Host-microbial crosstalk relies on "tuft" love.

How commensals influence intestinal immunity is incompletely understood. In this issue of Immunity, Eshleman et al. demonstrate that microbiota-derived butyrate restrains tuft cell development via HDAC3 modulation in intestinal epithelial cells, showing how microbial metabolites impact intestinal type 2 immunity.

The Chelating Ability of Plant Polyphenols Can Affect Iron Homeostasis and Gut Microbiota.

In the past decades, many studies have widely examined the effects of dietary polyphenols on human health. Polyphenols are well known for their antioxidant properties and for their chelating abilities, by which they can be potentially employed in cases of pathological conditions, such as iron overload. In this review, we have highlighted the chelating abilities of polyphenols, which are due to their structural specific sites, and the differences for each class of polyphenols. We have also explored how the dietary polyphenols and their iron-binding abilities can be important in inflammatory/immunomodulatory responses, with a special focus on the involvement of macrophages and dendritic cells, and how they might contribute to reshape the gut microbiota into a healthy profile. This review also provides evidence that the axes "polyphenol-iron metabolism-inflammatory responses" and "polyphenol-iron availability-gut microbiota" have not been very well explored so far, and the need for further investigation to exploit such a potential to prevent or counteract pathological conditions.

Deletion of TNF in Winnie-APCMin/+ Mice Reveals Its Dual Role in the Onset and Progression of Colitis-Associated Colorectal Cancer.

Colorectal cancer (CRC) is among the best examples for depicting the relationship between inflammation and cancer. The introduction of new therapeutics targeting inflammatory mediators showed a marked decrease in the overall risk of CRC, although their chemopreventive potential is still debated. Specifically, a monoclonal antibody that blocks tumor necrosis factor (TNF), infliximab, increases CRC risk in inflammatory bowel disease patients. To address the axis between TNF and CRC development and progression, we depleted the Tnf from our previously established murine model of colitis-associated cancer (CAC), the Winnie-ApcMin/+ line. We characterized the new Winnie-APCMin/+-TNF-KO line through macroscopical and microscopical analyses. Surprisingly, the latter demonstrated that the deletion of Tnf in Winnie-ApcMin/+ mice resulted in an initial reduction in dysplastic lesion incidence in 5-week-old mice followed by a faster disease progression at 8 weeks. Histological data were confirmed by the molecular profiling obtained from both the real-time PCR analysis of the whole tissue and the RNA sequencing of the macrodissected tumoral lesions from Winnie-APCMin/+-TNF-KO distal colon at 8 weeks. Our results highlight that TNF could exert a dual role in CAC, supporting the promotion of neoplastic lesions onset in the early stage of the disease while inducing their reduction during disease progression.

Extra virgin olive oil extract rich in secoiridoids induces an anti-inflammatory profile in peripheral blood mononuclear cells from obese children.

Obesity represents an important public health challenge of the twenty first century reaching epidemic proportions worldwide; this is especially true for the pediatric population. In this context, bioactive compounds from foods are crucial to counteract chronic inflammation as a typical feature of obesity. In particular, extra virgin olive oil (EVOO) is one of the most important functional foods exerting, among others, an anti-inflammatory activity not only due to its major (monounsaturated fatty acids) but also to its minor (phenolics) components, as reported in the last years. However, only a limited number of studies were performed on pediatric population, and even fewer are those focusing on EVOO phenolics that investigate the correlation of the chemical characterization with the biological function. Thus, starting from our in vitro data identifying an EVOO chemical profile characterized by a high content of secoiridoids correlating with an anti-inflammatory effect, we studied the ability of an EVOO extract with the same chemical profile to retain this function ex vivo. Specifically, peripheral blood mononuclear cells (PBMCs) collected from obese children were treated with EVOO and olive oil extracts, characterized by a low polyphenol content, to study the ability of secoiridoids to dampen the inflammatory response. A reduction of pro-inflammatory CD14+CD16+ monocytes was detected by cytofluorimetric analysis when PBMCs were treated with EVOO as compared to olive oil extracts. According to this, a down modulation of CCL2 and CCL4 chemokines involved in the recruitment of inflammatory cells, was reported in the supernatants of EVOO relative to olive oil extracts treated PBMCs. Moreover, a high-throughput gene expression analysis revealed that PBMCs molecular profile from obese children is greatly modulated after the treatment with EVOO extract in terms of metabolic and inflammatory pathways. Importantly, some of the significantly modulated genes were involved in the pathways promoting the development of severe obesity. Overall, our ex vivo data demonstrated the ability of EVOO to reduce the inflammatory milieu of PBMCs from obese children both at protein and molecular levels. Of note, a good correlation between the EVOO chemical profile and the biological modulations in terms of anti-inflammatory activity was reported.

The Tower of Babel of Pharma-Food Study on Extra Virgin Olive Oil Polyphenols.

Much research has been conducted to reveal the functional properties of extra virgin olive oil polyphenols on human health once EVOO is consumed regularly as part of a balanced diet, as in the Mediterranean lifestyle. Despite the huge variety of research conducted, only one effect of EVOO polyphenols has been formally approved by EFSA as a health claim. This is probably because EFSA's scientific opinion is entrusted to scientific expertise about food and medical sciences, which adopt very different investigative methods and experimental languages, generating a gap in the scientific communication that is essential for the enhancement of the potentially useful effects of EVOO polyphenols on health. Through the model of the Tower of Babel, we propose a challenge for science communication, capable of disrupting the barriers between different scientific areas and building bridges through transparent data analysis from the different investigative methodologies at each stage of health benefits assessment. The goal of this work is the strategic, distinctive, and cost-effective integration of interdisciplinary experiences and technologies into a highly harmonious workflow, organized to build a factual understanding that translates, because of trade, into health benefits for buyers, promoting EVOOs as having certified health benefits, not just as condiments.

Interleukin 1ß Blockade Reduces Intestinal Inflammation in a Murine Model of Tumor Necrosis Factor-Independent Ulcerative Colitis.

BACKGROUND & AIMS: Inflammatory bowel diseases are multifactorial diseases commonly treated with either immunomodulatory drugs or anti-tumor necrosis factor (TNF). Currently, failure to respond to anti-TNF therapy (assessed no earlier than 8-12 weeks after starting treatment) occurs in 20%-40% of patients enrolled in clinical trials and in 10%-20% in clinical practice. Murine models of inflammatory bowel disease provide important tools to better understand disease mechanism(s). In this context and among the numerous models available, Winnie-TNF-knockout (KO) mice recently were reported to show characteristics of ulcerative colitis (UC) that are independent of TNF, and with increased interleukin (IL)1ß production. METHODS: Herein, the efficacy of recombinant IL1-receptor antagonist (anakinra) administration was evaluated in Winnie-TNF-KO mice, used as a UC model of primary anti-TNF nonresponders. RESULTS: We analyzed gut mucosal biopsy specimens and circulating cytokine profiles of a cohort of 30 UC patients; approximately 75% of primary nonresponders were characterized by abundant IL1ß in both the serum and local intestinal tissues. In Winnie-TNF-KO mice, administration of anakinra efficiently reduced the histologic score of the distal colon, which represents the most common site of inflammation in Winnie mice. Furthermore, among lamina propria and mesenteric lymph node-derived T cells, interferon γ-expressing CD8+ T cells were reduced significantly after anakinra administration. CONCLUSIONS: Our study provides new insight and alternative approaches to treat UC patients, and points to anti-IL1 strategies (ie, anakinra) that may be a more effective therapeutic option for primary nonresponders to anti-TNF therapy.

Correlation between Chemical Characterization and Biological Activity: An Urgent Need for Human Studies Using Extra Virgin Olive Oil.

Extra virgin olive oil (EVOO) is one of the most important functional foods from the Mediterranean Diet due to its beneficial effect on human health in terms of prevention and/or adjuvant treatment of different pathological conditions. The positive effects linked to EVOO consumption are not only due to its major (monounsaturated fatty acids), but also to its minor components (phenolics), whose roles were greatly re-evaluated in the last years. Notwithstanding the huge number of studies demonstrating the antioxidant, anti-inflammatory and anti-cancer properties of EVOO's phenolic compounds, only their antioxidant ability was supported by a Health Claim. However, to bear the claim, a specific phenolic composition is needed, thus reinforcing the need to correlate the characterization of the phenolic compounds to their biological activity. In fact, although the chemical characterization of VOO's phenolic compounds was extensively studied, its correlation with biological effects is only partially investigated; this is especially true for human studies. This review aims to study the correlation between the chemical characterization of EVOO's phenolics and the biological effects in terms of antioxidant/anti-inflammatory potentials, with a focus on the human studies and the relative concern on getting a specific Health Claim.

Genetic, epigenetic and enviromental influencing factors on the regulation of precocious and delayed puberty.

The pubertal development onset is controlled by a network of genes that regulate the gonadotropin releasing hormone (GnRH) pulsatile release and the subsequent increase of the circulating levels of pituitary gonadotropins that activate the gonadal function. Although the transition from pre-pubertal condition to puberty occurs physiologically in a delimited age-range, the inception of pubertal development can be anticipated or delayed due to genetic and epigenetic changes or environmental conditions. Most of the genetic and epigenetic alterations concern genes which encode for kisspeptin, GnRH, LH, FSH and their receptor, which represent crucial factors of the hypothalamic-pituitary-gonadal (HPG) axis. Recent data indicate a central role of the epigenome in the regulation of genes in the hypothalamus and pituitary that could mediate the flexibility of pubertal timing. Identification of epigenetically regulated genes, such as Makorin ring finger 3 (MKRN3) and Delta-like 1 homologue (DLK1), respectively responsible for the repression and the activation of pubertal development, provides additional evidence of how epigenetic variations affect pubertal timing. This review aims to investigate genetic, epigenetic, and environmental factors responsible for the regulation of precocious and delayed puberty.

Extra Virgin Olive Oil Extracts Modulate the Inflammatory Ability of Murine Dendritic Cells Based on Their Polyphenols Pattern: Correlation between Chemical Composition and Biological Function.

Extra virgin olive oil (EVOO) represents one of the most important health-promoting foods whose antioxidant and anti-inflammatory activities are mainly associated to its polyphenols content. To date, studies exploring the effect of EVOO polyphenols on dendritic cells (DCs), acting as a crosstalk between the innate and the adaptive immune response, are scanty. Therefore, we studied the ability of three EVOO extracts (cv. Coratina, Cima di Mola/Coratina, and Casaliva), characterized by different polyphenols amount, to regulate DCs maturation in resting conditions or after an inflammatory stimulus. Cima di Mola/Coratina and Casaliva extracts were demonstrated to be the most effective in modulating DCs toward an anti-inflammatory profile by reduction of TNF and IL-6 secretion and CD86 expression, along with a down-modulation of Il-1ß and iNOS expression. From factorial analysis results, 9 polyphenols were tentatively established to play a synergistic role in modulating DCs inflammatory ability, thus reducing the risk of chronic inflammation.

Polyphenol Enriched Diet Administration During Pregnancy and Lactation Prevents Dysbiosis in Ulcerative Colitis Predisposed Littermates.

Neonatal colonization of the gastrointestinal tract depends on mother microbiome, thus mother microbiota dysbiosis is transmitted to the offspring during the delivery and shaped by breastmilk characteristics. Here we used a murine model of UC predisposition (Winnie-/-) to evaluate the effects of maternal diet during pregnancy and lactation. Using heterozygous breeders, we obtained both Winnie-/- and C57BL/6 littermates from the same mother and compared their microbiota at weaning and adult age, using a diet enriched with 1% tomato fruit of a line - named Bronze - highly enriched in bioactive polyphenols, or Control tomato. Females received enriched diets two weeks before the beginning of the breeding and never stopped for the following six months. No significant effect was observed in regard to the percentage of Winnie-/- offspring, as with both diets the percentage was about 25% as expected. Winnie littermates from breeders fed with the Bronze-enriched diet showed reduced dysbiosis at 4 weeks of age if compared with Winnie under the Control tomato diet. This effect was then reduced when mice reached adult age. Conversely, the microbiota of C57BL/6 does not change significantly, indicating that fortified mothers-diet significantly contribute to preventing dysbiosis in genetically predisposed offspring, but has mild effects on healthy littermates and adult mice. An overall tendency towards reduced inflammation was underlined by the colon weight and the percentage of Foxp3+ cells reduction in Winnie mice fed with Bronze diet. Control diet did not show similar tendency.

Dysbiosis Triggers ACF Development in Genetically Predisposed Subjects.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide, characterized by a multifactorial etiology including genetics, lifestyle, and environmental factors including microbiota composition. To address the role of microbial modulation in CRC, we used our recently established mouse model (the Winnie-APCMin/+) combining inflammation and genetics. METHODS: Gut microbiota profiling was performed on 8-week-old Winnie-APCMin/+ mice and their littermates by 16S rDNA gene amplicon sequencing. Moreover, to study the impact of dysbiosis induced by the mother's genetics in ACF development, the large intestines of APCMin/+ mice born from wild type mice were investigated by histological analysis at 8 weeks. RESULTS: ACF development in 8-week-old Winnie-APCMin/+ mice was triggered by dysbiosis. Specifically, the onset of ACF in genetically predisposed mice may result from dysbiotic signatures in the gastrointestinal tract of the breeders. Additionally, fecal transplant from Winnie donors to APCMin/+ hosts leads to an increased rate of ACF development. CONCLUSIONS: The characterization of microbiota profiling supporting CRC development in genetically predisposed mice could help to design therapeutic strategies to prevent dysbiosis. The application of these strategies in mothers during pregnancy and lactation could also reduce the CRC risk in the offspring.

Extra-Virgin Olive Oil from Apulian Cultivars and Intestinal Inflammation.

Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder characterized by chronic intestinal inflammation. The etiology of IBD is still unclear, although genetic, environmental and host factors have been associated to the disease. Extra-virgin olive oil (EVO) is a central component of the Mediterranean diet and it decreases chronic inflammation by interfering with arachidonic acid and NF-κB signaling pathways. Specifically, the different components of EVO are able to confer advantages in terms of health in their site of action. For instance, oleic acid displays a protective effect in liver dysfunction and gut inflammation, whereas phenolic compounds protect colon cells against oxidative damage and improve the symptoms of chronic inflammation in IBD. Given the biological properties of EVO, we investigated whether its administration is able to confer protection in a mouse model of dextrane sodium sulfate (DSS)-induced colitis. Four EVO cultivars from the Apulian Region of Italy, namely Ogliarola (Cima di Bitonto), Coratina, Peranzana and Cima di Mola, respectively, were used. Administration of EVO resulted in reduced body weight loss in our colitis model. Furthermore, mice treated with Ogliarola, Coratina and Cima di Mola EVO displayed a reduction of rectal bleeding and IL-1ß, TGFß, IL-6 gene expression levels. Furthermore, Ogliarola, Coratina and Peranzana EVO administration ameliorated intestinal permeability and histopathological features of inflammation. Our data further validate the well-known positive effects of EVO supplementation in promoting human health and suggest the bona fide contribution of EVO in preventing onset and reducing progression of intestinal inflammation.

Winnie-APCMin/+ Mice: A Spontaneous Model of Colitis-Associated Colorectal Cancer Combining Genetics and Inflammation.

(1) Background: Colorectal cancer (CRC) is among the best examples of the relationship between inflammation and increased cancer risk. (2) Methods: To examine the effects of spontaneous low-grade chronic inflammation on the pathogenesis of CRC, we developed a new murine model of colitis-associated cancer (CAC) by crossing Mucin 2 mutated mice (Winnie) with ApcMin/+ mice. (3) Results: The resulting Winnie-ApcMin/+ model combines an inflammatory background with a genetic predisposition to small intestinal polyposis. Winnie-ApcMin/+ mice show an early occurrence of inflammatory signs and dysplastic lesions in the distal colon with a specific molecular signature. (4) Conclusion: The Winnie-ApcMin/+ model is a perfect model to demonstrate that chronic inflammation represents a crucial risk factor for the onset and progression of tumoral lesions in individuals genetically predisposed to CRC.

Iron Overload Mimicking Conditions Skews Bone Marrow Dendritic Cells Differentiation into MHCIIlowCD11c+CD11b+F4/80+ Cells.

Iron overload is an undesired effect of frequent blood transfusions or genetic diseases. Myelodysplastic syndrome (MDS) patients become transfusion dependent, but due to the combination of ineffective haematopoiesis and repeated blood transfusions they are often subject to iron overload. In this study, we demonstrate that iron-overload mimicking condition alters bone marrow progenitor differentiation towards dendritic cells (DCs). Cells cultured in iron-enriched culture medium for seven days fail to differentiate into conventional CD11c+MHCIIhi DCs and fail to efficiently respond to LPS (Lipopolysaccharides). Cells appear smaller than control DCs but vital and able to perform FITC-dextran (Fluorescein isothiocyanate-dextran) endocytosis. At molecular level, cells cultured in iron-enriched conditions show increased ARG1 and PU.1, and decreased IRF8 expression.

Role of Oleic Acid in the Gut-Liver Axis: From Diet to the Regulation of Its Synthesis via Stearoyl-CoA Desaturase 1 (SCD1).

The consumption of an olive oil rich diet has been associated with the diminished incidence of cardiovascular disease and cancer. Several studies have attributed these beneficial effects to oleic acid (C18 n-9), the predominant fatty acid principal component of olive oil. Oleic acid is not an essential fatty acid since it can be endogenously synthesized in humans. Stearoyl-CoA desaturase 1 (SCD1) is the enzyme responsible for oleic acid production and, more generally, for the synthesis of monounsaturated fatty acids (MUFA). The saturated to monounsaturated fatty acid ratio affects the regulation of cell growth and differentiation, and alteration in this ratio has been implicated in a variety of diseases, such as liver dysfunction and intestinal inflammation. In this review, we discuss our current understanding of the impact of gene-nutrient interactions in liver and gut diseases, by taking advantage of the role of SCD1 and its product oleic acid in the modulation of different hepatic and intestinal metabolic pathways.

Extra Virgin Olive Oil: Lesson from Nutrigenomics.

Extra virgin olive oil (EVOO) consumption has a beneficial effect on human health, especially for prevention of cardiovascular disease and metabolic disorders. Here we underscore the peculiar importance of specific cultivars used for EVOO production since biodiversity among cultivars in terms of fatty acids and polyphenols content could differently impact on the metabolic homeostasis. In this respect, the nutrigenomic approach could be very useful to fully dissect the pathways modulated by different EVOO cultivars in terms of mRNA and microRNA transcriptome. The identification of genes and miRNAs modulated by specific EVOO cultivars could also help to discover novel nutritional biomarkers for prevention and/or prognosis of human disease. Thus, the nutrigenomic approach depicts a novel scenario to investigate if a specific EVOO cultivar could have a positive effect on human health by preventing the onset of cardiovascular disease and/or chronic inflammatory disorders also leading to cancer.

Quercetin-Induced miR-369-3p Suppresses Chronic Inflammatory Response Targeting C/EBP-ß.

SCOPE: Dendritic cells (DCs) are the most potent antigen-presenting cells that play an important role in the crosstalk between the innate and the adaptive immune response. Quercetin exposure is identified as an effective strategy to suppress the inflammatory response induced by LPS. METHODS AND RESULTS: In this study, using a next-generation sequencing analysis, the effect of quercetin on microRNAs (miRNAs) expression in DCs is examined. A signature of 113 miRNAs that are differentially regulated in LPS-stimulated DCs after quercetin exposure is defined. It is demonstrated that the loss of function of miR-369-3p in LPS-stimulated DCs during quercetin exposure led to an increase of CCAAT/enhancer binding protein ß (C/EBP-ß) mRNA and protein and its downstream targets tumor necrosis factor-α (TNF-α) and interleukin 6 (IL6). Conversely, it is shown that the ectopic induction of miR-369-3p without quercetin suppresses the inflammatory response of LPS reducing C/EBP-ß, TNF-α, and IL6 production. In vivo, oral administration of quercetin in dextran-sulfate-sodium-induced colitis induces miR-369-3p expression. CONCLUSIONS: These findings indicate that quercetin-induced miR-369-3p regulates the inflammatory cascade in chronic inflammatory response and present promising therapeutic implications.

Iatrogenic Kaposi sarcoma of the terminal ileum following short-term treatment with immunomodulators for Crohn disease: A case report.

RATIONALE: Kaposi sarcoma (KS) is a mesenchymal neoplasm associated with human herpes virus-8. It is often found in patients with primary or secondary immunodeficiency. An iatrogenic form of KS is detectable in patients who have received immunosuppressive therapy. To date, there are few reported cases of patients with KS treated with immunosuppressants for inflammatory bowel disease. PATIENT CONCERNS: We report the case of a 45-year-old young woman with abdominal pain, episodic diarrhea and a mild weight loss. The patient was treated with immunosuppressive therapy for a parietal thickening of the terminal ileum, wrongly diagnosed as Crohn disease. After 9 months after the beginning of antitumor necrosis factor-α, the patient was admitted for obstructive symptoms. A computed tomography suspected neoplasia of ileocecal region. The patient underwent an uneventful ileocecal surgical resection. DIAGNOSES: The histopathology showed endometriosis of the ileal wall and an irrefutable diagnosis of KS by immunohistochemistry-positive staining for human herpes virus-8. INTERVENTIONS AND OUTCOMES: The patient underwent surgical resection and is disease free at 6 years follow-up. LESSONS: This case underlines the interaction of immunosuppressive therapy with the possible consequent development of visceral KS.

A Bronze-Tomato Enriched Diet Affects the Intestinal Microbiome under Homeostatic and Inflammatory Conditions.

Inflammatory bowel diseases (IBD) are debilitating chronic inflammatory disorders that develop as a result of a defective immune response toward intestinal bacteria. Intestinal dysbiosis is associated with the onset of IBD and has been reported to persist even in patients in deep remission. We investigated the possibility of a dietary-induced switch to the gut microbiota composition using Winnie mice as a model of spontaneous ulcerative colitis and chow enriched with 1% Bronze tomato. We used the near isogenic tomato line strategy to investigate the effects of a diet enriched in polyphenols administered to mild but established chronic intestinal inflammation. The Bronze-enriched chow administered for two weeks was not able to produce any macroscopic effect on the IBD symptoms, although, at molecular level there was a significant induction of anti-inflammatory genes and intracellular staining of T cells revealed a mild decrease in IL17A and IFNγ production. Analysis of the microbial composition revealed that two weeks of Bronze enriched diet was sufficient to perturb the microbial composition of Winnie and control mice, suggesting that polyphenol-enriched diets may create unfavorable conditions for distinct bacterial species. In conclusion, dietary regimes enriched in polyphenols may efficiently support IBD remission affecting the intestinal dysbiosis.