by decreasing the levels of good bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus spp., Faecalibacterium prausnitzii, Roseburia spp., and Prevotella spp., and increasing the levels of bad bacteria's such as Bacteroides spp., Clostridium difficile, Escherichia coli, and Enterococcus spp. Alteration in these bacteria's concentrations in the gut further leads to the development of impaired glucose uptake by the muscles, increased gluconeogenesis in the liver, and increased lipolysis and inflammation in the adipose tissues. Thus, the present review paper aims to clarify the intricate interactions between estrogen deficiency, gut microbiota regulation, and the development of diabetes mellitus.

The global incidence of type 2 diabetes (T2D) has been steadily increasing in recent decades. The Mediterranean dietary pattern has shown a preventive effect on the risk of T2D. Evaluating the association between bioactive compounds such as phenolic compounds (PC) in a Mediterranean cohort could help to better understand the mechanisms implicated in this protection. We evaluated the association between dietary intake of PC and the risk of T2D in a relatively young cohort of 17,821 Spanish participants initially free of T2D, through the University of Navarra Follow-up Project ("Seguimiento Universidad de Navarra" or SUN cohort) after 10 years of median follow-up using time-dependent Cox models. Intake of PC was estimated at baseline and repeatedly at 10-year follow-up using a 136-item validated food frequency and the Phenol-Explorer database. The incidence of T2D was identified by a biennial follow-up, and only medically confirmed cases were included. During 224,751 person-years of follow-up, 186 cases of T2D were confirmed. A suboptimal intake of stilbenes was independently associated with a higher risk of T2D in subjects over 50 years (HR: 1.75, 95% CI: 1.06-2.90, p value < 0.05) after adjusting for potential confounders. Our results suggest that a moderate-high intake of stilbenes can decrease the risk of developing T2D in subjects over 50 years in our cohort.

Phytoestrogens are literally estrogenic substances of plant origin. Although these substances are useful for plants in many aspects, their estrogenic properties are essentially relevant to their predators. As such, phytoestrogens can be considered to be substances potentially dedicated to plant-predator interaction. Therefore, it is not surprising to note that the word phytoestrogen comes from the early discovery of estrogenic effects in grazing animals and humans. Here, several compounds whose activities have been discovered at nutritional concentrations in animals and humans are examined. The substances analyzed belong to several chemical families, i.e., the flavanones, the coumestans, the resorcylic acid lactones, the isoflavones, and the enterolignans. Following their definition and the evocation of their role in plants, their metabolic transformations and bioavailabilities are discussed. A point is then made regarding their health effects, which can either be beneficial or adverse depending on the subject studied, the sex, the age, and the physiological status. Toxicological information is given based on official data. The effects are first presented in humans. Animal models are evoked when no data are available in humans. The effects are presented with a constant reference to doses and plausible exposure.

Lignans are non-flavonoid polyphenols present in a wide range of foods frequently consumed in the Western world, such as seeds, vegetables and fruits, and beverages such as coffee, tea and wine. In particular, the human gut microbiota (GM) can convert dietary lignans into biologically active compounds, especially enterolignans (i.e., enterolactone and enterodiol), which play anti-inflammatory and anti-oxidant roles, act as estrogen receptor activators and modulate gene expression and/or enzyme activity. Interestingly, recent evidence documenting those dietary interventions involving foods enriched in lignans have shown beneficial and protective effects on various human pathologies, including colorectal and breast cancer and cardiovascular diseases. However, considering that more factors (e.g., diet, food transit time and intestinal redox state) can modulate the lignans bioactivation by GM, there are usually remarkable inter-individual differences in urine, fecal and blood concentrations of enterolignans; hence, precise and validated analytical methods, especially gas/liquid chromatography coupled to mass spectrometry, are needed for their accurate quantification. Therefore, this review aims to summarize the beneficial roles of enterolignans, their interaction with GM and the new methodological approaches developed for their evaluation in different biological samples, since they could be considered future promising nutraceuticals for the prevention of human chronic disorders.

Lignans are one of the most important and abundant phytochemicals found in flaxseed-diets. These have shown to possess several health-benefits, including anticancer, antioxidant, neuroprotective, cardioprotective, and estrogenic-properties etc. The potential of lignans health-promoting effects are circumscribed due to their poor-bioavailability resulting from their bound structure. Recent studies have demonstrated that various food design strategies can enhance the release of bound-lignans from agro-industrial residues, resulting in a higher bioaccessibility and bioavailability. This review focuses primarily on the bioavailability of flaxseed lignans, key factors affecting it and their pharmacokinetics, different strategies to improve the contents of lignans, their release and delivery. Present study will help to deepen our understanding of the applications of lignans and their dietary-supplements in the prevention and treatment of diseases. Several absorption issues of lignans have been observed such as impaired-bioavailability and variability in pharmacokinetics and pharmacodynamics. Therefore, the development of novel strategies for optimizing lignan bioavailability is critical to ensure its successful application, such as the delivery of lignans to biological targets via "targeted designs." In addition, some detailed examination is required to identify and understand the basis of variation in lignans bioavailability caused by interactions with the gastrointestinal system.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by persistent abnormally elevated blood sugar levels. T2DM affects millions of people and exerts a significant global public health burden. Danggui Buxue decoction (DBD), a classical Chinese herbal formula composed of Astragalus membranaceus (Huangqi) and Angelica sinensis (Danggui), has been widely used in the clinical treatment of diabetes and its complications. However, the effect of DBD on the gut microbiota of individuals with diabetes and its metabolism are still poorly understood. In this study, a T2DM model was established in Goto-Kakizaki (GK) rats, which were then treated with a clinical dose of DBD (4 g/kg) through tube feeding for 6 weeks. Next, we used 16S rRNA sequencing and untargeted metabolomics by liquid chromatography with mass spectrometry (LC-MS) to detect changes in the composition of the microbiota and cecal metabolic products. Our data show that DBD mediates the continuous increase in blood glucose in GK rats, improves insulin sensitivity, reduces expression of inflammatory mediators, and improves systemic oxidative stress. Moreover, DBD also improves microbial diversity (e.g., Romboutsia, Firmicutes, and Bacilli) in the intestines of rats with T2DM. Further, DBD intervention also regulates various metabolic pathways in the gut microbiota, including alanine, aspartate, and glutamate metabolism. In addition, arginine biosynthesis and the isoflavone biosynthesis may be a unique mechanism by which DBD exerts its effects. Taken together, we show that DBD is a promising therapeutic agent that can restore the imbalance found in the gut microbiota of T2DM rats. DBD may modify metabolites in the microbiota to realize its antidiabetic and anti-inflammatory effects.

Peroxidases and laccases are oxidative enzymes involved in physiological processes in plants, covering responses to biotic and abiotic stress as well as biosynthesis of health-promoting specialized metabolites. Although they are thought to be involved in the biosynthesis of (+)-pinoresinol, a comprehensive investigation of this class of enzymes has not yet been conducted in the emerging oil crop sesame and no information is available regarding the potential (+)-pinoresinol synthase genes in this crop. In the present study, we conducted a pan-genome-wide identification of peroxidase and laccase genes coupled with transcriptome profiling of diverse sesame varieties. A total of 83 and 48 genes have been identified as coding for sesame peroxidase and laccase genes, respectively. Based on their protein domain and Arabidopsis thaliana genes used as baits, the genes were classified into nine and seven groups of peroxidase and laccase genes, respectively. The expression of the genes was evaluated using dynamic transcriptome sequencing data from six sesame varieties, including one elite cultivar, white vs black seed varieties, and high vs low oil content varieties. Two peroxidase genes (SiPOD52 and SiPOD63) and two laccase genes (SiLAC1 and SiLAC39), well conserved within the sesame pan-genome and exhibiting consistent expression patterns within sesame varieties matching the kinetic of (+)-pinoresinol accumulation in seeds, were identified as potential (+)-pinoresinol synthase genes. Cis-acting elements of the candidate genes revealed their potential involvement in development, hormonal signaling, and response to light and other abiotic triggers. Transcription factor enrichment analysis of promoter regions showed the predominance of MYB binding sequences. The findings from this study pave the way for lignans-oriented engineering of sesame with wide potential applications in food, health and medicinal domains.

The intake of polyphenols has been associated with a risk reduction of type 2 diabetes. Nevertheless, to the best of our knowledge, the molecules that might be metabolically active after ingestion are only starting to be investigated regarding this metabolic disease. To investigate the association between one-year changes in urinary microbial phenolic metabolites (MPM) and the incidence of type 2 diabetes, we performed a case-control study using data and samples of the PREDIMED trial including 46 incident type 2 diabetes cases of 172 randomly selected participants. Eight urinary MPMs were quantified in urine by liquid chromatography coupled to mass spectrometry and used to assess their associations with type 2 diabetes risk by multivariable logistic regression models. Compared to participants in the lowest tertile of one-year changes in hydroxybenzoic acid glucuronide, those in the highest tertile had a significantly lowered probability of developing type 2 diabetes (OR [95% CI], 0.39 [0.23−0.64]; p < 0.001 for trend). However, when additionally adjusting for fasting plasma glucose, the statistical significance was lost. Changes in the dietary pattern can increase the concentrations of this compound, derived from many (poly)phenol-rich foods, and might be changing the gut microbial population as well, promoting the production of the metabolite.

The conversion of plant lignans to bioactive enterolignans in the gastrointestinal tract is mediated through microbial processing. The goal of this study was to examine the relationships between lignan intake, plasma enterolactone concentrations, gut microbiome composition, and metabolic risk in free-living male adults.

In 303 men participating in the Men's Lifestyle Validation Study (MLVS), lignan intake was assessed using two sets of 7-day diet records, and gut microbiome was profiled through shotgun sequencing of up to 2 pairs of fecal samples (n = 911). A score was calculated to summarize the abundance of bacteria species that were significantly associated with plasma enterolactone levels. Of the 138 filtered species, plasma enterolactone levels were significantly associated with the relative abundances of 18 species at FDR < 0.05 level. Per SD increment of lignan intake was associated with 20.7 nM (SEM: 2.3 nM) higher enterolactone concentrations among participants with a higher species score, whereas the corresponding estimate was 4.0 nM (SEM: 1.7 nM) among participants with a lower species score (P for interaction < 0.001). A total of 12 plasma metabolites were also significantly associated with these enterolactone-predicting species. Of the association between lignan intake and metabolic risk, 19.8% (95%CI: 7.3%-43.6%) was explained by the species score alone, 54.5% (95%CI: 21.8%-83.7%) by both species score and enterolactone levels, and 79.8% (95%CI: 17.7%-98.6%) by further considering the 12 plasma metabolites.

We identified multiple gut bacteria species that were enriched or depleted at higher plasma levels of enterolactone in men. These species jointly modified the associations of lignan intake with plasma enterolactone levels and explained the majority of association between lignan intake and metabolic risk along with enterolactone levels and certain plasma metabolites.

Previous studies suggested that dietary polyphenols could reduce the incidence and complications of type-2 diabetes (T2D); although the evidence is still limited and inconsistent. This work analyzes whether changing to a diet with a higher polyphenolic content is associated with an improved glucose profile. At baseline, and at 1 year of follow-up visits, 5921 participants (mean age 65.0 ± 4.9, 48.2% women) who had overweight/obesity and metabolic syndrome filled out a validated 143-item semi-quantitative food frequency questionnaire (FFQ), from which polyphenol intakes were calculated. Energy-adjusted total polyphenols and subclasses were categorized in tertiles of changes. Linear mixed-effect models with random intercepts (the recruitment centers) were used to assess associations between changes in polyphenol subclasses intake and 1-year plasma glucose or glycosylated hemoglobin (HbA1c) levels. Increments in total polyphenol intake and some classes were inversely associated with better glucose levels and HbA1c after one year of follow-up. These associations were modified when the analyses were run considering diabetes status separately. To our knowledge, this is the first study to assess the relationship between changes in the intake of all polyphenolic groups and T2D-related parameters in a senior population with T2D or at high-risk of developing T2D.

Dietary lignans are phytoestrogens that are mostly found in plant-based foods, especially whole grains, seeds, nuts, legumes and vegetables. An accurate assessment of lignan exposure is crucial to evaluate their potential health benefits and to establish future recommendations and dietary guidelines. This narrative review aimed to (i) summarize the pros and the cons of the current main assessment methods for lignan exposure─i.e., dietary questionnaires, food composition tables and biomarkers, (ii) describe the individual lignans more consumed from a worldwide perspective, as well as their main food sources, (iii) determine the lignans concentrations in both urine and blood, and explore their heterogeneity among countries, and finally (iv) discuss the main determinants of lignan exposure.

Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.

Evidence regarding lignan consumption in relation to coronary heart disease (CHD) risk remains limited and mixed.

The aim of this study was to prospectively examine associations between lignan intake and CHD risk in U.S. men and women.

We prospectively followed 214,108 men and women in 3 cohorts who did not have cardiovascular disease or cancer at baseline. Diet was repeatedly assessed using a validated food frequency questionnaire every 2-4 years since baseline.

During 5,517,225 person-years of follow-up, we documented 10,244 CHD cases, including 6,283 nonfatal myocardial infarction and 3,961 fatal CHD cases. In multivariable-adjusted analyses, comparing extreme quintiles, the pooled hazard ratios of CHD were 0.85 (95% CI: 0.79-0.92) for total lignans, 0.76 (95% CI: 0.71-0.82) for matairesinol, 0.87 (95% CI: 0.81-0.93) for secoisolariciresinol, 0.89 (95% CI: 0.83-0.95) for pinoresinol, and 0.89 (95% CI: 0.83-0.95) for lariciresinol (all P values for trend ≤0.003). Nonlinear relationships were found for total lignan, matairesinol, and secoisolariciresinol: the risk reduction plateaued at intakes above approximately 300 μg/d, 10 μg/d, and 100 μg/d, respectively (P < 0.01 for all nonlinearity). The inverse associations for total lignan intake appeared to be more apparent among participants with higher total fiber intake (P = 0.04 for interaction). In addition, lignan intake was more strongly associated with plasma concentrations of enterolactone when fiber intake was higher.

Increased long-term intake of lignans was associated with a significantly lower risk of total CHD in both men and women. Possible synergistic effects may exist between lignan and fiber intake in relation to CHD risk reduction, possibly through enhancing the production of enterolignans.

Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas, meglinides), alpha-glucosidase inhibitors, and the newest incretin-based therapies and sodium-glucose co-transporter 2 inhibitors. However, their long-term application can cause many harmful side effects, emphasising the importance of the using natural therapeutic products. Natural health substances including non-flavonoid polyphenols (e.g., resveratrol, curcumin, tannins, and lignans), flavonoids (e.g., anthocyanins, epigallocatechin gallate, quercetin, naringin, rutin, and kaempferol), plant fruits, vegetables and other products (e.g., garlic, green tea, blackcurrant, rowanberry, bilberry, strawberry, cornelian cherry, olive oil, sesame oil, and carrot) may be a safer alternative to primary pharmacological therapy. They are recommended as food supplements to prevent and/or ameliorate T2DM-related complications. In the advanced stage of T2DM, the combination therapy of synthetic agents and natural compounds with synergistic interactions makes the treatment more efficient. In this review, both pharmaceutical drugs and selected natural products, as well as combination therapies, are characterized. Mechanisms of their action and possible negative side effects are also provided.

Diabetes is a highly prevalent metabolic disease that has emerged as a global challenge due to its increasing prevalence and lack of sustainable treatment. Diabetic kidney disease (DKD), which is one of the most frequent and severe microvascular complications of diabetes, is difficult to treat with contemporary glucose-lowering medications. The gut microbiota plays an important role in human health and disease, and its metabolites have both beneficial and harmful effects on vital physiological processes. In this review, we summarize the current findings regarding the role of gut microbial metabolites in the development and progression of DKD, which will help us better understand the possible mechanisms of DKD and explore potential therapeutic approaches for DKD.

A healthy gut microbiota (GM) is paramount for a healthy lifestyle. Alterations of the GM have been involved in the aetiology of several chronic diseases, including obesity and type 2 diabetes, as well as cardiovascular and neurodegenerative diseases. In pathological conditions, the diversity of the GM is commonly reduced or altered, often toward an increased Firmicutes/Bacteroidetes ratio. The colonic fermentation of dietary fiber has shown to stimulate the fraction of bacteria purported to have beneficial health effects, acting as prebiotics, and to increase the production of short chain fatty acids, e.g. propionate and butyrate, while also improving gut epithelium integrity such as tight junction functionality. However, a variety of phytochemicals, often associated with dietary fiber, have also been proposed to modulate the GM. Many phytochemicals possess antioxidant and anti-inflammatory properties that may positively affect the GM, including polyphenols, carotenoids, phytosterols/phytostanols, lignans, alkaloids, glucosinolates and terpenes. Some polyphenols may act as prebiotics, while carotenoids have been shown to alter immunoglobulin A expression, an important factor for bacteria colonization. Other phytochemicals may interact with the mucosa, another important factor for colonization, and prevent its degradation. Certain polyphenols have shown to influence bacterial communication, interacting with quorum sensing. Finally, phytochemicals can be metabolized in the gut into bioactive constituents, e.g. equol from daidzein and enterolactone from secoisolariciresinol, while bacteria can use glycosides for energy. In this review, we strive to highlight the potential interactions between prominent phytochemicals and health benefits related to the GM, emphasizing their potential as adjuvant strategies for GM-related diseases.

Accumulating evidence has suggested that human gut microbiota metabolize certain dietary compounds and subsequently produce bioactive metabolites that may exert beneficial or harmful effects on coronary artery disease (CAD) risk.

This study examined the joint association of 2 gut microbiota metabolites, enterolactone and trimethylamine N-oxide (TMAO), that originate from intake of plant-based foods and animal products, respectively, in relation to CAD risk.

A prospective nested case-control study of CAD was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in the Nurses' Health Study II and the Health Professionals Follow-up Study. Plasma concentrations of enterolactone and TMAO, as well as choline and L-carnitine, were assayed among 608 CAD case-control pairs.

A high enterolactone and low TMAO profile was associated with better diet quality, especially higher intake of whole grains and fiber and lower intake of red meats, as well as lower concentrations of plasma triglycerides and C-reactive protein. Participants with a high enterolactone/low TMAO profile had a significantly lower risk of CAD: the multivariate-adjusted OR was 0.58 (95% CI: 0.38, 0.90), compared with participants with a low enterolactone/high TMAO profile. No significant interaction between enterolactone and TMAO on CAD risk was observed. Neither TMAO nor enterolactone alone were associated with CAD risk in pooled analyses. In women, a higher enterolactone concentration was significantly associated with a 54% lower CAD risk (P trend = 0.03), although the interaction by sex was not significant.

Our results show that a profile characterized by high enterolactone and low TMAO concentrations in plasma is linked to a healthful dietary pattern and significantly associated with a lower risk of CAD. Overall, these data suggest that, compared with individual markers, multiple microbiota-derived metabolites may facilitate better differentiation of CAD risk and characterization of the relations between diet, microbiota, and CAD risk.

Type 2 diabetes Mellitus (T2DM) prevalence has significantly increased worldwide in recent years due to population age, obesity, and modern sedentary lifestyles. The projections estimate that 439 million people will be diabetic in 2030. T2DM is characterized by an impaired β-pancreatic cell function and insulin secretion, hyperglycemia and insulin resistance, and recently the epigenetic regulation of β-pancreatic cells differentiation has been underlined as being involved. It is currently known that several bioactive molecules, widely abundant in plants used as food or infusions, have a key role in histone modification and DNA methylation, and constituted potential epidrugs candidates against T2DM. In this sense, in this review the epigenetic mechanisms involved in T2DM and protein targets are reviewed, with special focus in studies addressing the potential use of phytochemicals as epidrugs that prevent and/or control T2DM in vivo and in vitro. As main findings, and although some controversial results have been found, bioactive molecules with epigenetic regulatory function, appear to be a potential replacement/complementary therapy of pharmacological hypoglycemic drugs, with minimal side effects. Indeed, natural epidrugs have shown to prevent or delay the T2DM development and the morbidity associated to dysfunction of blood vessels, eyes and kidneys due to sustained hyperglycemia in T2DM patients.

Lifestyle factors, especially diet and nutrition, are currently regarded as essential avenues to decrease modern-day cardiometabolic disorders (CMD), including obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis. Many groups around the world attribute these trends, at least partially, to bioactive plant polyphenols given their anti-oxidant and anti-inflammatory actions. In fact, polyphenols can prevent or reverse the progression of disease processes through many distinct mechanisms. In particular, the crosstalk between polyphenols and gut microbiota, recently unveiled thanks to DNA-based tools and next generation sequencing, unravelled the central regulatory role of dietary polyphenols and their intestinal micro-ecology metabolites on the host energy metabolism and related illnesses. The objectives of this review are to: (1) provide an understanding of classification, structure, and bioavailability of dietary polyphenols; (2) underline their metabolism by gut microbiota; (3) highlight their prebiotic effects on microflora; (4) discuss the multifaceted roles of their metabolites in CMD while shedding light on the mechanisms of action; and (5) underscore their ability to initiate host epigenetic regulation. In sum, the review clearly documents whether dietary polyphenols and micro-ecology favorably interact to promote multiple physiological functions on human organism.