Gut microbiota in relation to frailty and clinical outcomes.

PURPOSE OF REVIEW: The gut microbiota is involved in several aspects of host health and disease, but its role is far from fully understood. This review aims to unveil the role of our microbial community in relation to frailty and clinical outcomes. RECENT FINDINGS: Ageing, that is the continuous process of physiological changes that begin in early adulthood, is mainly driven by interactions between biotic and environmental factors, also involving the gut microbiota. Indeed, our gut microbial counterpart undergoes considerable compositional and functional changes across the lifespan, and ageing-related processes may be responsible for - and due to - its alterations during elderhood. In particular, a dysbiotic gut microbiota in the elderly population has been associated with the development and progression of several age-related disorders. SUMMARY: Here, we first provide an overview of the lifespan trajectory of the gut microbiota in both health and disease. Then, we specifically focus on the relationship between gut microbiota and frailty syndrome, that is one of the major age-related burdens. Finally, examples of microbiome-based precision interventions, mainly dietary, prebiotic and probiotic ones, are discussed as tools to ameliorate the symptoms of frailty and its overlapping conditions (e.g. sarcopenia), with the ultimate goal of actually contributing to healthy ageing and hopefully promoting longevity.

Gut-derived metabolites mediating cognitive development in 5-year-old children: Early-life transplant in mice has lasting effects throughout adulthood.

The gut microbiota has been causally linked to cognitive development. We aimed to identify metabolites mediating its effect on cognitive development, and foods or nutrients related to most promising metabolites. Faeces from 5-year-old children (DORIAN-PISAC cohort, including 90 general population families with infants, 42/48 females/males, born in 2011-2014) were transplanted (FMT) into C57BL/6 germ-free mice. Children and recipient mice were stratified by cognitive phenotype, or based on protective metabolites. Food frequency questionnaires were obtained in children. Cognitive measurements in mice included five Y-maze tests until 23 weeks post-FMT, and (at 23 weeks) PET-CT for brain metabolism and radiodensity, and ultrasound-based carotid vascular indices. Children (faeces, urine) and mice (faeces, plasma) metabolome was measured by 1H NMR spectroscopy, and the faecal microbiota was profiled in mice by 16S rRNA amplicon sequencing. Cognitive scores of children and recipient mice were correlated. FMT-dependent modifications of brain metabolism were observed. Mice receiving FMT from high-cognitive or protective metabolite-enriched children developed superior cognitive-behavioural performance. A panel of metabolites, namely xanthine, hypoxanthine, formate, mannose, tyrosine, phenylalanine, glutamine, was found to mediate the gut-cognitive axis in donor children and recipient mice. Vascular indices partially explained the metabolite-to-phenotype relationships. Children's consumption of legumes, whole-milk yogurt and eggs, and intake of iron, zinc and vitamin D appeared to support protective gut metabolites. Overall, metabolites involved in inflammation, purine metabolism and neurotransmitter synthesis mediate the gut-cognitive axis, and holds promise for screening. The related dietary and nutritional findings offer leads to microbiota-targeted interventions for cognitive protection, with long-lasting effects.

Cooking, Digestion, and In Vitro Colonic Fermentation of Nigerian Wholegrains Affect Phenolic Acid Metabolism and Gut Microbiota Composition.

Wholegrains contain both fibre and phenolic acids (PAs), and their gastrointestinal modifications are critical for their bioavailability and bioactivity. We evaluated the modifications on the PA profile and gut microbiota composition of selected Nigerian wholegrains, following cooking and gastrointestinal digestion. Red fonio, red millet, red sorghum, and white corn were cooked, digested, and fermented using an in vitro colonic model. A total of 26 PA derivatives were quantified in soluble and bound fractions using Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) analysis. DNA samples were analysed using 16S rRNA amplicon sequencing to profile the microbiota composition. The results show that cooking and digestion significantly affected the levels of PAs in all grains (p ≤ 0.05) compared to raw grains. Colonic fermentation resulted in a peak of total soluble PAs at 4-6 h for red sorghum and white corn and at 24 h for red millet and red fonio. Enterobacteriaceae genera were the most abundant at 24 h in all grains studied. 3-hydroxybenzaldehyde correlated positively with the relative abundance of Dorea and the mucus-degrader bacteria Akkermansia (p ≤ 0.05), whereas hydroferulic acid and isoferulic acid levels correlated negatively with Oscillospira and Ruminococcus (p ≤ 0.05), respectively. Our data indicate that cooking, digestion, and colonic fermentation affect the release of bound PAs from wholegrains and, consequently, their metabolic conversion. Furthermore, PA fermentation in the gut is associated with potentially relevant changes in the microbiota. This in vitro study provides the basis for the design of an in vivo human intervention study that can confirm the trends herein observed but also assess the impact on health outcomes.

Multi-omics gut microbiome signatures in obese women: role of diet and uncontrolled eating behavior.

BACKGROUND: Obesity and related co-morbidities represent a major health challenge nowadays, with a rapidly increasing incidence worldwide. The gut microbiome has recently emerged as a key modifier of human health that can affect the development and progression of obesity, largely due to its involvement in the regulation of food intake and metabolism. However, there are still few studies that have in-depth explored the functionality of the human gut microbiome in obesity and even fewer that have examined its relationship to eating behaviors. METHODS: In an attempt to advance our knowledge of the gut-microbiome-brain axis in the obese phenotype, we thoroughly characterized the gut microbiome signatures of obesity in a well-phenotyped Italian female cohort from the NeuroFAST and MyNewGut EU FP7 projects. Fecal samples were collected from 63 overweight/obese and 37 normal-weight women and analyzed via a multi-omics approach combining 16S rRNA amplicon sequencing, metagenomics, metatranscriptomics, and lipidomics. Associations with anthropometric, clinical, biochemical, and nutritional data were then sought, with particular attention to cognitive and behavioral domains of eating. RESULTS: We identified four compositional clusters of the gut microbiome in our cohort that, although not distinctly associated with weight status, correlated differently with eating habits and behaviors. These clusters also differed in functional features, i.e., transcriptional activity and fecal metabolites. In particular, obese women with uncontrolled eating behavior were mostly characterized by low-diversity microbial steady states, with few and poorly interconnected species (e.g., Ruminococcus torques and Bifidobacterium spp.), which exhibited low transcriptional activity, especially of genes involved in secondary bile acid biosynthesis and neuroendocrine signaling (i.e., production of neurotransmitters, indoles and ligands for cannabinoid receptors). Consistently, high amounts of primary bile acids as well as sterols were found in their feces. CONCLUSIONS: By finding peculiar gut microbiome profiles associated with eating patterns, we laid the foundation for elucidating gut-brain axis communication in the obese phenotype. Subject to confirmation of the hypotheses herein generated, our work could help guide the design of microbiome-based precision interventions, aimed at rewiring microbial networks to support a healthy diet-microbiome-gut-brain axis, thus counteracting obesity and related complications.

Early-life gut microbiota and neurodevelopment in preterm infants: any role for Bifidobacterium?

Despite the well-recognized importance of proper gut microbiota assembly for the child's future health, the connections between the early-life gut microbiota and neurocognitive development in humans have not been thoroughly explored so far. In this pilot observational study, we aimed to unveil the relation between dynamic succession of the gut microbiota in very low birth weight infants during the first month of life and their neurodevelopment, assessed at 24-month corrected age. According to our data, the early-life gut microbiota of preterm infants with normal vs. impaired neurodevelopment followed distinct temporal trajectories with peculiar compositional rearrangements. In this context, early Bifidobacterium deficiency appears to be a negative biomarker of adverse neurological outcomes. CONCLUSION: Our data might pave the way for future in-depth studies focusing on the potential impact of bifidobacteria or specific microbiota patterns on neonatal neurodevelopment and lay the foundation for microbiome-based clinical practices to modulate altered profiles and improve long-term health. WHAT IS KNOWN: • Preterm infants are at increased risk for adverse neurological outcomes and gut microbiota dysbiosis. • The gut microbiota and the nervous system share critical developmental windows in early life. WHAT IS NEW: • The absence of Bifidobacterium at 30 days of life in preterm infants is associated with neurodevelopmental impairment in early childhood. • The administration of Bifidobacterium strains could promote optimal neurocognitive development in fragile infants.

Fecal Microbiota Monitoring in Elite Soccer Players Along the 2019-2020 Competitive Season.

Physical exercise affects the human gut microbiota, which in turn influences athletes' performance. The current understanding of how the microbiota of professional athletes changes along with different phases of training is sparse. We aim to characterize the fecal microbiota in elite soccer players along with different phases of a competitive season using 16 S rRNA gene sequencing. Fecal samples were collected after the summer off-season period, the pre-season retreat, the first half of the competitive season, and the 8 weeks of COVID-19 lockdown that interrupted the season 2019-2020. According to our results, the gut microbiota of professional athletes changes along with the phases of the season, characterized by different training, diet, nutritional surveillance, and environment sharing. Pre-season retreat, during which nutritional surveillance and exercise intensity were at their peak, caused a decrease in bacterial groups related to unhealthy lifestyle and an increase in health-promoting symbionts. The competitive season and forced interruption affected other features of the athletes' microbiota, i.e., bacterial groups that respond to dietary fiber load and stress levels. Our longitudinal study, focusing on one of the most followed sports worldwide, provides baseline data for future comparisons and microbiome-targeting interventions aimed at developing personalized training and nutrition plans for performance maximization.

Influence of a High-Impact Multidimensional Rehabilitation Program on the Gut Microbiota of Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high-impact multidimensional rehabilitation program (B-HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B-HIPE resulted in modulation of the MS-typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short-chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro-inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients' quality of life.

An In Vitro Pilot Fermentation Study on the Impact of Chlorella pyrenoidosa on Gut Microbiome Composition and Metabolites in Healthy and Coeliac Subjects.

The response of a coeliac and a healthy gut microbiota to the green algae Chlorella pyrenoidosa was evaluated using an in vitro continuous, pH controlled, gut model system, which simulated the human colon. The effect of C. pyrenoidosa on the microbial structure was determined by 16S rRNA gene sequencing and inferred metagenomics, whereas the metabolic activitywas determined by1H-nuclear magnetic resonancespectroscopic analysis. The addition of C. pyrenoidosa significantly increased the abundance of the genera Prevotella, Ruminococcus and Faecalibacterium in the healthy donor, while an increase in Faecalibacterium, Bifidobacterium and Megasphaera and a decrease in Enterobacteriaceae were observed in the coeliac donor. C. pyrenoidosa also altered several microbial pathways including those involved in short-chain fatty acid (SCFA) production. At the metabolic level, a significant increase from baseline was seen in butyrate and propionate (p < 0.0001) in the healthy donor, especially in vessels 2 and 3. While acetate was significantly higher in the healthy donor at baseline in vessel 3 (p < 0.001) compared to the coeliac donor, this was markedly decreased after in vitro fermentation with C. pyrenoidosa. This is the first in vitro fermentation study of C. pyrenoidosa and human gut microbiota, however, further in vivo studies are needed to prove its efficacy.

Impact of lignans in oilseed mix on gut microbiome composition and enterolignan production in younger healthy and premenopausal women: an in vitro pilot study.

BACKGROUND: Dietary lignans belong to the group of phytoestrogens together with coumestans, stilbenes and isoflavones, and themselves do not exhibit oestrogen-like properties. Nonetheless, the gut microbiota converts them into enterolignans, which show chemical similarity to the human oestrogen molecule. One of the richest dietary sources of lignans are oilseeds, including flaxseed. The aim of this pilot study was to determine the concentration of the main dietary lignans in an oilseed mix, and explore the gut microbiota-dependent production of enterolignans for oestrogen substitution in young and premenopausal women. The oilseed mix was fermented in a pH-controlled batch culture system inoculated with women's faecal samples. The lignan content and enterolignan production were measured by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and the faecal-derived microbial communities were profiled by 16S rRNA gene-based next-generation sequencing. RESULTS: In vitro batch culture fermentation of faecal samples inoculated with oilseed mix for 24 h resulted in a substantial increase in enterolactone production in younger women and an increase in enterodiol in the premenopausal group. As for the gut microbiota, different baseline profiles were observed as well as different temporal dynamics, mainly related to Clostridiaceae, and Klebsiella and Collinsella spp. CONCLUSIONS: Despite the small sample size, our pilot study revealed that lignan-rich oilseeds could strongly influence the faecal microbiota of both younger and premenopausal females, leading to a different enterolignan profile being produced. Further studies in larger cohorts are needed to evaluate the long-term effects of lignan-rich diets on the gut microbiota and find out how enterolactone-producing bacterial species could be increased. Diets rich in lignans could potentially serve as a safe supplement of oestrogen analogues to meet the cellular needs of endogenous oestrogen and deliver numerous health benefits, provided that the premenopausal woman microbiota is capable of converting dietary precursors into enterolignans.

Characterization of the human DNA gut virome across populations with different subsistence strategies and geographical origin.

It is a matter of fact that the human gut microbiome also includes a non-bacterial fraction represented by eukaryotic cells and viruses. To further explore the gut microbiome variation in human populations, here we characterized the human DNA viral community from publicly available gut metagenome data sets from human populations with different geographical origin and lifestyle. In particular, such data sets encompass microbiome information from two western urban societies (USA and Italy), as well as two traditional hunter-gatherer communities (the Hadza from Tanzania and Matses from Peru) and one pre-agricultural tribe (Tunapuco from Peru). Our results allowed for the first taxonomic reconstruction of the complex viral metacommunities within the human gut. The core virome structure included herpesviruses, papillomaviruses, polyomaviruses, adenoviruses and anelloviruses. Using Random Forests and a co-occurrence analysis approach, we identified the viruses that distinguished populations according to their geographical origin and/or lifestyle. This paves the way for new research aimed at investigating the biological role of the gut virome in human physiology, and the importance of our viral counterpart in the microbiome-host co-evolutionary process.

Early-life gut microbiota and neurodevelopment in preterm infants: a narrative review.

Infants born preterm are at a high risk of both gut microbiota (GM) dysbiosis and neurodevelopmental impairment. While the link between early dysbiosis and short-term clinical outcomes is well established, the relationship with long-term infant health has only recently gained interest. Notably, there is a significant overlap in the developmental windows of GM and the nervous system in early life. The connection between GM and neurodevelopment was first described in animal models, but over the last decade a growing body of research has also identified GM features as one of the potential mediators for human neurodevelopmental and neuropsychiatric disorders. In this narrative review, we provide an overview of the developing GM in early life and its prospective relationship with neurodevelopment, with a focus on preterm infants. Animal models have provided evidence for emerging pathways linking early-life GM with brain development. Furthermore, a relationship between both dynamic patterns and static features of the GM during preterm infants' early life and brain maturation, as well as neurodevelopmental outcomes in early childhood, was documented. Future human studies in larger cohorts, integrated with studies on animal models, may provide additional evidence and help to identify predictive biomarkers and potential therapeutic targets for healthy neurodevelopment in preterm infants.

Microbiota-gut-brain axis and ketogenic diet: how close are we to tackling epilepsy?

The microbiota-gut-brain axis refers to the intricate bidirectional communication between commensal microorganisms residing in the digestive tract and the central nervous system, along neuroendocrine, metabolic, immune, and inflammatory pathways. This axis has been suggested to play a role in several neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and epilepsy, paving the way for microbiome-based intervention strategies for the mitigation and treatment of symptoms. Epilepsy is a multifaceted neurological condition affecting more than 50 million individuals worldwide, 30% of whom do not respond to conventional pharmacological therapies. Among the first-hand microbiota modulation strategies, nutritional interventions represent an easily applicable option in both clinical and home settings. In this narrative review, we summarize the mechanisms underlying the microbiota-gut-brain axis involvement in epilepsy, discuss the impact of antiepileptic drugs on the gut microbiome, and then the impact of a particular dietary pattern, the ketogenic diet, on the microbiota-gut-brain axis in epileptic patients. The investigation of the microbiota response to non-pharmacological therapies is an ever-expanding field with the potential to allow the design of increasingly accessible and successful intervention strategies.

A personalized diet intervention improves depression symptoms and changes microbiota and metabolite profiles among community-dwelling older adults.

Introduction: The impact of diet on mental well-being and gut microorganisms in humans is well recognized. However, research on the connections between food nutrients, gut microbiota, and mental health remains limited. To address this, the present study aimed to assess the effects of a personalized diet, based on individual needs and aligned with the Mediterranean diet principles, on depression symptoms, quality of life, nutritional intake, and gut microbiota changes among older adults living in the community. Methods: The intervention involved regular visits from a registered dietitian, who provided tailored dietary recommendations. During the 6-month study, participants completed questionnaires to evaluate their depression levels, quality of life, and dietary habits. Additionally, they provided stool samples for analysis of gut microbiota and metabolites. Results: The results demonstrated that the personalized dietary intervention reduced depression symptoms and improved the quality of life among older adults. Furthermore, significant changes in the intake of certain nutrients, such as folate, lutein, zeaxanthin, EPA, and DHA, were observed following the intervention. Moreover, the intervention was associated with increased diversity in the gut microbiome and reduced total short-chain fatty acids, the main metabolites produced by gut microorganisms. The study also revealed correlations between food nutrients, gut microbiota, and mental health parameters. Discussion: In conclusion, this research highlights the potential advantages of personalized dietary interventions in managing depression and enhancing overall well-being among older populations. It also sheds light on the role of gut microbiota and its metabolites in these effects. The findings offer valuable insights into the significance of nutrition and gut health for mental well-being in older adults.

Cerrado and Pantanal fruit flours affect gut microbiota composition in healthy and post-COVID-19 individuals: an in vitro pilot fermentation study.

Cerrado and Pantanal plants can provide fruits with high nutritional value and antioxidants. This study aims to evaluate four fruit flours (from jatobá pulp, cumbaru almond, bocaiuva pulp and bocaiuva almond) and their effects on the gut microbiota in healthy (HD) and post-COVID-19 individuals (PC). An in vitro batch system was carried out, the microbiota was analysed by 16S rRNA amplicon sequencing and the short-chain fatty acids ratio was determined. Furthermore, the effect of jatobá pulp flour oil (JAO) on cell viability, oxidative stress and DNA damage was investigated in a myelo-monocytic cell line. Beyond confirming a microbiota imbalance in PC, we identified flour-specific effects: (i) reduction of Veillonellaceae with jatobá extract in PC samples; (ii) decrease in Akkermansia with jatoba and cumbaru flours; (iii) decreasing trend of Faecalibacterium and Ruminococcus with all flours tested, with the exception of the bocaiuva almond in HD samples for Ruminococcus and (iv) increase in Lactobacillus and Bifidobacterium in PC samples with bocaiuva almond flour. JAO displayed antioxidant properties protecting cells from daunorubicin-induced cytotoxicity, oxidative stress and DNA damage. The promising microbiota-modulating abilities of some flours and the chemopreventive effects of JAO deserve to be further explored in human intervention studies.

Gut microbiota resilience and recovery after anticancer chemotherapy.

Although research on the role of the gut microbiota (GM) in human health has sharply increased in recent years, what a "healthy" gut microbiota is and how it responds to major stressors is still difficult to establish. In particular, anticancer chemotherapy is known to have a drastic impact on the microbiota structure, potentially hampering its recovery with serious long-term consequences for patients' health. However, the distinguishing features of gut microbiota recovery and non-recovery processes are not yet known. In this narrative review, we first investigated how gut microbiota layouts are affected by anticancer chemotherapy and identified potential gut microbial recovery signatures. Then, we discussed microbiome-based intervention strategies aimed at promoting resilience, i.e., the rapid and complete recovery of a healthy gut microbial network associated with a better prognosis after such high-impact pharmacological treatments.

Levofloxacin prophylaxis and parenteral nutrition have a detrimental effect on intestinal microbial networks in pediatric patients undergoing HSCT.

The gut microbiome (GM) has shown to influence hematopoietic stem cell transplantation (HSCT) outcome. Evidence on levofloxacin (LVX) prophylaxis usefulness before HSCT in pediatric patients is controversial and its impact on GM is poorly characterized. Post-HSCT parenteral nutrition (PN) is oftentimes the first-line nutritional support in the neutropenic phase, despite the emerging benefits of enteral nutrition (EN). In this exploratory work, we used a global-to-local networking approach to obtain a high-resolution longitudinal characterization of the GM in 30 pediatric HSCT patients receiving PN combined with LVX prophylaxis or PN alone or EN alone. By evaluating the network topology, we found that PN, especially preceded by LVX prophylaxis, resulted in a detrimental effect over the GM, with low modularity, poor cohesion, a shift in keystone species and the emergence of modules comprising several pathobionts, such as Klebsiella spp., [Ruminococcus] gnavus, Flavonifractor plautii and Enterococcus faecium. Our pilot findings on LVX prophylaxis and PN-related disruption of GM networks should be considered in patient management, to possibly facilitate prompt recovery/maintenance of a healthy and well-wired GM. However, the impact of LVX prophylaxis and nutritional support on short- to long-term post-HSCT clinical outcomes has yet to be elucidated.

Gut microbiome-micronutrient interaction: The key to controlling the bioavailability of minerals and vitamins?

Micronutrients, namely, vitamins and minerals, are necessary for the proper functioning of the human body, and their deficiencies can have dramatic short- and long-term health consequences. Among the underlying causes, certainly a reduced dietary intake and/or poor absorption in the gastrointestinal tract play a key role in decreasing their bioavailability. Recent evidence from clinical and in vivo studies suggests an increasingly important contribution from the gut microbiome. Commensal microorganisms can in fact regulate the levels of micronutrients, both by intervening in the biosynthetic processes and by modulating their absorption. This short narrative review addresses the pivotal role of the gut microbiome in influencing the bioavailability of vitamins (such as A, B, C, D, E, and K) and minerals (calcium, iron, zinc, magnesium, and phosphorous), as well as the impact of these micronutrients on microbiome composition and functionality. Personalized microbiome-based intervention strategies could therefore constitute an innovative tool to counteract micronutrient deficiencies by modulating the gut microbiome toward an eubiotic configuration capable of satisfying the needs of our organism, while promoting general health.

Age-related diseases, therapies and gut microbiome: A new frontier for healthy aging.

The gut microbiome is undoubtedly a key modulator of human health, which can promote or impair homeostasis throughout life. This is even more relevant in old age, when there is a gradual loss of function in multiple organ systems, related to growth, metabolism, and immunity. Several studies have described changes in the gut microbiome across age groups up to the extreme limits of lifespan, including maladaptations that occur in the context of age-related conditions, such as frailty, neurodegenerative diseases, and cardiometabolic diseases. The gut microbiome can also interact bi-directionally with anti-age-related disease therapies, being affected and in turn influencing their efficacy. In this framework, the development of integrated microbiome-based intervention strategies, aimed at favoring a eubiotic configuration and trajectory, could therefore represent an innovative approach for the promotion of healthy aging and the achievement of longevity.

Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties.

Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, and it is generally reported that a substantial elevation of their plasma concentration can only be achieved when they are consumed at pharmacological levels. Even so, positive effects have been reported associated with an average dietary consumption of several nutraceutical classes, meaning that the primary compound might not be solely responsible for all the biological effects. The in vivo activities of such biomolecules might be carried out by metabolites derived from gut microbiota fermentative transformation. This review discusses the structure and properties of phenolic nutraceuticals (i.e., polyphenols and tannins) and the putative role of the human gut microbiota in influencing the beneficial effects of such compounds.