Limosilactobacillus fermentum CECT5716: Mechanisms and Therapeutic Insights

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 164Instituto de Salud Carlos III European Commission PI19/01058European Commissio

Intestinal anti-inflammatory and visceral analgesic effects of a Serpylli herba extract in an experimental model of irritable bowel syndrome in rats

Ethnopharmacological relevance: Serpylli herba extract (SHE), composed of the aerial parts of wild thyme (Thymus serpyllum L.) (Lamiaceae family), is traditionally used in Europe and North Africa to treat diarrhea, gastric ulcers, intestinal parasites and upper respiratory tract infections. Recently, SHE has generated a great interest for irritable bowel syndrome (IBS) management, probably due to its intestinal anti-inflammatory properties shown in experimental colitis and the fact that its active components could preserve the intestinal barrier integrity, which is altered in patients with IBS. Aim of study: We aimed to test the effects of a SHE in a rat experimental model resembling human IBS. Materials and methods: IBS was provoked by deoxycholic acid (DCA). Rats were then treated with SHE (100 mg/kg) or gabapentin (70 mg/kg) and different inflammatory and gut barrier integrity markers were evaluated. Moreover, several gut hypersensitivity and hyperalgesia determinations were performed. Results: SHE improved referred pain and visceral hypersensitivity. Additionally, SHE enhanced immune status by downregulating of the expression of the proinflammatory mediators Il-1β, Il-6, Ifn-γ, Tlr-4, and the inducible enzyme Cox-2, thus inducing visceral analgesia, and promoting the restore of the gut barrier function by upregulating the mucins Muc-2 and Muc-3. These antiinflammatory effects could be related to its action on mast cells since it significantly inhibited the β-Hexosaminidase production in RBL-2H3 cells. Lastly, SHE also seems to modulate the serotonin pathway by restoring the altered expression of the 5-HT receptors Htr-3 and Htr-4. Conclusion: SHE could be considered a potential new treatment for IBS, since it ameliorates hypersensitivity, visceral hyperalgesia, and inflammation. These beneficial effects may be due to the inhibition of mast cells degranulation and serotonin pathway.Junta de Andalucia AGR6826 CTS 164Spanish Government SAF 2011-29648Instituto de Salud Carlos IIIEuropean Commission PI19/01058 PI20/0144

Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response

Junta de Andalucía (CTS 164)Instituto de Salud Carlos III (Spain)Fondo Europeo de Desarrollo Regional (FEDER)European Union, through the research grants PI18/00826, P18-RT-4930, PI0206–2016, PIE16/00045 and PI19/01058Spanish Ministry of Science and Innovation (MCIN/AEI/ 10.13039/501100011033/FEDER)RTI2018–101309-BC22Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963Spanish Ministry of Science and Innovation (“Programa de Doctorado: Medicina Clínica y Salud Pública” B12.56.1).Instituto de Salud Carlos III (FI17/00176)Junta de Andalucía (P18-RT-4930)University of GranadaCIBER-EHD is funded by the Instituto de Salud Carlos II

The Antioxidant Activity of Thymus serpyllum Extract Protects against the Inflammatory State and Modulates Gut Dysbiosis in Diet-Induced Obesity in Mice

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 164Instituto de Salud Carlos III European Commission PI19.01058Spanish Government AGL201567995-C3-3-REuropean CommissionInstituto de Salud Carlos II

The Antioxidant Properties of Lavandula multifida Extract Contribute to Its Beneficial Effects in High-Fat Diet-Induced Obesity in Mice

Obesity is a worldwide public health problem whose prevalence rate has increased steadily over the last few years. Therefore, it is urgent to improve the management of obesity and its comorbidities, and plant-based treatments are receiving increasing attention worldwide. In this regard, the present study aimed to investigate a well-characterized extract of Lavandula multifida (LME) in an experimental model of obesity in mice and explore the underlying mechanisms. Interestingly, the daily administration of LME reduced weight gain as well as improved insulin sensitivity and glucose tolerance. Additionally, LME ameliorated the inflammatory state in both liver and adipose tissue by decreasing the expression of various proinflammatory mediators (Il-6, Tnf-a, Il-1b, Jnk-1, Ppara, Pparg, and Ampk) and prevented increased gut permeability by regulating the expression of mucins (Muc-1, Muc-2, and Muc-3) and proteins implicated in epithelial barrier integrity maintenance (Ocln, Tjp1, and Tff-3). In addition, LME showed the ability to reduce oxidative stress by inhibiting nitrite production on macrophages and lipid peroxidation. These results suggest that LME may represent a promising complementary approach for the management of obesity and its comorbidities.Junta de Andalucía (CTS 164), by the Instituto de Salud Carlos III (ISCIII) (PI19.01058)Spanish Ministry of Economy and Competitiveness (AGL2015-67995-C3-3-R)European Commission (FEDER/ERDF). The CIBEREHDInstituto de Salud Carlos II

Beneficial Effects of Limosilactobacillus fermentum in the DCA Experimental Model of Irritable Bowel Syndrome in Rats

Limosilactobacillus fermentum CECT5716, a probiotic strain isolated from human milk, has reported beneficial effects on different gastrointestinal disorders. Moreover, it has shown its ability to restore altered immune responses, in association with microbiome modulation in different pathological conditions. Therefore, our aim was to assess the effects of a Limosilacbacillus fermentum CECT5716 in a rat experimental model of irritable bowel syndrome (IBS) that resembles human IBS. The experimental IBS was induced by deoxycholic acid (DCA) in rats and then, Limosilactobacillus fermentum CECT5716 (109 CFU/day/rat) was administered. Behavioral studies, hyperalgesia and intestinal hypersensitivity determinations were performed and the impact of the probiotic on the inflammatory and intestinal barrier integrity was evaluated. Additionally, the gut microbiota composition was analyzed. Limosilactobacillus fermentum CECT5716 attenuated the anxiety-like behavior as well as the visceral hypersensitivity and referred pain. Moreover, this probiotic ameliorated the gut inflammatory status, re-establishing the altered intestinal permeability, reducing the mast cell degranulation and re-establishing the gut dysbiosis in experimental IBS. Therefore, our results suggest a potential use of Limosilactobacillus fermentum CECT5716 in clinical practice for the management of IBS patients.Junta de Andalucia A-CTS-447-UGR18 CTS 164Instituto de Salud Carlos IIIEuropean Commission PI19/01058 PI20/0144

Intestinal mesenchymal cells regulate immune responses and promote epithelial regeneration in vitro and in dextran sulfate sodium-induced experimental colitis in mice

This work was funded by the Junta de Andalucia (CTS 164) and by the Instituto de Salud Carlos III (Spain) and Fondo Europeo de Desarrollo Regional (FEDER), from the European Union, through the research grants PI18/00826, PI0206-2016 and PI19/01058. L.H-G and A.J.R-M are predoctoral fellows funded by the Spanish Ministry of Science and Innovation ("Programa de Doctorado: Medicina Clinica y Salud Publica" B12.56.1). J.A.M-T is a predoctoral fellow from the Instituto de Salud Carlos III (FI17/00176). P.A is supported by the Consejeria de Salud, Junta de Andalucia through the contract "Nicolas Monardes" (C-0013-2018). A. R-N is a postdoctoral fellow from the Instituto de Salud Carlos III (Miguel Servet program [CP19/00191]). CIBER-EHD is funded by the Instituto de Salud Carlos III.We would like to express our gratitude to Dr E. Aksoy and Dr L. Medrano Gonzalez (William Harvey Research Institute, Queen Mary University of London, London, UK) for providing us the cell line NCM356. Additionally, we thank Juan N. Moliz, Ana Santos and Mohamed Tassi of the Centre for Scientific Instrumentation (CIC, University of Granada) for their technical guidance and assistance.Aim Disruption of the intestinal mucosal tolerance, that is, the immunological unresponsiveness to innocuous food antigens and the commensal microbiota, in the colon is associated with several chronic diseases including inflammatory bowel disease (IBD). Understanding the mechanisms responsible for intestinal mucosal tolerance has potential translational value for its therapy and management. Human intestinal mesenchymal cells (iMCs) play important roles in colonic mucosal tolerance, but further studies on their tissue regenerative and immunomodulatory capacities are necessary in order to fully understand their function in health and disease. Methods In this study, we have isolated and analysed the capacity of human iMCs to promote wound healing and modulate immune responses in vitro and in vivo, using the dextran sulfate sodium (DSS)-induced colitis model. Results Cultured iMCs were CD45(-)CD73(+)CD90(+)CD105(+) and accelerated the wound closure in a normal colon mucosa (NCM) 356 human epithelial cell wound healing assay. Furthermore, iMCs blocked the LPS-mediated induction of TNF-alpha in THP-1 macrophages and inhibited the proliferation of peripheral blood mononuclear cells, partly through the induction of indoleamine-2,3-dioxygenase. In DSS colitic mice, iMCs administration reduced the disease activity index and ameliorated intestinal tissue damage and permeability. Furthermore, iMCs reduced intestinal inflammation, evidenced by a decreased mRNA expression of pro-inflammatory cytokines, reduced IL-1 beta secretion by intestinal explants and inhibited colonic iNOS protein expression. Conclusions Our data show that human iMCs isolated from the noninflamed intestine possess tissue-regenerative and immunomodulatory capacities that could potentially be harnessed/restored in order to reduce IBD severity.Junta de Andalucia CTS 164Instituto de Salud Carlos III European CommissionFondo Europeo de Desarrollo Regional (FEDER), from the European Union PI18/00826 PI0206-2016 PI19/01058Spanish Ministry of Science and Innovation ("Programa de Doctorado: Medicina Clinica y Salud Publica") B12.56.1Junta de Andalucia C-0013-2018Miguel Servet program CP19/00191Instituto de Salud Carlos III European Commissio

Silk fibroin nanoparticles enhance quercetin immunomodulatory properties in DSS-induced mouse colitis

This work has been supported from the European Commission ERDF/FEDER Operational Programme `Murcia' CCI N. 2007ES161PO001 (Project No. 14-20/20), the Junta de Andalucia (CTS164), Instituto de Salud Carlos III (PI19/01058) and the Spanish MINECO (Ref. CTQ201787708-R). P.D.-E. is a postdoctoral from Junta de Andalucia (European Commission FEDER); A.J.R.-M and L.H.-G. are predoctoral fellows from University of Granada ("Programa de Doctorado: Medicina Clinica y Salud Publica"); A.A.L.-P's research contract was supported by the ERDF/FEDER Operational Programme `Murcia' CCI N 2007ES161PO001 (Project No. 14-20/20); A.R.-N. is a postdoctoral fellow of Instituto de Salud Carlos III (Miguel Servet Program); T.V. is a postdoctoral fellow from Instituto de Investigación Biosanitaria de Granada.Inflammatory bowel disease (IBD) is a chronic and idiopathic inflammatory disorder affecting the gastrointes-tinal tract. The pharmacological treatments used currently for its treatment lack efficacy, so new therapeutic strategies should be developed. In this context, flavonoids loaded in biopolymeric nanoparticles can be considered as novel promising candidates. The aim of the present study was to evaluate the intestinal anti-inflammatory effects of quercetin when is administered loaded in silk fibroin nanoparticles (QSFN) in the dextran sulphate sodium experimental model of mouse colitis, which displays some similarities to human IBD. Previously characterized quercetin-loaded silk fibroin nanoparticles (QSFN). QSFN showed a reversible aggre-gation profile induced by the acidification of the solution but did not affect the loaded quercetin. Daily administration of QSFN significantly reduced disease activity index values compared to the control colitic group. This beneficial effect was not only corroborated by the histological examination of the colonic specimens but also the improvement of the colonic expression of the different proinflammatory cytokines (Tnf-alpha, Il-1 beta, Il-6, Mcp-1, Icam-1, Nlrp3 and iNOS). Therefore, these data suggest that QSFN could be a promising alternative to current treatments as a drug delivery system for IBD treatment.European Commission ERDF/FEDER Operational Programme `Murcia' CCI 2007ES161PO001- 14-20/20Junta de Andalucia CTS164Instituto de Salud Carlos III European Commission PI19/01058Spanish MINECO CTQ201787708-RERDF/FEDER Operational Programme 'Murcia' CCI 2007ES161PO001- 14-20/2

The Prebiotic Effects of an Extract with Antioxidant Properties from Morus alba L. Contribute to Ameliorate High-Fat Diet-Induced Obesity in Mice

Obesity is a global health issue, in which modifications in gut microbiota composition have a key role. Different therapeutic strategies are being developed in combination with diet and exercise, including the use of plant extracts, such as those obtained from Morus alba L. leaves. Recent studies have revealed their anti-inflammatory and antioxidant properties. The aim of the present work was to evaluate whether the beneficial effects of M. alba L. leaf extract in high-fat diet-induced obesity in mice is correlated with its impact on gut microbiota. The extract reduced body weight gain and attenuated lipid accumulation, as well as increased glucose sensitivity. These effects were associated with an amelioration of the obesity-associated inflammatory status, most probably due to the described antioxidant properties of the extract. Moreover, M. alba L. leaf extract mitigated gut dysbiosis, which was evidenced by the restoration of the Firmicutes/Bacteroidota ratio and the decrease in plasma lipopolysaccharide (LPS) levels. Specifically, the extract administration reduced Alistipes and increased Faecalibaculum abundance, these effects being correlated with the beneficial effects exerted by the extract on the obesity-associated inflammation. In conclusion, anti-obesogenic effects of M. alba L. leaf extract may be mediated through the amelioration of gut dysbiosis.Junta de Andalucia CTS 164Instituto de Salud Carlos III PI19.01058Spanish Government AGL2015-67995-C3-3-Rperational Programme of the Region of Murcia (CCI) 2007ES161PO001 14-20/20European CommissionInstituto de Salud Carlos IIIi-pFIS, Instituto de Salud Carlos III; Programa de Doctorado BiomedicinapFIS, Instituto de Salud Carlos III; Programa de Doctorado Nutricio

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections A Randomized Clinical Trial

Importance The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. Objective To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. Design, Setting, and Participants This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. Interventions Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or parenteral ertapenem for the comparator group after 4 days. Main Outcomes and Measures The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. Results Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, −9.4 percentage points; 1-sided 95% CI, −21.5 to ∞ percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, −5.4 percentage points; 1-sided 95% CI, −∞ to 4.9; percentage points; P = .19), an increased rate of adverse event–related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). Conclusions and Relevance This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event–related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections