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Probiotics, included in functional foods, nutritional supplements, or nutraceuticals, exhibit different beneficial effects on gut function. They are extensively used to improve the digestive processes as well as reduce the symptoms and progression of different diseases. Probiotics have shown to improve dysbiosis and modulate the immune response of the host by interacting with different cell types. Probiotics and the host can interact in a direct way, but it is becoming apparent that communication occurs also through extracellular vesicles (EVs) derived from probiotics. EVs are key for bacteria–bacteria and bacteria–host interactions, since they carry a wide variety of components that can modulate different signaling pathways, including those involved in the immune response. Interestingly, EVs are recently starting to be considered as an alternative to probiotics in those cases for which the use of live bacteria could be dangerous, such as immunocompromised individuals or situations where the intestinal barrier is impaired. EVs can spread through the mucus layer and interact with the host, avoiding the risk of sepsis. This review summarizes the existing knowledge about EVs from different probiotic strains, their properties, and their potential use for the prevention or treatment of different gastrointestinal diseases. ; This work was supported by Junta de Andalucia (Spain) (research grants CTS 164 and PI-0206-2016) and the Spanish Ministry of Economy and Competitiveness (research grant AGL2015-67995-C3-3-R) and cofinanced by the Fondo Europeo de Desarollo Regional (FEDER) from the European Union. JA-MT is a Ph.D. student from the Postgraduate Program Nutricion y Ciencias de los Alimentos at the University of Granada (Spain). The CIBER-EHD is funded by the Instituto de Salud Carlos III.

This work was supported by Junta de Andalucia (Spain) (research grants CTS 164 and PI-0206-2016), the Spanish Ministry of Economy and Competitiveness (research grant AGL2015-67995- C3-3-R) and Fondo de Investigaciones Sanitarias ISCIII (Spain) (research grant PI15/00794) cofinanced by the Fondo Europeo de Desarollo Regional (FEDER) from the European Union. LH-G is a Ph.D. student from the Postgraduate Program Medicina Clinica y Salud Publica at the University of Granada (Spain) (FPU16/05651), supported by Initiation-Research fellowship from the Vice-Rectorate of Scientific Policy and Research of University of Granada. PA has a Miguel Servet Type II Contract (CPII15/00032), cofinanced by the Fondo Europeo de Desarollo Regional (FEDER) from the European Union.

Critically ill patients have an alteration in the microbiome in which it becomes a disease-promoting pathobiome. It is characterized by lower bacterial diversity, loss of commensal phyla, like Firmicutes and Bacteroidetes, and a domination of pathogens belonging to the Proteobacteria phylum. Although these alterations are multicausal, many of the treatments administered to these patients, like antibiotics, play a significant role. Critically ill patients also have a hyperpermeable gut barrier and dysregulation of the inflammatory response that favor the development of the pathobiome, translocation of pathogens, and facilitate the emergence of sepsis. In order to restore the homeostasis of the microbiome, several nutritional strategies have been evaluated with the aim to improve the management of critically ill patients. Importantly, enteral nutrition has proven to be more efficient in promoting the homeostasis of the gut microbiome compared to parenteral nutrition. Several nutritional therapies, including prebiotics, probiotics, synbiotics, and fecal microbiota transplantation, are currently being used, showing variable results, possibly due to the unevenness of clinical trial conditions and the fact that the beneficial effects of probiotics are specific to particular species or even strains. Thus, it is of great importance to better understand the mechanisms by which nutrition and supplement therapies can heal the microbiome in critically ill patients in order to finally implement them in clinical practice with optimal safety and efficacy. ; This work was supported by Junta de Andalucía (Spain) (research grants CTS 164 and PI-0206-2016) and cofinanced by the Fondo Europeo de Desarollo Regional (FEDER) from the European Union. RM has a Río Hortega contract (CM17/00237) and PA has a Nicolás Monardes contract (C-0013-2018).

Inflammatory bowel diseases, mainly ulcerative colitis and Crohn's disease are characterized by chronic inflammation in the intestine. Currently several therapeutic strategies available to treat inflammatory bowel diseases. Though, most treatments can be associated with serious adverse effects what justifies the search for new treatments. In this sense, we highlight the interest in herbal products rich in bioactive compounds which immunomodulatory and antioxidant properties as is the case of Bryophyllum pinnatum (Crassulaceae). This plant is used in traditional medicine in Brazil for treating inflammatory diseases. We hypothesized that hydroethanolic B. pinnatum leaf extract has intestinal anti-inflammatory effects on two experimental colitis models: 2.4-dinitrobenzene sulfonic acid (DNBS) in rats, and dextran sulfate sodium (DSS) in mice. Ultra-fast liquid chromatography method used for the quantification of the main compounds indicated good linearity, specificity, selectivity, precision, robustness and accuracy. The major flavonoids (mg/g of the extract) quantified were: quercetin 3-O-a-L-arabinopyranosyl-(1!2)-a-L-rhamnopyranoside (35.56 ± 0.086 mg/g), kaempferol 3-O-a-L-arabinopyranosyl-(1!2)-a-L-rhamnopyranoside (4.66 ± 0.076 mg/g) and quercetin-3-O-rhamnopyranoside (4.56 ± 0.026 mg/g). The results obtained in the DNBS and DSS models indicate that extract has both chemopreventive and antiinflammatory effects, observing a significant reduction in the disease activity index score, and less macroscopic and microscopic damage. The extract promoted downregulation of Tolllike receptor and kappa B p65 nuclear factor gene expression, leading to a reduction in pro-inflammatory and oxidative mediators, chemokines, and cell adhesion molecules. This immunomodulatory property was proposed that one of the possible action mechanisms of extract. An improvement in intestinal damage was also associated with a reduction in oxidative stress and infiltration of leukocytes, as evidenced by the reduction in malonaldialdehyde and myeloperoxidase activity and increase in total glutathione in the colonic tissue. Moreover, the extract improved the cytoarchitecture of the colonic tissue and the integrity of the intestinal epithelial barrier by restoring the expression of the proteins associated with mucosa protection. In view of the beneficial effects showed by the B. pinnatum leaf extract in preclinical rodent models of colitis there is the potential to conduct some future clinical studies to ensure safe and effective development of a phytotherapeutic treatment for human inflammatory bowel diseases. ; CAPES ; Junta de Andalucia CTS 164 ; Spanish Ministry of Economy and Competitiveness AGL2015-67995-C3-3-R ; European Union (EU) ; Instituto de Salud Carlos III

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine that compromises the patients' life quality and requires sustained pharmacological and surgical treatments. Since their etiology is not completely understood, non-fully-efficient drugs have been developed and those that have shown effectiveness are not devoid of quite important adverse effects that impair their long-term use. In this regard, a growing body of evidence confirms the health benefits of flavonoids. Flavonoids are compounds with low molecular weight that are widely distributed throughout the vegetable kingdom, including in edible plants. They may be of great utility in conditions of acute or chronic intestinal inflammation through different mechanisms including protection against oxidative stress, and preservation of epithelial barrier function and immunomodulatory properties in the gut. In this review we have revised the main flavonoid classes that have been assessed in different experimental models of colitis as well as the proposed mechanisms that support their beneficial effects. ; This work was supported by Junta de Andalucia (P10-AGR-6826 and CTS 164) and by the Spanish Ministry of Economy and Competitiveness (AGL2015-67995-C3-3-R) with funds from the European Union. ; The CIBER-EHD is funded by the Instituto de Salud Carlos III.

This work was supported by the Junta de Andalucía (CTS 164) and Instituto de Salud Carlos III (PI19/01058) with funds from the European Union. ; M.J. Rodríguez-Sojo is a predoctoral fellow from University of Granada ("Programa de Doctorado en Biomedicina"); A.J. Ruiz-Malagón is a predoctoral fellow from Formación de Profesorado Universitario Program ("Programa de Doctorado en Medicina Clínica y Salud Pública"), and A. Rodríguez-Nogales is a postdoctoral fellow of Instituto de Salud Carlos III (Miguel Servet Program). ; Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches. ; Junta de Andalucia CTS 164 ; Instituto de Salud Carlos III European Commission PI19/01058 ; European Commission

This work was supported by Instituto de Salud Carlos III (grants PI15/01361 and PI18/01947), and Conserjeria de Salud y Familias, Junta de Andalucia (grant PIN-0235-2019). Instituto de Salud Carlos III (ISCIII) is a public organization that belongs to the Spanish Ministry of Health. ISCIII funds scientific projects on competitive open calls. Conserjeria de Salud y Familias, Junta de Andalucia is a department of the regional government of Andalucia (Spain) that funds scientific projects on competitive open calls. ; The paradigm of mast cells in type 2 diabetes is changing. Although they were first considered deleterious inflammatory cells, now they seem to be important players driving adipose tissue homeostasis. Here we have employed a flow cytometry-based approach for measuring the surface expression of 4 proteins (CD45, CD117, CD203c, and FcϵRI) on mast cells of omental (o-WAT) and subcutaneous white adipose tissue (s-WAT) in a cohort of 96 patients with morbid obesity. The cohort was split into three groups: non-T2D, pre- T2D, and T2D. Noteworthy, patients with T2D have a mild condition (HbA1c <7%). In o- WAT, mast cells of patients with T2D have a decrease in the surface expression of CD45 (p=0.0013), CD117 (p=0.0066), CD203c (p=0.0025), and FcϵRI (p=0.043). Besides, in s- WAT, the decrease was seen only in CD117 (p=0.046). These results indicate that T2D affects more to mast cells in o-WAT than in s-WAT. The decrease in these four proteins has serious effects on mast cell function. CD117 is critical for mast cell survival, while CD45 and FcϵRI are important for mast cell activation. Additionally, CD203c is only present on the cell surface after granule release. Taking together these observations, we suggest that mast cells in o-WAT of patients with T2D have a decreased survival, activation capacity, and secretory function. ; Instituto de Salud Carlos III ; European Commission PI15/01361 PI18/01947 ; Junta de Andalucia FPU18/04432 PIN-0235-2019 ; Spanish Ministry of Health. ISCIII funds ; Junta de ...

Pyruvate is a normal constituent of the body that participates in carbohydrate metabolism and functions as a scavenger of free radicals. Calcium pyruvate monohydrate (CPM) is a more stable derivative that has proved its anti-inflammatory effect in experimental colitis, among other disorders, and that could also be considered a source of calcium. Thus, it would be useful for the treatment of diseases with an inflammatory component and a high prevalence of osteoporosis like the irritable bowel syndrome (IBS). The aim of the present study is to evaluate the effects of CPM in a rat model of chronic post-inflammatory visceral pain induced by deoxycholic acid (DCA) that resembles IBS. Rats were administered DCA for three days intracolonically and then treated daily with CPM (40 and 100 mg/kg) or gabapentin (70 mg/kg) (positive control) by oral gavage for 17 days. The treatments reduced the visceral hypersensitivity measured by response to colorectal distension and referred pain. DCA induced changes in the colonic immune response characterized by increased expression of the cytokine Il-1b and the inducible enzyme Cox-2, which was reduced by the treatments. DCA also decreased the gut expression of the mucins Muc-2 and Muc-3, which was normalized by CPM, whereas gabapentin only increased significantly Muc-3. Moreover, DCA increased the expression of Tlr3, which was decreased to basal levels by all the treatments. However, the serotonin receptor Htr-4, which was also elevated, was not affected by any of the treatments, indicating no effect through this signalling pathway. In conclusion, CPM ameliorated the visceral hypersensitivity and the referred pain caused by DCA, being as effective as the control drug. Furthermore, it improved the immune status of the animals, which could contribute to the visceral analgesia and the regeneration of the intestinal epithelial barrier integrity. ; This work was supported by the Junta de Andalucía (CTS 164) and by the Spanish Ministry of Economy and Competitiveness (AGL2015-67995-C3-3-R) with funds from the European Union. The CIBER-EHD is funded by the Instituto de Salud Carlos III.

Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated in vitro assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide. In vitro systems based in human liver microsomes and activated mouse macrophages were developed for these purposes. Additionally in vitro production the hepatic metabolites of dual inhibitor, roxithromycin, was investigated achieving the identification and isolation of main hepatic biotransformation products. Our results suggested that for some macrolide compounds, the cytochrome P450 3A4 derived drug metabolites have an important effect on nitric oxide production and might critically contribute to the pharmacological immunomodulatory activity observed. ; This work was supported by the Spanish Ministry of Economy and Competitivity (SAF2011-29648) and Junta de Andalucía (AGR-6826 and CTS 164) with funds from the European Union; FA is a predoctoral fellow of Junta de Andalucia; MR is a postdoctoral fellow of CIBER-EHD. The CIBEREHD is funded by the Instituto de Salud Carlos III. The MEDINA authors disclosed the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp and Dohme de España S.A./Universidad de Granada/Junta de Andalucía. In the case of Noemi Vergara Segura, she was a CEIBioTic fellow from the program at the Granada University. The results presented in this work will be compiled in the doctoral thesis (knowledge area code 32089 and subject code 320903) entitled "Evaluación de la actividad de los metabolitos hepáticos derivados de compuestos inmunomodulares e inhibidores de GSK3," carried out currently by JP at FUNDACIÓN MEDINA in collaboration with the department of Pharmacology at the University of Granada, being the thesis directors, FV (FUNDACIÓN MEDINA) and JG (Universidad de Granada).

The beneficial effects of probiotics on immune-based pathologies such as inflammatory bowel disease (IBD) have been well reported. However, their exact mechanisms have not been fully elucidated. Few studies have focused on the impact of probiotics on the composition of the colonic microbiota. The aim of the present study was to correlate the intestinal anti-inflammatory activity of the probiotic Escherichia coli Nissle 1917 (EcN) in the dextran sodium sulfate (DSS) model of mouse colitis with the changes induced in colonic microbiota populations. EcN prevented the DSSinduced colonic damage, as evidenced by lower disease activity index (DAI) values and colonic weight/length ratio, when compared with untreated control mice. The beneficial effects were confirmed biochemically, since the probiotic treatment improved the colonic expression of different cytokines and proteins involved in epithelial integrity. In addition, it restored the expression of different micro-RNAs (miR-143, miR-150, miR-155, miR- 223, and miR-375) involved in the inflammatory response that occurs in colitic mice. Finally, the characterization of the colonic microbiota by pyrosequencing showed that the probiotic administration was able to counteract the dysbiosis associated with the intestinal inflammatory process. This effect was evidenced by an increase in bacterial diversity in comparison with untreated colitic mice. The intestinal anti-inflammatory effects of the probiotic EcN were associated with an amelioration of the altered gut microbiome in mouse experimental colitis, especially when considering bacterial diversity, which is reduced in these intestinal conditions. Moreover, this probiotic has shown an ability to modulate expression levels of miRNAs and different mediators of the immune response involved in gut inflammation. This modulation could also be of great interest to understand the mechanism of action of this probiotic in the treatment of IBD. ; This work was supported by the Junta de Andalucía (CTS 164) and by the Spanish Ministry of Economy and Competitiveness (SAF2011-29648 and AGL2015-67995-C3-3-R) with funds from the European Union. The funders had no role in the study design, data collection, and analysis.

Nowadays, there is an increasing interest in alternative therapies in the treatment of metabolic syndrome that combine efficacy and safety profiles. Therefore, this study aimed to evaluate the effect of an extract of Thymus serpyllum, containing rosmarinic acid, on high-fat diet (HFD)- induced obesity mice, highlighting the impact of its antioxidant activity on the inflammatory status and gut dysbiosis. The extract was administered daily (50, 100 and 150 mg/kg) in HFD-fed mice. The treatment reduced body weight gain, glucose and lipid metabolic profiles. Moreover, the extract ameliorated the inflammatory status, with the c-Jun N-terminal kinases (JUNK) pathway being involved, and showed a significant antioxidant effect by the reduction of radical scavenging activity and the mitigation of lipid peroxidation. Moreover, the extract was able to modulate the altered gut microbiota, restoring microbial richness and diversity, and augmenting the counts of short-chain fatty acid producing bacteria, which have been associated with the maintenance of gut permeability and weight regulation. In conclusion, the antioxidant activity of Thymus serpyllum extract displayed a positive impact on obesity and its metabolic alterations, also reducing systemic inflammation. These effects may be mediated by modulation of the gut microbiota. ; Junta de Andalucia CTS 164 ; Instituto de Salud Carlos III European Commission PI19.01058 ; Spanish Government AGL201567995-C3-3-R ; European Commission ; Instituto de Salud Carlos III

Purpose: We aimed to evaluate the intestinal anti-inflammatory properties of silk fibroin nanoparticles, around 100 nm in size, when loaded with the stilbene compound resveratrol, in an experimental model of rat colitis. Methods: Nanoparticles were loaded with resveratrol by adsorption. The biological effects of the resveratrol-loaded nanoparticles were tested both in vitro, in a cell culture of RAW 264.7 cells (mouse macrophages), and in vivo, in the trinitrobenzenesulfonic acid model of rat colitis, when administered intracolonically. Results: The resveratrol liberation in 1× phosphate-buffered saline (PBS; pH 7.4) was characterized by fast liberation, reaching the solubility limit in 3 hours, which was maintained over a period of 80 hours. The in vitro assays revealed immunomodulatory properties exerted by these resveratrol-loaded nanoparticles since they promoted macrophage activity in basal conditions and inhibited this activity when stimulated with lipopolysaccharide. The in vivo experiments showed that after evaluation of the macroscopic symptoms, inflammatory markers, and intestinal barrier function, the fibroin nanoparticles loaded with resveratrol had a better effect than the single treatments, being similar to that produced by the glucocorticoid dexamethasone. Conclusion: Silk fibroin nanoparticles constitute an attractive strategy for the controlled release of resveratrol, showing immunomodulatory properties and intestinal anti-inflammatory effects. ; This work was supported by the Spanish Ministry of Science and Innovation (grant number SAF2011-29648) with funds from the European Union, and by the Junta de Andalucia (grant numbers AGR-6826 and CTS 164). Parts of the experiments were financed by funds of the European Regional Development Fund (ERDF) Operative Program of the Region of Murcia 2007–2013. The research contract of Dr A Abel Lozano-Pérez was partially supported (at 80%) by the FEDER Operative Program of the Region of Murcia 2007–2013. F Algieri is a predoctoral fellow of the Junta de Andalucia; J Garrido-Mesa is a predoctoral fellow of the Spanish Ministry of Education, Culture and Sport; N Garrido-Mesa is a postdoctoral fellow of the Ramon Areces Foundation; ME Rodríguez-Cabezas is a postdoctoral fellow of Centro de Investigaciones Biomédicas en Red – Enfermedades Hepáticas y Digest (CIBER-EHD), which is funded by the Instituto de Salud Carlos III.

This research was funded by the FEDER-INNTERCONECTA-CDTI program (CDTI, Centre for the Development of Industrial Technology; NATURPICK Project ITC-20181038), by the Junta de Andalucia (CTS 164) and by Instituto de Salud Carlos III (PI19/01058) with funds from the European Union. T.V. is a postdoctoral fellow from Instituto de Investigacion Biosanitaria de Granada; A.J.R.-M. and L.H.-G. are predoctoral fellows from University of Granada ("Programa de Doctorado: Medicina Clinica y Salud Publica"); P.D.-E. is a postdoctoral fellow from University of Granada. The CIBER-EHD and CIBERCV are funded by the Instituto de Salud Carlos III. ; Background: Propyl propane thiosulfonate (PTSO) is an organosulfur compound from Allium spp. that has shown interesting antimicrobial properties and immunomodulatory effects in different experimental models. In this sense, our aim was to evaluate its effect on an experimental model of obesity, focusing on inflammatory and metabolic markers and the gut microbiota. Methods and results: Mice were fed a high-fat diet and orally treated with different doses of PTSO (0.1, 0.5 and 1 mg/kg/day) for 5 weeks. PTSO lessened the weight gain and improved the plasma markers associated with glucose and lipid metabolisms. PTSO also attenuated obesityassociated systemic inflammation, reducing the immune cell infiltration and, thus, the expression of pro-inflammatory cytokines in adipose and hepatic tissues (Il-1ß, Il-6, Tnf-a, Mcp-1, Jnk-1, Jnk-2, Leptin, Leptin R, Adiponectin, Ampk, Ppar-a, Ppar-g, Glut-4 and Tlr-4) and improving the expression of different key elements for gut barrier integrity (Muc-2, Muc-3, Occludin, Zo-1 and Tff-3). Additionally, these effects were connected to a regulation of the gut microbiome, which was altered by the high-fat diet. Conclusion: Allium-derived PTSO can be considered a potential new tool for the treatment of metabolic syndrome. ; FEDER-INNTERCONECTA-CDTI program (CDTI, Centre for the Development of Industrial Technology) ITC-20181038 ; Junta de Andalucia CTS 164 ; Instituto de Salud Carlos III European Commission PI19/01058 European Commission Instituto de Salud Carlos III ; European Commission