Complications and Patient-Centered Outcomes of an Implant- Supported Single Crown after Immediate and Delayed Loading: A Systematic Review and Meta-analysis.

Single implants are a predictable treatment, and immediate loading can be an option with acceptable survival rates. Clinical and patient-centered outcomes comparing immediate and delayed protocol of single implants are unclear. The purpose of this study was to assess complications, satisfaction, and quality of life of patients rehabilitated with delayed and immediate loading single crowns. An electronic search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, and Embase databases up to February 2023. Only prospective studies, randomized and non-randomized clinical trials comparing immediate and delayed loading were included. For the quantitative analysis, dichotomous and continuous variables were evaluated with a 95% confidence interval. A total of 20 studies were evaluated. No statistically significant difference between protocols was observed: satisfaction (I2: 0%; P = 0.42), quality of life (I2: 0 %; P = 0.05), biological complications (I2: 9%; P = 0.17) mechanical complications (I2: 58%; P = 0.84), and survival rate (I2: 0%; P = 0.38). Subgroup analysis showed significant differences only for marginal bone loss when immediate implants were placed in the mandible (IÇ: 15%; P = 0.01) and posterior zone (I2: 0%; P = 0.001). Complications and patient-centered outcomes for immediate single-implant crowns were comparable to delayed loading. Scientific evidence showed no significant difference between loading protocols for survival rates. Although several factors could interfere with the complication events, implant failures, and marginal bone loss, the subgroup analysis evidenced that only immediate implants placed in the posterior mandible zone had higher statistically significant mean marginal bone loss.

Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice.

Intestinal γδ T cells play an important role in shaping the gut microbiota, which is critical not only for maintaining intestinal homeostasis but also for controlling brain function and behavior. Here, we found that mice deficient for γδ T cells (γδ-/-) developed an abnormal pattern of repetitive/compulsive (R/C) behavior, which was dependent on the gut microbiota. Colonization of WT mice with γδ-/- microbiota induced R/C behavior whereas colonization of γδ-/- mice with WT microbiota abolished the R/C behavior. Moreover, γδ-/- mice had elevated levels of the microbial metabolite 3-phenylpropanoic acid in their cecum, which is a precursor to hippurate (HIP), a metabolite we found to be elevated in the CSF. HIP reaches the striatum and activates dopamine type 1 (D1R)-expressing neurons, leading to R/C behavior. Altogether, these data suggest that intestinal γδ T cells shape the gut microbiota and their metabolites and prevent dysfunctions of the striatum associated with behavior modulation.

Complete denture rehabilitation for a patient with Parkinson's disease using clinical strategies: A case report.

OBJECTIVE: To present clinical strategies for prosthetic rehabilitation with complete dentures (CDs) of a Parkinson's disease patient. CASE REPORT: An 82-year-old patient sought the Department of Dentistry at UFRN, reporting retention dissatisfaction and hamper to the mandibular CD adaptation. Patient-reported a dry mouth sensation, and exhibited disordered mandibular movements, tremors, and resorbed mandibular ridge. Aiming retention and stability, double molding with zinc enolic oxide impression paste, neutral zone technique, and non-anatomic teeth were proposed as clinical strategies. At delivery, identification and relief in the supercompression areas were performed to facilitate the acceptance and use of the new dentures. CONCLUSION: The strategies promoted patient satisfaction regarding retention, stability, and comfort. This treatment may be considered for the rehabilitation of Parkinson's disease patients, favoring the adaptation process.

Toward low-cost gene therapy: mRNA-based therapeutics for treatment of inherited retinal diseases.

Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated costs impede widespread access, particularly in low-to-middle income countries. The primary challenge remains: how can we make these therapies globally affordable? Leveraging advancements in mRNA therapies might offer a more economically viable alternative. Furthermore, transitioning to nonviral delivery systems could provide a dual benefit of reduced costs and increased scalability. Relevant stakeholders must collaboratively devise and implement a research agenda to realize the potential of mRNA strategies in equitable access to treatments to prevent vision loss.

Immunomodulatory effects of different strains of Lactococcus lactis in DSS-induced colitis.

Inflammatory bowel diseases (IBD) are gastrointestinal disorders characterized by a breakdown in intestinal homeostasis by inflammatory immune responses to luminal antigens. Novel strategies for ameliorating IBD have been proposed in many studies using animal models. Our group has demonstrated that administration of Lactococcus lactis NCDO 2118 can improve clinical parameters of colitis induced by oral administration of dextran sulphate sodium (DSS). However, it is not clear whether other strains of L. lactis can yield the same effect. The objective of present study was to analyze the effects of three different L. lactis strains (NCDO2118, IL1403 and MG1363) in the development of DSS-induced colitis in C57BL/6 mice. Acute colitis was induced in C57/BL6 mice by the administration of 2% DSS during 7 consecutive days. Body weight loss and shortening of colon length were observed in DSS-treated mice, and none of L. lactis strains had an impact in these clinical signs of colitis. On the other hand, all strains improved the global macroscopical disease index and prevented goblet cells depletion as well as the increase of intestinal permeability. TNF-α production was reduced in gut mucosa of L. lactis DSS-treated mice indicating a modulation of a critical pro-inflammatory response by all strains tested. However, only L. lactis NCDO2118 and MG1363 induced a higher frequency of CD11c+CD11b-CD103+ tolerogenic dendritic cells in lymphoid organs of mice at steady state. We conclude that all tested strains of L. lactis improved the clinical scores and parameters of colitis, which confirm their anti-inflammatory properties in this model of colitis.

Gamma-delta T cells modulate the microbiota and fecal micro-RNAs to maintain mucosal tolerance.

BACKGROUND: Gamma-delta (γδ) T cells are a major cell population in the intestinal mucosa and are key mediators of mucosal tolerance and microbiota composition. Little is known about the mechanisms by which intestinal γδ T cells interact with the gut microbiota to maintain tolerance. RESULTS: We found that antibiotic treatment impaired oral tolerance and depleted intestinal γδ T cells, suggesting that the gut microbiota is necessary to maintain γδ T cells. We also found that mice deficient for γδ T cells (γδ-/-) had an altered microbiota composition that led to small intestine (SI) immune dysregulation and impaired tolerance. Accordingly, colonizing WT mice with γδ-/- microbiota resulted in SI immune dysregulation and loss of tolerance whereas colonizing γδ-/- mice with WT microbiota normalized mucosal immune responses and restored mucosal tolerance. Moreover, we found that SI γδ T cells shaped the gut microbiota and regulated intestinal homeostasis by secreting the fecal micro-RNA let-7f. Importantly, oral administration of let-7f to γδ-/- mice rescued mucosal tolerance by promoting the growth of the γδ-/--microbiota-depleted microbe Ruminococcus gnavus. CONCLUSIONS: Taken together, we demonstrate that γδ T cell-selected microbiota is necessary and sufficient to promote mucosal tolerance, is mediated in part by γδ T cell secretion of fecal micro-RNAs, and is mechanistically linked to restoration of mucosal immune responses. Video Abstract.

Age-Related Changes of the Synucleins Profile in the Mouse Retina.

Alpha-synuclein (aSyn) plays a central role in Parkinson's disease (PD) and has been extensively studied in the brain. This protein is part of the synuclein family, which is also composed of beta-synuclein (bSyn) and gamma-synuclein (gSyn). In addition to its neurotoxic role, synucleins have important functions in the nervous system, modulating synaptic transmission. Synucleins are expressed in the retina, but they have been poorly characterized. However, there is evidence that they are important for visual function and that they can play a role in retinal degeneration. This study aimed to profile synucleins in the retina of naturally aged mice and to correlate their patterns with specific retinal cells. With aging, we observed a decrease in the thickness of specific retinal layers, accompanied by an increase in glial reactivity. Moreover, the aSyn levels decreased, whereas bSyn increased with aging. The colocalization of both proteins was decreased in the inner plexiform layer (IPL) of the aged retina. gSyn presented an age-related decrease at the inner nuclear layer but was not significantly changed in the ganglion cell layer. The synaptic marker synaptophysin was shown to be preferentially colocalized with aSyn in the IPL with aging. At the same time, aSyn was found to exist at the presynaptic endings of bipolar cells and was affected by aging. Overall, this study suggests that physiological aging can be responsible for changes in the retinal tissue, implicating functional alterations that could affect synuclein family function.

Hsp65-producing Lactococcus lactis inhibits experimental autoimmune encephalomyelitis by preventing cell migration into spinal cord.

Multiple sclerosis is an autoimmune disease that affects the central nervous system. Because of its complexity and the difficulty to treat, searching for immunoregulatory responses that reduce the clinical signs of disease by non-aggressive mechanisms and without adverse effects is a scientific challenge. Herein we propose a protocol of oral tolerance induction that prevented and controlled MOG-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The genetically modified strain HSP65-producing Lactococcus lactis was orally administered for 5 consecutive days either before or during disease development in mice. Both protocols of feeding HSP65 resulted in significant reduction in the clinical score of EAE. Frequencies of LAP+CD4+Foxp3- regulatory T cells were higher in spleens and inguinal lymph nodes of fed mice. In addition, intravital microscopy showed that adherence of leukocytes to venules in the spinal cord was reduced in orally treated mice. Oral treatment with HSP65-producing L.lactis prevented leukocytes to leave the secondary lymphoid organs, therefore they could not reach the central nervous system. Despite the inhibition of pathological immune response that drive EAE development, activated T cells were at normal frequencies suggesting that oral tolerance did not induce general immunosuppression, but it led to specific control of pathogenic T cells. Our results indicate a novel therapeutic strategy to prevent and control autoimmune diseases such as multiple sclerosis.

Neuroimmune circuits involved in ß-lactoglobulin-induced food allergy.

Several antigens can act as allergens eliciting IgE-mediated food allergy reactions when fed to sensitized animals. One of them is ovalbumin (OVA) which is the main allergen in egg white. Allergic mice develop aversion to OVA consumption. This aversive behavior is associated with anxiety, and it can be transferred to non-sensitized mice by injection of serum of allergic mice. However, it is yet to be determined whether altered behavior is a general component of food allergy or whether it is specific for some types of allergens. Cow's milk allergy is the most prevalent food allergy that usually begins early in life and ß-lactoglobulin (BLG) is the milk component with the highest allergenicity. In this study, we investigated behavioral and neuroimmune circuits triggered by allergic sensitization to BLG. A neuroimmune conflict between aversion and reward was observed in a model of food allergy induced by BLG intake. Mice sensitized to BLG did not present aversive behavior when BLG was used for sensitization and oral challenge. Mice allergic to BLG preferred to drink the allergen-containing solution over water even though they had high levels of specific IgE, inflammatory cells in the intestinal mucosa and significant weight loss. When sensitized to OVA and challenged with the same antigen, mice had increased levels of neuron activation in the amygdala, a brain area related to anxiety. On the other hand, when mice were sensitized to OVA and received a mixture of BLG and OVA in the oral challenge, mice preferred to drink this mixture, despite their aversion to OVA, which was associated with neuron activation in the nucleus accumbens, an area related to reward behavior. Thus, the aversive behavior observed in food allergy to OVA does not apply to all antigens and some allergens may activate the brain reward system rather than anxiety and aversion. Our study provides novel insights into the neuroimmune conflicts regarding preference and avoidance to a common antigen associated with food allergy.

Epha1 is a cell-surface marker for the neuromesodermal competent population.

The vertebrate body is built during embryonic development by the sequential addition of new tissue as the embryo grows at its caudal end. During this process, progenitor cells within the neuromesodermal competent (NMC) region generate the postcranial neural tube and paraxial mesoderm. Here, we have applied a genetic strategy to recover the NMC cell population from mouse embryonic tissues and have searched their transcriptome for cell-surface markers that would give access to these cells without previous genetic modifications. We found that Epha1 expression is restricted to the axial progenitor-containing areas of the mouse embryo. Epha1-positive cells isolated from the mouse tailbud generate neural and mesodermal derivatives when cultured in vitro. This observation, together with their enrichment in the Sox2+/Tbxt+ molecular phenotype, indicates a direct association between Epha1 and the NMC population. Additional analyses suggest that tailbud cells expressing low Epha1 levels might also contain notochord progenitors, and that high Epha1 expression might be associated with progenitors entering paraxial mesoderm differentiation. Epha1 could thus be a valuable cell-surface marker for labeling and recovering physiologically active axial progenitors from embryonic tissues.

Therapeutic Effects of Probiotic Minas Frescal Cheese on the Attenuation of Ulcerative Colitis in a Murine Model.

Inflammatory bowel diseases (IBDs) constitute disturbances of gastrointestinal tract that cause irreversible changes in the structure and function of tissues. Ulcerative colitis (UC), the most frequent IBD in the population, is characterized by prominent inflammation of the human colon. Functional foods containing probiotic bacteria have been studied as adjuvants to the treatment or prevention of IBDs. The selected probiotic strain Lactococcus lactis NCDO 2118 (L. lactis NCDO 2118) exhibits immunomodulatory effects, with promising results in UC mouse model induced by dextran sodium sulfate (DSS). Additionally, cheese is a dairy food that presents high nutritional value, besides being a good delivery system that can be used to improve survival and enhance the therapeutic effects of probiotic bacteria in the host. Therefore, this work investigated the probiotic therapeutic effects of an experimental Minas Frescal cheese containing L. lactis NCDO 2118 in DSS-induced colitis in mice. During colitis induction, mice that consumed the probiotic cheese exhibited reduced in the severity of colitis, with attenuated weight loss, lower disease activity index, limited shortening of the colon length, and reduced histopathological score. Moreover, probiotic cheese administration increased gene expression of tight junctions' proteins zo-1, zo-2, ocln, and cln-1 in the colon and increase IL-10 release in the spleen and lymph nodes. In this way, this work demonstrates that consumption of probiotic Minas Frescal cheese, containing L. lactis NCDO 2118, prevents the inflammatory process during DSS-induced colitis in mice, opening perspectives for the development of new probiotic functional foods for personalized nutrition in the context of IBD.

A tree nymph of the Brazilian Atlantic Forest: Dryades (Galipeinae, Rutaceae), a new neotropical genus segregated from Conchocarpus.

Subtribe Galipeinae (tribe Galipeeae) is the most diverse group of Rutaceae (the orange family) in the Neotropics, with 27 genera and ca. 130 species. The largest genus in the subtribe is Conchocarpus, with ca. 50 species, distributed from Central America to southern Brazil, and is particularly diverse in the Brazilian Atlantic Forest. The circumscription of the genus was recently changed to accommodate the species of Almeidea. However, even with this inclusion, Conchocarpus did not appear as monophyletic because the position of C. concinnus, which appeared in a clade with the other genera of Galipeinae rather than in the clade with the other species of Conchocarpus. The objective of the present study is to investigate the phylogenetic position of four other species of Conchocarpus (hereafter called "C. gauchaudianus group") that share morphological traits and geographical distribution with C. concinnus suggesting a close phylogenetic affinity. Phylogenetic analyses were based on morphological and molecular data from nuclear regions ITS-1 and ITS-2 as well as plastid regions trnL-trnF and rps-16, and were conducted with parsimony and Bayesian inference as optimization criteria. Results showed Conchocarpus as polyphyletic with its species divided in two clades, one, herein called "the Conchocarpus sensu stricto group," includes the type species C. macrophyllus, and the other "the Conchocarpus gaudichaudianus group" includes C. concinnus. The latter group is here recognized as a new genus, Dryades, the name given by Carl Friederich von Martius (1794-1868) to the Domain of the Atlantic Forest in Brazil, inspired by the tree nymphs in Greek mythology. Floral structure and leaf morphology provided further support to the findings of phylogenetic analysis. A description of the new genus, new combinations, a key to the species of the new genus, discussions of the affinities of the species are also provided, as well as data on the conservation status of the species of Dryades. Additionally, new data on floral structure of C. heterophyllus, C. macrophyllus and C. minutiflorus (all from the Conchocarpus sensu stricto group) are provided.

Host dysbiosis negatively impacts IL-9-producing T-cell differentiation and antitumour immunity.

BACKGROUND: Host-microbiota interactions shape T-cell differentiation and promote tumour immunity. Although IL-9-producing T cells have been described as potent antitumour effectors, their role in microbiota-mediated tumour control remains unclear. METHODS: We analysed the impact of the intestinal microbiota on the differentiation of colonic lamina propria IL-9-producing T cells in germ-free and dysbiotic mice. Systemic effects of the intestinal microbiota on IL-9-producing T cells and the antitumour role of IL-9 were analysed in a model of melanoma-challenged dysbiotic mice. RESULTS: We show that germ-free mice have lower frequency of colonic lamina propria IL-9-producing T cells when compared with conventional mice, and that intestinal microbiota reconstitution restores cell frequencies. Long-term antibiotic treatment promotes host dysbiosis, diminishes intestinal IL-4 and TGF-ß gene expression, decreases the frequency of colonic lamina propria IL-9-producing T cells, increases the susceptibility to tumour development and reduces the frequency of IL-9-producing T cells in the tumour microenvironment. Faecal transplant restores intestinal microbiota diversity, and the frequency of IL-9-producing T cells in the lungs of dysbiotic animals, restraining tumour burden. Finally, recombinant IL-9 injection enhances tumour control in dysbiotic mice. CONCLUSIONS: Host-microbiota interactions are required for adequate differentiation and antitumour function of IL-9-producing T cells.

Beneficial Propionibacteria within a Probiotic Emmental Cheese: Impact on Dextran Sodium Sulphate-Induced Colitis in Mice.

BACKGROUNDS AND AIMS: Inflammatory Bowel Diseases (IBD), including Ulcerative Colitis (UC), coincide with alterations in the gut microbiota. Consumption of immunomodulatory strains of probiotic bacteria may induce or prolong remission in UC patients. Fermented foods, including cheeses, constitute major vectors for bacteria consumption. New evidences revealed anti-inflammatory effects in selected strains of Propionibacterium freudenreichii. We thus hypothesized that consumption of a functional cheese, fermented by such a strain, may exert a positive effect on IBD. METHODS: We investigated the impact of cheese fermented by P. freudenreichii on gut inflammation. We developed an experimental single-strain cheese solely fermented by a selected immunomodulatory strain of P. freudenreichii, CIRM-BIA 129. We moreover produced, in industrial conditions, an Emmental cheese using the same strain, in combination with Lactobacillus delbrueckii CNRZ327 and Streptococcus thermophilus LMD-9, as starters. Consumption of both cheeses was investigated with respect to prevention of Dextran Sodium Sulphate (DSS)-induced colitis in mice. RESULTS: Consumption of the single-strain experimental cheese, or of the industrial Emmental, both fermented by P. freudenreichii CIRM-BIA 129, reduced severity of subsequent DSS-induced colitis, weight loss, disease activity index and histological score. Both treatments, in a preventive way, reduced small bowel Immunoglobulin A (IgA) secretion, restored occludin gene expression and prevented induction of Tumor Necrosis Factor α (TNFα), Interferon γ (IFNγ) and Interleukin-17 (IL-17). CONCLUSIONS: A combination of immunomodulatory strains of starter bacteria can be used to manufacture an anti-inflammatory cheese, as revealed in an animal model of colitis. This opens new perspectives for personalised nutrition in the context of IBD.

Short period of high-intensity inspiratory muscle training improves inspiratory muscle strength in patients with chronic kidney disease on hemodialysis: a randomized controlled trial.

BACKGROUND: Chronic kidney disease is a complex disease that impacts multiple organs and systems (including musculoskeletal and cardiorespiratory) leading to reduction of functional capacity. OBJECTIVE: The aim of this study was to investigate the effect of a short period of high intensity inspiratory muscle training on maximum inspiratory pressure, functional capacity and endothelial function of chronic kidney disease patients on hemodialysis. METHODS: This randomized controlled trial enrolled 25 patients who were allocated into two groups: intervention (IMTG=14) and control (CG=11) groups. Intervention patients received the exercise protocol over a period of 5 weeks, 6 times per week, with each session consisting of 5 sets of 10 repetitions with an initial load of 50% progressing to 70% of maximum inspiratory pressure , measured weekly. The primary outcome was inspiratory muscle strength and the secondary outcomes were functional capacity and endothelial function evaluated before and after the training protocol. RESULTS: The inspiratory muscle training induced a marked improvement in maximum inspiratory pressure which was evident after the training period (mean difference 19.0cmH2O - 95%CI 0.4-37.5; IMTG: 102±25.7cmH2O vs CG: 83±19.2; p=0.046). The magnitude of maximum inspiratory pressure improvement was 33.5% at the end of the protocol for the IMTG. Functional capacity and endothelial function did not vary between or within groups. CONCLUSION: A short period of high-intensity inspiratory muscle training for five weeks was able to improve inspiratory muscle strength of chronic kidney disease patients on hemodialysis (ClinicalTrials.gov registration NCT03082404).

Early life history of the Caribbean coral Orbicella faveolata (Scleractinia: Merulinidae)

Introduction: Rehabilitation of hermatypic coral species that have declined in the Caribbean in recent decades is a priority. Production of sexual recruits is considered the best restoration method to aid affected populations. Objective: To gain knowledge of early life stages of Orbicella faveolata and to enhance production of new sexual recruits. Methods: Gamete bundles from the coral species O. faveolata were collected over two years (2018 and 2019) from Los Corales del Rosario y de San Bernardo Natural National Park, Cartagena, Colombia. Assisted fertilization, larval rearing, settlement (onto crustose coralline algae, CCA) and post settlement survival in laboratory conditions were monitored. Results: Embryonic and larval development were documented over 55 hours after the first cleavage, when larvae were fully developed and started pre-settlement behavior. Settlement began 7 days after first cleavage and after 37 days polyps had acquired zooxanthellae. Larval settlement was higher on Lythophyllum congestum and Titanoderma prototypum than in response to Porolithon pachydermum, Neogoniolithon sp., Hydrolithon sp., and Lythophyllum sp. Larvae did not settle on dead coral or on the negative control (sterilized seawater). After the first week post settlement survival was 59 % amongst O. faveolata recruits. During the second week, survival dropped to 42 %, and was further reduced to 0 % at the end of the third week. Conclusions: O. faveolata larvae require cues from certain CCA species to settle, they do not settle in absence of CCA. Increased larvae availability is possible through assisted fertilization in the laboratory, however, due to the high mortality in early post-settlement phases, additional research needs to be conducted in order to scale up larvae production and improve understanding of the cues that enhance settlement and the factors which cause post-settlement mortality.

Introducción: La rehabilitación de las especies de corales hermatípicos del Caribe que han disminuido en las últimas décadas es una prioridad. La producción de reclutas sexuales se considera el mejor método de restauración para ayudar a las poblaciones afectadas. Objetivo: Obtener conocimiento de las primeras etapas de la vida de O. faveolata y mejorar la producción de nuevos reclutas sexuales. Métodos: Por dos años (2018 y 2019), seis días después de luna llena en septiembre, se recolectaron paquetes gaméticos en arrecifes del Parque Nacional Natural Los Corales del Rosario y de San Bernardo, Cartagena, Colombia. Se siguió la fertilización asistida, la cría de larvas, el asentamiento y la supervivencia posterior al asentamiento en algas coralinas costrosas (ACC) en condiciones de laboratorio. Resultados: El desarrollo de embriones y larvas se documenta a lo largo de 55 h después del primer clivaje, cuando la larva está desarrollada completamente y comenzó el comportamiento previo al asentamiento. El asentamiento comienza 7 días después del primer clivaje y 37 días después, la mayoría de los pólipos presentan zooxantelas. El asentamiento larval fue más alto en Lythophyllum congestum y Titanoderma prototypum que en respuesta a Porolithon pachydermum, Neogoniolithon sp., Hydrolithon sp., y Lythophyllum sp. No hubo asentamiento sobre coral muerto ni en el control negativo (agua de mar esterilizada). La supervivencia bajó de un 59 % en la primera semana después del asentamiento, a 42 % durante la segunda semana y 0 % para el final de la tercera semana. Conclusiones: Las larvas de O. faveolata requieren señales de ciertas especies de ACC para asentarse, ellas no se asientan en ausencia de ACC. La disponibilidad de larvas es posible mediante la fertilización asistida en laboratorio. Sin embargo, debido a la alta mortalidad en las primeras fases posteriores al asentamiento, queda mucho por hacer para aumentar la producción de larvas y mejorar nuestro conocimiento y comprensión de las señales que mejoran el asentamiento y las que previenen o inhiben la supervivencia del recluta.

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes.

Alterations in the composition of the intestinal microbiota have been associated with development of type 1 diabetes (T1D), but little is known about changes in intestinal homeostasis that contribute to disease pathogenesis. Here, we analyzed oral tolerance induction, components of the intestinal barrier, fecal microbiota, and immune cell phenotypes in non-obese diabetic (NOD) mice during disease progression compared to non-obese diabetes resistant (NOR) mice. NOD mice failed to develop oral tolerance and had defective protective/regulatory mechanisms in the intestinal mucosa, including decreased numbers of goblet cells, diminished mucus production, and lower levels of total and bacteria-bound secretory IgA, as well as an altered IEL profile. These disturbances correlated with bacteria translocation to the pancreatic lymph node possibly contributing to T1D onset. The composition of the fecal microbiota was altered in pre-diabetic NOD mice, and cross-fostering of NOD mice by NOR mothers corrected their defect in mucus production, indicating a role for NOD microbiota in gut barrier dysfunction. NOD mice had a reduction of CD103+ dendritic cells (DCs) in the MLNs, together with an increase of effector Th17 cells and ILC3, as well as a decrease of Th2 cells, ILC2, and Treg cells in the small intestine. Importantly, most of these gut alterations precede the onset of insulitis. Disorders in the intestinal mucosa of NOD mice can potentially interfere with the development of T1D due the close relationship between the gut and the pancreas. Understanding these early alterations is important for the design of novel therapeutic strategies for T1D prevention.

Tail Bud Progenitor Activity Relies on a Network Comprising Gdf11, Lin28, and Hox13 Genes.

During the trunk-to-tail transition, axial progenitors relocate from the epiblast to the tail bud. Here, we show that this process entails a major regulatory switch, bringing tail bud progenitors under Gdf11 signaling control. Gdf11 mutant embryos have an increased number of such progenitors that favor neural differentiation routes, resulting in a dramatic expansion of the neural tube. Moreover, inhibition of Gdf11 signaling recovers the proliferation ability of these progenitors when cultured in vitro. Tail bud progenitor growth is independent of Oct4, relying instead on Lin28 activity. Gdf11 signaling eventually activates Hox genes of paralog group 13, which halt expansion of these progenitors, at least in part, by down-regulating Lin28 genes. Our results uncover a genetic network involving Gdf11, Lin28, and Hox13 genes controlling axial progenitor activity in the tail bud.

Probiotic Propionibacterium freudenreichii requires SlpB protein to mitigate mucositis induced by chemotherapy.

Propionibacterium freudenreichii CIRM-BIA 129 (P. freudenreichii wild type, WT) is a probiotic bacterium, which exerts immunomodulatory effects. This strain possesses extractable surface proteins, including SlpB, which are involved in anti-inflammatory effect and in adhesion to epithelial cells. We decided to investigate the impact of slpB gene mutation on immunomodulation in vitro and in vivo. In an in vitro assay, P. freudenreichii WT reduced expression of IL-8 (p<0.0001) and TNF-α (p<0.0001) cytokines in LPS-stimulated HT-29 cells. P. freudenreichii ΔslpB, lacking the SlpB protein, failed to do so. Subsequently, both strains were investigated in vivo in a 5-FU-induced mucositis mice model. Mucositis is a common side effect of cytotoxic chemotherapy with 5-FU, characterized by mucosal injury, inflammation, diarrhea, and weight loss. The WT strain prevented weight loss, reduced inflammation and consequently histopathological scores. Furthermore, it regulated key markers, including Claudin-1 (cld1, p<0.0005) and IL-17a (Il17a, p<0.0001) genes, as well as IL-12 (p<0.0001) and IL-1ß (p<0.0429) cytokines levels. Mutant strain displayed opposite regulatory effect on cld1 expression and on IL-12 levels. This work emphasizes the importance of SlpB in P. freudenreichii ability to reduce mucositis inflammation. It opens perspectives for the development of probiotic products to decrease side effects of chemotherapy using GRAS bacteria with immunomodulatory surface protein properties.

Whey Protein Isolate-Supplemented Beverage, Fermented by Lactobacillus casei BL23 and Propionibacterium freudenreichii 138, in the Prevention of Mucositis in Mice.

Mucositis is a clinically important gastrointestinal inflammatory infirmity, generated by antineoplastic drugs cytotoxic effects. The inflammatory process caused by this disease frequently leads to derangements in the alimentary tract and great malaise for the patient. Novel strategies are necessary for its prevention or treatment, as currently available treatments of mucositis have several limitations in relieving its symptoms. In this context, several research groups have investigated the use of probiotic bacteria, and in particular dairy bacterial strains. Compelling evidences reveal that milk fermented by certain probiotic bacteria has the capacity to ameliorate intestinal inflammatory disorders. In addition, innovative probiotic delivery strategies, based on probiotics incorporation into protective matrices, such as whey proteins, were able to increase the therapeutic effect of probiotic strains by providing extra protection for bacteria against environmental stresses. Therefore, in this study, we evaluated the role of the whey protein isolate (WPI), when added to skim milk fermented by Lactobacillus casei BL23 (L. casei BL23) or by Propionibacterium freudenreichii CIRM-BIA138 (P. freudenreichii 138), as a protective matrix against in vitro stress challenges. In addition, we investigated the therapeutic effect of these fermented beverages in a murine model of mucositis induced by 5-Fluorouracil (5-FU). Our results demonstrated that milk supplementation with 30% (w/v) of WPI increases the survival rate of both strains when challenged with acid, bile salts, high temperature and cold storage stresses, compared to fermented skim milk without the addition of WPI. Moreover, treatment with the probiotic beverages prevented weight loss and intestinal damages in mice receiving 5-FU. We conclude that the presence of WPI maximizes the anti-inflammatory effects of L. casei BL23, but not for P. freudenreichii 138, suggesting that whey protein enhancement of probiotic activity might be strain-dependent.