Akkermansia muciniphila

Akkermansia muciniphila Akkermansia muciniphila restored the efficacy of PD-1 blockade in an interleukin-12dependent manner by increasing the recruitment of CCR9 + CXCR3 + CD4+ T lymphocytes in tumoral microenvironment. From: Neoplasia, 2018 Related terms: Butyric AcidFirmicutesSerositisGut MicrobiotaGut MicrobiomeBacteroidetesMicrobiomeObesityBacterium View all Topics Download as PDF Set alert About this page Germ-Free Mouse Technology in Cardiovascular Research Alexandra Grill, Christoph Reinhardt, in Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications, 2019 Antiatherogenic Bacteria Apoe-deficient mice on a Western diet, which had a probiotic intervention with the gut bacterium Akkermansia muciniphila, showed a reduced atherosclerotic lesion size in the aortic root and reduced macrophage infiltration into aortic atherosclerotic lesions [94]. In this study, immunofluorescence analysis of aortic sections revealed increased staining for MCP-1 and ICAM-1 in the lesion endothelium, but the serum levels of total cholesterol, total triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were unchanged. Furthermore, it was demonstrated that intervention A. muciniphila decreased intestinal permeability and reduced serum LPS levels. In contrast, LPS infusion reversed the protective effects of A. muciniphila. The Gut Microbiome After Bariatric Surgery Camila Solar, ... Daniel Garrido, in Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications, 2019 Individual Markers of Obesity Another interesting taxon associated with a lean phenotype is Christensenella minuta. This microorganism from the Firmicutes phylum is able to reduce weight gain in a murine model of obesity [55]. Akkermansia muciniphila (phylum Verrucomicrobia) is a mucin-degrading bacteria, believed to contribute to intestinal health and glucose homeostasis [56,57]. It could represent 3%–5% of the bacterial community [58], mainly residing in the intestinal mucosa, an interface between the gut microbiome and host tissues [59]. Its abundance is negatively correlated with body mass [60–63]. Mice fed a high-fat diet [64] significantly reduced body weight and adiposity with such a supplement. An increase in the gene expression of adipocyte differentiation and lipid oxidation markers was observed, suggesting that A. muciniphila could regulate adipose tissue metabolism, and therefore fat storage [64]. In addition, fasting diet-induced hyperglycemia was reversed. It is thought that fermentation products derived from A. muciniphila mucin utilization could serve as energy source for other gut microbes, in a cross-feeding mechanism [65], which could have a positive effect on host metabolism [66,67]. Yet metaanalyses indicate that the association between obesity, BMI, and gut microbiome alterations is rather weak and of small effect. Obesity is a multifactorial disease, and there are differences in methodologies assessing gut microbiome composition and dietary patterns of the studied subjects [66,67]. Polyphenols and Intestinal Health Kristina B. Martinez, ... Michael K. McIntosh, in Nutrition and Functional Foods for Healthy Aging, 2017 Altering the Gut Microbiome and Improving Barrier Function Dietary polyphenols increase the abundance and diversity of microbial populations (Tuohy et al., 2012). For example, a decreased ratio of Firmicutes to Bacteroidetes and increased Lactobacilli, Bifidobacteria, Akkermansia muciniphila, Roseburia spp., Bacteroides, and Prevotella spp. attenuates gut dysbiosis and accompanying metabolic complications (Selma et al., 2009; Roopchand et al., 2013; Neyrinck et al., 2013; Anhe et al., 2014). High-fat-fed mice consuming Concord grape polyphenols had a robust increase in fecal A. muciniphila abundance, which is associated with improved gut barrier function (Roopchand et al., 2015). Mice fed high levels of fat and sugar but supplemented with proanthocyanidin-rich cranberry extract had an increased abundance of fecal A. muciniphila (Anhe et al., 2014), a commensal, mucin-degrading bacteria that play a key role in enhancing gut barrier function and reducing inflammation, insulin resistance, and adiposity (Everard et al., 2013). Polyphenol-rich grape juice increased the growth of the probiotics L. acidophilus and Lactobacillus delbruekii, and decreased the growth of Escherichia coli in vivo (Agte et al., 2010). Resveratrol supplementation of rats treated with dextran sulfate sodium (DSS) saw increased the levels of Lactobacilli and Bifidobacteria and improved colon mucosa architecture and inflammatory profile compared to controls (Larrosa et al., 2009b). Quercetin supplementation increased the growth of the probiotics L. acidophilus and L. plantarum (Yadav et al., 2011). Malvindin-3-glucoside increased the growth of Bifidobacterium and bacteria from the genuses Lactobacillus and Enterococcus (Hidalgo et al., 2012). Rats consuming polyphenol-rich grape fiber had increased cecum levels of Lactobacillus spp. (Pozuelo et al., 2012). Rats fed polyphenol-rich grape pomace juice had increased abundance of Lactobacillus and Bifidobacterium and decreased levels of secondary bile acids in their feces (Sembries et al., 2006). A reduction in secondary bile acids is positively associated with a reduced risk of GI cancers. Similarly, rats consuming red wine polyphenols had lower levels of Clostridium spp. and higher levels of Lactobacillus spp. (Dolara et al., 2005). In addition, adults consuming red wine had an increased abundance of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta, Blautia coccoides, and Eubacterium rectale groups compared to a baseline. The wine consumers had lower blood pressure, blood cholesterol, and CRP levels, which were positively correlated with Bifidobacteria (Queipo-Ortuño et al., 2012). Wine polyphenols increased the growth of the probiotic L. plantarum (Barrosa et al., 2014). Adult males given a proanthocyanin-rich extract had reduced fecal microbial populations of Bacteriodes, Clostridium, and Propionibacterium genuses and higher levels of the probiotics Bacteriodes, Lactobacillus, and Bifidobacterium (Cardona et al., 2013). High-fat diets cause gut dysbiosis, including increasing the abundance of deleterious sulfidogenic bacteria (Zhang et al., 2010; Shen et al., 2013, 2014) that produce hydrogen sulfide, a toxic gas that damages intestinal cells (Carbonero et al., 2012; Devkota et al., 2012). We demonstrated in butter-fed mice that table grape powder reduced adiposity, improved hepatic TG levels, modestly reduced WAT inflammatory gene expression, and lowered the cecum levels of deleterious sulfidogenic bacteria while tending to increase the abundance of A. muciniphila and Allobaculum in the proximal colon and cecum (Baldwin et al., 2016). In a follow-up study, we examined the impact of a polyphenol-rich, extractable fraction from table grape powder in mice fed a high-fat, American-type diet. The extractable fraction was rich in polyphenols, particularly anthocyanins and proanthocyanidins. The polyphenol-rich fraction attenuated diet-induced obesity, insulin resistance, steatosis, and chronic inflammation in WAT while improving gut barrier function and altering the bacterial structure of the cecum mucosa (Collins et al., 2016). Quercetin or trans-resveratrol supplementation of mice consuming a high-fat, high-sugar diet decreased body weights and insulin resistance compared to control mice (Etxeberria et al., 2015). Notably, quercetin-mediated improvements in systemic health were positively correlated with a decreased ratio of Firmicutes and Bacteroidetes and an abundance of deleterious bacteria (e.g., Erysipelotrichaceae, Bacillus, and Enubacterium cylindroides), thereby reducing diet-induced dysbiosis. Quercetin-mediated increases in the Bacteroidetes phylum were accompanied by increases in the Bacteriodaceae and Prevotellaceae families (Etxeberria et al., 2015), which have been previously reported to be decreased in high-fat-fed mice (Hildebrandt et al., 2009). Trans-resveratrol–fed mice had suppressed intestinal markers of inflammation and enhanced markers of barrier function but only alterations in gut microbial profiles. Gastrointestinal Microbiology in the Normal Host S.M. Finegold, in Encyclopedia of Microbiology (Third Edition), 2009 Studies of Individual or Special Groups Various groups have used a variety of methods to detect and sometimes quantitate special populations such as sulfate-reducing bacteria (Desulfovibrio specifically), Bifidobacterium, lactobacilli, Methanobrevibacter smithii, various clostridia, and a mucin-degrading bacterium known as Akkermansia muciniphila. Fecal flora studies have also been undertaken to study the relationship between intestinal bacteria (particularly bifidobacteria and lactobacilli) and aging, to note changes in bowel flora following administration of certain antimicrobial agents, to study microflora changes in relation to administration of lactulose and Saccharomyces boulardii, to study the GI tract microflora in certain diseases such as inflammatory bowel disease, Clostridium difficile-associated colitis or diarrhea, and autism, in comparison with control subjects, and to note flora involved in lactate formation and conversion to short-chain fatty acids. A fascinating paper on the symbiotic relationships between the human host and its GI tract microflora has been published. Their studies involved models of germ-free mice colonized with specific human microflora and comparisons of genomes of members of the bowel flora. One striking example of this research is documentation of the importance of Bacteroides thetaiotaomicron for the host and its highly developed environmental sensing apparatus and its capacity for retrieving polysaccharides from the gut lumen. These workers point out that polysaccharides are the most abundant biological polymer on Earth and that polysaccharide fermentation is an important activity in bacterial communities and contributes to ecologically important processes, including the recycling of carbon. Follow-up publications have attracted a great deal of interest; they describe an obesity-associated GI tract microbiome with a transmissible trait such that colonization of germ-free mice with an obese microbiota leads to significant increase in total body fat. Genetically obese mice have fewer Bacteroidetes and correspondingly more Firmicutes. Studies on 12 obese people showed similar proportions of these phyla and when they were placed on either a fat-restricted or a carbohydrate-restricted low calorie diet for 1 year showed an increase in Bacteroidetes and a decrease in Firmicutes, regardless of diet type. Remarkably, these changes were division-wide and not related to specific bacterial species. It has been pointed out that, in relation to dietary advice, consideration needs to be given to the role of carbohydrates in maintenance of gut health and function. Microbial fermentation releases as much as 10% of dietary energy in the form of short-chain fatty acids that act as a source of energy for host cells. Butyrate is a preferred energy source for colonic epithelial cells and has been implicated in the prevention of colitis and colorectal cancer. Counts of Roseburia spp. and Eubacterium rectale, and bifidobacteria to a lesser extent, decrease as carbohydrate intake decreases. This correlates with a decline in fecal butyrate. Diabetes Mellitus as a Risk Factor for Aging Ramfis Nieto-Martinez, ... Emiliano Corpas, in Endocrinology of Aging, 2021 Effects on Macrobiota42 Unlabelled Image Sign in to download full-size image Metformin modulates the abundance of specific gut bacteria to increase insulin sensitivity in the liver and adipose tissue. Metformin increases the abundance of mucus-producing species, short chain fatty acids (SCFA)-producing species Bifidobacterium adolescentis, Lactobacilli and Escherichia species. Metformin decreases Fusobacterium nucleatum and Firmicutes (e.g., Clostridium perfringens). Akkermansia muciniphila promotes the barrier function of the gut, limiting the leakage of endotoxins (e.g., LPS). In turn, lower systemic endotoxemia would benefit the liver and the adipose tissue by decreasing their inflammatory status, thus increasing insulin sensitivity. Similarly, decreased Clostridium clusters may alter the bile acid metabolism, with a net reduction of proinflammatory bile acids. Higher circulating levels of SCFAs per se also foster antiinflammatory and metabolism-improving effects through GPR41- and GPR43-mediated AMPK activation in multiple tissues. Lactobacilli promote GLP-1 release from L cells by increasing the apical expression of the SGLT1 cotransporter. The Microbiome in Health and Disease Takahiro Kageyama, ... Teruyuki Sano, in Progress in Molecular Biology and Translational Science, 2020 10 Cancer immune therapy and microbiota It has been considered that the development of cancer is a result of the defects of immunosurveillance.141 Immune checkpoint molecules such as CTLA4 and PD1 are expressed on activated T cells and serve as the negative regulators to prevent from further and unnecessary T cell activation.142,143 Therefore, Immune checkpoint inhibitors (ICIs) induce the activation of the immune system and then promote immune responses to the tumor.144 During this decade, the ICIs significantly have been expanded as the treatment of cancer patients. Recently, many reports suggested that gut microbiome plays an important role in determining the efficacy and toxicity of the ICIs therapies. The mechanisms of gut microbiome regulating the efficacy of ICIs treatments mainly can be divided into three parts describing below. 10.1 Microbiota and Th1 immune response on cancer immune therapy The first point is to enhance T helper 1 immune responses.145,146 In a mice model of sarcoma, the effect of CTLA-4 blockade was remarkably reduced in GF mice and SPF mice treated with broad-spectrum antibiotics.146 Furthermore, this defect was overcome by oral administration with Bacteroides fragilis or by adoptive transfer of Bacteroides fragilis-specific T cells.146 Oral feeding of Bacteroides fragilis promotes anti-CTLA-4 efficacy via upregulating Th1 immune responses in the tumor-draining lymph nodes and maturation of intratumoral dendritic cells. Besides, the correlation between clinical response to immune check inhibitors and the relative abundance of Akkermansia muciniphila was reported.145 Oral administration of Akkermansia muciniphila to GF C57BL/6 mice restored the compromised efficacy of PD-1 blockade observed after the fecal microbiome transplantation from cancer patients who didn't respond to immune check inhibitors.145 Moreover, the mechanism of immune modulation by Akkermansia muciniphila was suggested to induce dendritic cell secretion of IL-12, a Th1 cytokine.145 10.2 Microbiota and IFN-γ-producing CD8+ T cells on cancer immune therapy The second point is to induce IFN-γ-producing CD8+ T cells.147,148 Sivan et al. described that commensal Bifidobacterium was shown to promote the effect of anti-tumor by anti-PD-L1 in murine melanoma. Bifidobacterium-derived signals modulate the activation of DCs in the steady-state and enhance effector function of CD8+ T cells.147 Moreover, a consortium of 11 bacterial strains from human feces could induce IFN-γ-producing CD8+ T cells.148 Although the 11 strains localized to the caecum and colon, an increase in IFN-γ-producing CD8+ T cells frequency was observed in several other organs. The 11-strain mixture enhanced the efficacy of immune checkpoint inhibitors in syngeneic tumor mice models by an increase in the frequency of IFN-γ+ CD8 + tumor-infiltrating lymphocytes. 10.3 Microbiota and regulatory T cells on cancer immune therapy The third point is to lead to decreased peripherally derived regulatory T cells.149 Enterococcus faecium, Collinsella aerofaciens, Bifdobacterium adolesentis, and Parabacteroides merdae were increased in good responders to PD-1 blockade and reported to result in a decreased frequency of peripherally derived colonic regulatory T cells.149 It is easy to expect that decreased Treg cells in host will promote stronger immune response and result in the promotion of anti-tumor immunity. However, the loss of Treg cells raises the possibility of increasing autoreactive T cells. Although the treatment with ICIs has shown great clinical impact as a new class of cancer therapeutics, 68.7% of patients showed immunotoxic effects in various organs following ICI treatment in a key trial.150 Notably, 36.4% of these patients discontinued the therapy due to treatment-related immune adverse events such as autoimmune diseases and tissue inflammation. Because the systemic exposure to the ICI highly activates the immune system, resulting in anti-tumor immunity and the reduction of cancer, this stimulation might lead to undesirable non-specific T cell activation and causes inflammatory diseases, such as colitis, hepatitis, and pneumonitis.150,151 Once cancer patients show immunotoxicity in response to treatment, the ICI administration must be terminated or postponed.150 As we described in previous chapter, it has been reported that gut microbiota is associated with various autoimmune and inflammatory diseases such as RA, autism, MS, and IBD. Some of the commensal bacteria in our bodies can induce their antigen-specific T cell response. Thus, there would be a strong correlation among the microbiota, T cells, and ICI-induced toxicities. The Microbiome in Health and Disease Bree J. Tillett, Emma E. Hamilton-Williams, in Progress in Molecular Biology and Translational Science, 2020 10.1 Probiotics In rodents, introduction of single strains of commensal bacteria, including traditional and ‘next-generation’ probiotic strains, were able to prevent disease onset. For example, early administration of Clostridium butyricum and Lactobacillaceae prevented disease onset by reducing the activation of pro-inflammatory IL-1β cytokines while stimulating indoleamine 2,3-dioxygenase (IDO) and IL-33 which are protolerogenic.23,88 Oral gavage of Akkermansia muciniphila prevented diabetes accompanied by increased intestinal mucous production and increased Treg frequency.22 Lactobacillus johnsonii and Lactobacillis casei have also been shown to have disease protective effects.24,89 Human use of probiotics was investigated as an environmental protective factor in the TEDDY study, which found that probiotic supplementation in the first month of life reduced the risk of islet autoimmunity, but only in children with high-risk HLA genotypes.51 Administration of probiotics during this very early life period may aid in colonization of the probiotic strains, resulting in a more pronounced impact on disease progression. To date, few clinical trials have been completed investigating the potential for probiotics to mitigate disease risk or preserve residual beta cell function. A clinical study commenced in 2017 aims to assess the combined effects of 6-month supplementation with Lactobacillus rhamnosus and Bifidobacterium lactis on Beta-cell function in newly diagnosed children.90 A number of registered clinical trials include supplementation with Lactobacillus johnsonii or various combined treatments of Bifidobacterium and lactobacillus either in at-risk or newly diagnosed cohorts. They will investigate parameters such as intestinal permeability, progression to islet autoimmunity or c-peptide levels and other immune parameters. These studies will all take considerable time to complete and many factors such as the timing of the intervention and patient stratification (e.g., HLA type) must be considered. The Microbiome in Health and Disease Stephen L. Chan, in Progress in Molecular Biology and Translational Science, 2020 4 Discovery from translational studies and potential clinical applications Basic science has become an important part of clinical science to translate laboratory findings into clinical applications. Several metagenomic studies on cancer patients' gut bacteria have provided important clues to increase our understanding on the interaction between the bacteria and anti-tumor immunity. One of the studies by Routy et al.23 explored the association between fecal bacterial composition and response to ICI in RCC and NSCLC patients. The commensal most significantly associated with favorable tumor response to ICI and better survival outcomes was Akkermansia muciniphila, and both the bacteria species and diversity were also found different between responders and non-responders. Another metagenomic study by Gopalakrishnan et al.22 further explored the casual relationship between favorable microbiota and response to ICI. Through investigating the immune profiling of germ-free mice having been transplanted with stool from responding patients (R-FMT) and non-responding patients (NR-FMT) to anti-PD1 therapy, the study observed a higher density of CD8+ T-cell in tumor and increased number of CD45+ immune and CD8+ T cells in the gut of the R-FMT mice than those of NR-FMT mice. It seems favorable microbiota from responding patients is associated with enhanced systemic and local immune response. In addition to fecal microbiota transplantation, Routy et al.23 also treated the transplanted mice with PD-1 monoclonal antibody and examined changes of immune cells in the tumor. Interestingly, an increased formation of intratumoral granulomas and the increased CD4+/Foxp3+ ratios in tumors from animals co-treated with anti-PD1 agent and A. muciniphila were observed. Favorable microbes could probably enhance helper T cell function with the treatment of PD-1 blockade. According to the currently available evidence, favorable gut microbiota is considered able to enhance antigen presentation as “pseudovaccination,” enhance helper T cells functions and activate cytotoxic T cells. Despite the encouraging results of the above-mentioned studies, it is important to explore the feasibility of clinically using favorable microbiota to maximize the therapeutic effect of immunotherapy so as to benefit a wider group of patients. Indeed, with more extensive research to understand the profile of favorable gut bacteria, it may help clinicians identify and select patients more suitable to be treated by immunotherapy, and predict the treatment response and prognosis. For non-responders, bacteriotherapy may be prescribed to improve response or even overcome resistance to treatment. Should fecal microbiota transplantation be considered, it is critical to identify an optimal donor with particular target bacteria for transplantation. To date, several bacteria such as Bifidobacteria spp.7,25, A. muciniphilia23, and Bacteroides spp.26 were reported effective in improving anti-tumor immunity and controlling tumor growth in vivo (Table 1). Therefore, not only would a specific test be required to help identify an appropriate donor, selection of right bacteria is essential as bacteria may also play a role in inflammation-induced carcinogenesis. Nevertheless, modifying gut microbiota is a possible approach to restore patient's response to immunotherapy. Table 1. Potential gut microbiome to modulate immune checkpoint inhibitors. Bacteria Immunotherapy Effect References Bifidobacterium Anti-PD-1 Augmented T cell response 7 Akkermansia Anti-PD-1 Increased recruitment of CCR9+ CXCR3+ CD4+ T lymphocytes 23 Bifidobacterium Anti-PD-L1 Induced tumor-specific T-cell response and increased accumulation of CD8+ T cells within the tumor 25 Bacteroidales CTLA-4 blockade Decreased activation of splenic effector CD4+ T cells and tumor-infiltrating lymphocytes 26 Correlating the Gut Microbiome to Health and Disease T.M. Marques, ... W.M. de Vos, in The Gut-Brain Axis, 2016 Inflammatory Bowel Disease IBD comprises several disorders that affect the gastrointestinal tract and are characterized by chronic inflammation. The most common and well-studied diseases are Crohn’s disease and ulcerative colitis (UC). Microscopic colitis (MC), comprising lymphocytic colitis and collagenous colitis, is also regarded as IBD. The causes of IBD are still not understood. One hypothesis is that IBD is caused by an excessive immune response to the commensal gut microbiota in genetically susceptible subjects. In addition, a normal immune response to an altered microbiota is considered a putative pathophysiologic mechanism. Similar to IBS, several studies have been conducted to compare the intestinal microbiota in IBD in relation to healthy controls. A common result is a reduced microbial diversity in IBD (Ott et al., 2004). With regard to the microbiota composition, results are more divergent. However, it seems that a lower abundance of butyrate- or propionate-producing bacteria, such as Faecalibacterium prausnitzii (Sokol et al., 2008) and Akkermansia muciniphila (Png et al., 2010; Rajilić-Stojanović et al., 2013), respectively, is a common feature. The localization of the disease and the different pathophysiologic mechanisms behind each case make interpretation of the intestinal microbiota composition difficult. For instance, Willing et al. (2010) reported that two different phenotypes in Crohn’s disease, one localized in the ileum (ICD) and one localized in the colon (CCD), also resulted in a different microbiota composition. CCD patients had more Firmicutes compared with healthy subjects whereas ICD patients tended to have a lower abundance. Fusobacterium nucleatum is one of the bacterial strains that is supposed to play a role in the pathogenesis of IBD. This bacterium is more abundant in colonic biopsies of IBD patients than in healthy controls and the strains isolated from inflamed tissue in IBD patients are more invasive in vivo (Strauss et al., 2011). A critical question with regard to an altered microbiota composition in IBD is whether this microbial alteration either is secondary to the intestinal inflammation or an independent risk factor of IBD. Nevertheless, two recent clinical trials, applying FMT, have shown that exchanging the microbiota in UC patients may result in symptom improvement in at least a subset of the patients (Moayyedi et al., 2015; Rossen et al., 2015). It seems that success is dependent on repeated microbial transfers and is highly donor dependent. MC is a chronic inflammatory disorder that is mainly characterized by its microscopic appearance. Two different types of MC have been described according to their histological aberrations. Collagenous colitis and lymphocytic colitis show an increased density of lymphocytes in the lamina propria of the colonic mucosa, but collagenous colitis also features a thickened subepithelial collagen layer. The pathophysiology of MC is not well understood, but the combination of an aberrant immune response and an altered microbiota composition seems to play a major role. Fischer et al. (2015) has described this altered microbiota composition in patients with MC. They found that the feces of patients with MC was significantly depleted in Verruccomicrobia (Akkermansia spp.) compared with feces of healthy subjects. In addition, other species such as Bacteroides and Prevotella differed in MC patients compared with healthy controls; however, no statistical significance was reached. Polyphenols as Supplements in Foods and Beverages: Recent Discoveries and Health Benefits, an Update Andréa Pittelli Boiago GollückeRogério Correa PeresDaniel Araki RibeiroOdair Aguiar, in Polyphenols: Mechanisms of Action in Human Health and Disease (Second Edition), 2018 2 New Insights on Polyphenol Metabolism and Action Only recently, the role of microbiota in polyphenol metabolism has become known. In 2013, Cardona and colleagues published a review of the few studies available at that time, investigating the subject [8]. According to the authors, only 5%–10% of the dietary polyphenols is absorbed in the small intestine. The remainder accumulates in the large intestine where it becomes part of the enzymatic activities of the gut microbiota. These reactions result in the release of low molecular weight phenolic metabolites, which are then absorbed. For that reason, not only are the dietary differences interfering with specific polyphenol amounts in the blood, but also the individual microbiota composition. Moreover, it has been observed that polyphenols may also be able to modify gut microbiota composition, selecting the bacterial groups present in that environment. On that note, in 2015, Roopchand and colleagues [9] tested the hypothesis that the mechanisms of action of polyphenols intrinsically involve the gut microbiota. In order to test it, the authors fed a high-fat diet to mice, containing 1% grape polyphenols. The results showed that, apart from the physiological benefits (attenuation of inflammatory markers and of glucose intolerance), the grape polyphenol supplementation increased intestinal expression of genes involved in barrier function, protecting its integrity. Moreover, it was demonstrated that grape polyphenols considerably increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes. Prior studies have reported that this change in the microbiota was associated with protection against obesity and metabolic disease. With parallel findings in 2017, Novotny and colleagues [10] compared polyphenol levels in plasma of overweight/obese subjects with lean individuals before and after consumption of resveratrol, grape seed extract, and grape juice for 11 days. After consumption, plasma levels of catechin, epicatechin, and quercetin were higher in lean individuals but did not differ in the obese group, suggesting that obesity may affect polyphenol absorption or metabolism, maybe due to disparity in gut microbiota between lean and obese individuals. The ability of polyphenols to modulate fecal microbiota was successfully proposed by Moreno-Indias and colleagues in 2016 [11]. After a 30-day consumption of red wine (272 mL/day), changes in gut microbiota were observed in metabolic syndrome patients. Red wine polyphenols increased the number of fecal bifidobacteria and Lactobacillus, which are intestinal barrier protectors. At the same time, the presence of less desirable groups, such as the LPS (bacterial lipopolysaccharide) producers was diminished. The authors concluded that the decrease of LPS in the bloodstream may be due to the improvement of the intestinal barrier of the host, produced by the change in the gut microbiota promoted by red wine consumption. The result was an improvement in the insulin sensitivity and obesity in metabolic syndrome patients. In spite of the great efforts and the success in explaining the role of gut microbiota in metabolizing polyphenols (and of polyphenols in modulating the microbiota), there are gaps that need further elucidation. In 2017, Espín and colleagues [12] listed some of the future challenges of scientists in this field. They are: conduct more studies in humans (most of the reported results are in mice); investigate the stability of the newly discovered polyphenol metabolites; undertake clinical trials to verify health parameters after exposure to such metabolites; investigate the large interindividual variability in gut metabolism and attempt to correlate the specific polyphenol with both the gut microbiota responsible for its metabolism as well as the observed biological activities. Recommended publications Publication cover Cell Metabolism Journal Publication cover Gastroenterology Journal Publication cover Anaerobe Journal Publication cover Translational Research Journal