Update: Innate Lymphoid Cells in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic and nonspecific intestinal inflammatory condition with high relapse rate. Its pathogenesis has been linked to dysbacteriosis, genetic and environmental factors. In recent years, a new type of lymphocytes, termed innate lymphoid cells, has been described and classified into three subtypes of innate lymphoid cells-group 1, group 2 and group 3. An imbalance among these subsets' interaction with gut microbiome, and other immune cells affects intestinal mucosal homeostasis. Understanding the role of innate lymphoid cells may provide ideas for developing novel and targeted approaches for treatment of IBD.

Serum Inflammatory Factor Profiles in the Pathogenesis of High-Altitude Polycythemia and Mechanisms of Acclimation to High Altitudes.

High-altitude polycythemia (HAPC) is a common aspect of chronic mountain sickness (CMS) caused by hypoxia and is the main cause of other symptoms associated with CMS. However, its pathogenesis and the mechanisms of high-altitude acclimation have not been fully elucidated. Exposure to high altitude is associated with elevated inflammatory mediators. In this study, the subjects were recruited and placed into a plain control (PC) group, plateau control (PUC) group, early HAPC (eHAPC) group, or a confirmed HAPC (cHAPC) group. Serum samples were collected, and inflammatory factors were measured by a novel antibody array methodology. The serum levels of interleukin-2 (IL-2), interleukin-3 (IL-3), and macrophage chemoattractant protein-1 (MCP-1) in the eHAPC group and the levels of interleukin-1 beta (IL-1 beta), IL-2, IL-3, tumor necrosis factor-alpha (TNF-alpha), MCP-1, and interleukin-16 (IL-16) in the cHAPC group were higher than those in the PUC group. More interestingly, the expression of IL-1 beta, IL-2, IL-3, TNF-alpha, MCP-1, and IL-16 in the PUC group showed a remarkable lower value than that in the PC group. These results suggest that these six factors might be involved in the pathogenesis of HAPC as well as acclimation to high altitudes. Altered inflammatory factors might be new biomarkers for HAPC and for high-altitude acclimation.

Fecal Microbiota Transplant via Endoscopic Delivering Through Small Intestine and Colon: No Difference for Crohn's Disease.

BACKGROUND AND AIMS: Crohn's disease (CD) is a chronic inflammatory bowel disorder associated with intestinal dysbiosis. This study aimed to determine the efficacy and safety of different methods of fecal microbiota transplantation (FMT), a potential therapy for CD. METHODS: Patients with CD were randomized to receive FMT by gastroscopy or colonoscopy; a second transplantation was performed 1 week later. Patients were assessed by clinical evaluation and serum testing (at weeks 1, 2, 4, 6, and 8) and endoscopy (8 weeks after transplantation). Fecal DNA was extracted and analyzed using the Illuminal sequencing platform. RESULTS: Of the 27 patients included in the study, clinical remission was achieved in 18 (66.7%); no significant difference was seen between the two methods. 76.9% of gastroscopy group patients and 64.3% of colonoscopy group patients experienced mild adverse events during or shortly after treatment. Microbiota diversity analyses showed that, in comparison with the donors, patients had lower operational taxonomic units (OTU; 117 vs. 258, p < 0.05) and Shannon diversity index (2.05 vs. 3.46, p < 0.05). The CD patients showed a significant increase in OTU and Shannon diversity index 2 weeks after FMT. In comparison with the donors, CD patients had lower levels of Bacteroides, Eubacterium, faecalibacterium, and Roseburia, and higher levels of Clostridium, Cronobacter, Fusobacterium, and Streptococcus. CONCLUSIONS: FMT was seen to be safe and effective in this cohort of patients with CD. No significant differences in clinical remission rate and adverse events were seen between the gastroscopy and colonoscopy groups. FMT was seen to increase the species richness in CD patients.

Roseburia intestinalis inhibits oncostatin M and maintains tight junction integrity in a murine model of acute experimental colitis.

Objective: Levels of oncostatin M (OSM) and the composition of gut microbiota predict responses to anti-TNF agents used for IBD therapy. Here, the aim was to investigate the effects of Roseburia intestinalis, a gut microbiota, on OSM and on intestinal barrier in colitis. Methods: In the murine model of 3% dextran sulfate sodium (DSS)-induced colitis, we tested disease activity index (DAI), colon length, histological score and expression of tight junction (TJ) proteins (ZO-1, occludin and claudin-1), OSM, TNF-α and TLR5. In addition, a cellular model was used to examine the role of R. intestinalis during secretion of OSM by lipopolysaccharide (LPS)-induced bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and TLR5 knockout (TLR5 KO) mice. Furthermore, we evaluated the impact of OSM on expressions of TJ proteins by Caco-2 cells. Results: R. intestinalis in DSS-induced colitis decreased DAI score (p < .001), colon length shortening (6.46 ± 0.36 cm vs 5.65 ± 0.47 cm, p = .022), histological score (2.667 ± 1.15 vs 5.33 ± 1.14, p = .018) and increased expression of TJ proteins (p < .05). In addition, R. intestinalis reduced expression of OSM (p < .05) and TNF-α (p < .05), while increasing expression of TLR5 (p < .05). Furthermore, R. intestinalis reduced secretion of OSM (p < .05) by LPS-induced BMDMs isolated from WT and TLR5 KO mice. Moreover, OSM downregulated expression of TJ proteins (p < .05) by Caco-2 cells in a concentration-dependent manner. Conclusions: These results indicate that R. intestinalis attenuates inflammation in IBD by decreasing secretion of OSM and by promoting intestinal barrier function. Taken together, the data provide insight into the role of the gut microbiota in patients with IBD who are resistant to anti-TNF therapy.

Knockdown of long non-coding RNA MAP3K20 antisense RNA 1 inhibits gastric cancer growth through epigenetically regulating miR-375.

Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) play a critical role in tumorigenesis of gastric cancer. LncRNA MAP3K20 antisense RNA 1 (MLK7-AS1) has been identified as one of gastric cancer-specific lncRNAs. However, its precise role in gastric cancer remains unknown. In this study, we found that lncRNA MLK7-AS1 was significantly increased in gastric cancer tissues compared with in adjacent tissues. Gastric cancer patients with high MLK7-AS1 expression had a shorter survival and poorer prognosis. By loss-function assay, we demonstrated that knockdown of MLK7-AS1 inhibited cell proliferation and induced apoptosis in HGC27and MKN-45 cells. Furthermore, we identified miR-375 as a target of MLK7-AS1. MLK7-AS1 interacted with Dnmt1 and recruited it to miR-375 promotor, hyper-methylating miR-375 promotor and repressing miR-375 expression. Taken together, our findings demonstrate that knockdown of MLK7-AS1 by siRNA inhibits gastric cancer growth by epigenetically regulating miR-375. Thus, MLK7-AS1 may be a useful prognostic marker and therapeutic target for gastric cancer patients.

Roseburia intestinalis-derived flagellin is a negative regulator of intestinal inflammation.

Our previous study showed that the Roseburia intestinalis (R. intestinalis), one of the dominant intestinal bacterial microbiota, was significantly decreased in Crohn's disease patients and protected colon epithelial cells from inflammatory damage. However, the roles of lncRNAs in R. intestinalis flagellin-mediated anti-inflammation remain unclear. In this study, we investigate global lncRNA expression profiles using microarray analysis of ulcerative colitis samples from DSS/Flagellin-challenged mice and identified a Flagellin-induced upregulated lncRNA (HIF1A-AS2). Flagellin induced HIF1A-AS2 expression in a dose- and time-dependent manner via p38-stat1 activation. Selective pharmacological inhibitors of Stat1 and p38, and genetic knockdown of these genes abolished Flagellin-induced HIF1A-AS2 expression. In addition, luciferase reporter assay showed that Flagellin activated HIF1A-AS2 promotor via increasing stat1 phosphorylation. Silencing of HIF1A-AS2 abolished Flagellin-mediated anti-inflammatory effects, evaluating by upregulation of cytokines expression, including TNF-α, IL-1ß, IL-6 and IL-12, but not TNFß. In addition, knockdown of HIF1A-AS2 significantly increased p65 and Jnk phosphorylation, and sufficiently abolished Flagellin-mediated anti-inflammatory affects in vivo. Our study provides new insights into the mechanisms that lncRNAs regulate flagellin-mediated alleviation of colonic inflammation. It is indicated that HIF1A-AS2 may be a modulator of intestinal inflammation and represent a novel target for future therapeutics.

Insights into Roseburia intestinalis which alleviates experimental colitis pathology by inducing anti-inflammatory responses.

BACKGROUND AND AIM: The study aims to elucidate the anti-inflammatory effect and mechanism of Roseburia intestinalis (R. intestinalis) in Crohn's disease (CD). METHODS: 16S-rRNA genome sequencing technique is used to detect the characteristics of intestinal microbiota in untreated CD patients and healthy controls. Then the study investigates the effects of R. intestinalis on disease activity index score, intestinal pathology, the differentiation of Treg cells, and the expressions of Thymic stromal lymphopoietin (TSLP), TGF-ß and IL-10 by using TNBS colitis models. At the cellular level, the study uses LPS to stimulate Caco-2 cells to conduct inflammation models and then co-culture with R. intestinalis and detect changes of TSLP and TGF-ß. The study then uses R. intestinalis to stimulate peripheral blood mononuclear cells, and the change of Treg cells was detected. RESULTS: Genome sequencing of fecal samples from untreated CD patients (n = 10) revealed decreases in the abundance and diversity of intestinal microbiota, including R. intestinalis. Moreover, R. intestinalis reduced disease activity index scores, colon shortening, intestinal mucosal epithelial injury, and mucosal lymphocyte infiltration in a colitis mice model. It suppressed intestinal inflammation by increasing Treg cell numbers and expression of the anti-inflammatory cytokines TSLP, TGF-ß, and interleukin-10 (P < 0.05). R. intestinalis also increased secretion of TSLP and TGF-ß in lipopolysaccharide-treated Caco-2 cells. CONCLUSION: These findings suggest that R. intestinalis suppresses CD pathogenesis by inducing anti-inflammatory responses.

Update on intestinal microbiota in Crohn's disease 2017: Mechanisms, clinical application, adverse reactions, and outlook.

The pathogenesis of Crohn's disease (CD) is complex, and it is thought to be associated with the environment, immune, hereditary, microbe, and other factors. If the balance between the host and the intestinal microbes in CD patients was broken, immune-inflammatory response of susceptible individuals might be triggered. Probiotics could improve the intestinal microbial flora balance and treat human effectively. There are several new mechanisms that might explain the role of probiotics. Fecal microbiota transplantation (FMT) is becoming more and more attractive in treating a large amount of digestive system diseases that are related to the dysbiosis of intestinal microbiota. FMT has been widely used in recurrent Clostridium difficile infection. More and more attention has been paid on the clinical application of FMT in CD, while the exact mechanism is still a mystery. So in this review, we explore the mechanism, clinical application, and adverse reactions of intestinal microbiota in CD so that we can use the tool to cure more diseases. Enteric microbiota leads to new therapeutic strategies for CD.

AMD3100 and G-CSF disrupt the cross-talk between leukemia cells and the endosteal niche and enhance their sensitivity to chemotherapeutic drugs in biomimetic polystyrene scaffolds.

BACKGROUND: The multidrug resistance of leukemia cells is closely related to the microenvironment. The present leukemia microenvironment models focus on two-dimensional co-culture system in vitro which does not mimic the in vivo cell growth, while the 3D polystyrene (PS) scaffolds have the advantage. Stromal cell derived factor-1 may be involved in the shielding of endosteal niche from leukemia cells by binding to its receptor CXCR4, but the relationship between SDF-1/CXCR4 axis and leukemia cells is unclear. DESIGN AND METHODS: The experiments were built on the 3D PS scaffolds coated with osteoblasts. Stromal cells and MV4-11 cells were plated on the scaffolds. Then G-CSF, AMD3100 and cytarabine were added. Adhesive rate, SDF-1 level, migration state, apoptosis rate, and cell cycle of leukemia cells were observed after incubation at 24h and 48h. RESULTS: G-CSF decreased the level of SDF-1 and inhibited the expression of CXCR4 and promoted stationary phase leukemia cells to enter the mitotic phase and enhanced the killing effect of chemotherapeutic drugs. AMD3100 disrupted the interaction between tumors and matrix, mobilized the leukemia cells to keep away from the protective microenvironment and strengthened the cytotoxic effect of Ara-C. The combination of G-CSF and AMD3100 had stronger effects on killing the leukemia cells induced by Ara-C. CONCLUSION: It demonstrates that AMD3100 and G-CSF may inhibit adhesion and migration abilities of leukemia cells with the bone marrow niche. Both of them inhibit the role of SDF-1/CXCR4 directly or indirectly. Thus inhibiting SDF-1/CXCR4 axis may be helpful to the treatment of refractory AML.

Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systematic review.

Fetal liver tyrosine kinase 3 (FLT3)-internal tandem duplications (ITDs) has been used as a powerful adverse prognostic indicator for acute myeloid leukemia (AML) in any age group. Evidence is mixed regarding the effects of allogeneic transplantation (allo-HSCT) in first complete remission (CR) for patients with FLT3/ITD AML. To fill this gap, this study provides a systematic review and meta-analysis of patients with FLT3/ITD AML receiving HSCT. A search of PubMed, Embase, and OVID yielded 1706 abstracts, two researchers screening the trials based on inclusion and exclusion criteria, and assessed the methodology quality independently. Meta-analysis showed that compared with chemotherapy, both allo-HSCT and autologous hematopoietic cell transplantation (auto-HSCT) can reduce the relapse rate (p < 0.01) and improve both the OS (p < 0.01) and DFS (p < 0.01). But when compared allo-HSCT with auto-HSCT, the OS (p = 0.27) and DFS (p = 0.19) have no statistical significance, and only the relapse indicator has statistical significance, p < 0.01. Based on the results, we can conclude that allo-HSCT is an efficient therapy approach for patients with FLT3/ITD AML. Chemotherapy cannot change the poor prognosis. Auto-HSCT can improve OS and DFS, but it cannot reduce the relapse rate.

Bacteroides vulgatus alleviates dextran sodium sulfate-induced colitis and depression-like behaviour by facilitating gut-brain axis balance.

Background: Patients with inflammatory bowel disease (IBD) have a higher prevalence of depression. Gut microbiota dysbiosis plays an important role in IBD and depression. However, few studies have explored the characteristic microbiota of patients with IBD and depression (IBDD), or their role in IBDD. Methods: We performed deep metagenomic sequencing and 16S rDNA quantitative PCR to characterise the gut microbial communities of patients with IBDD and patients with IBD without depression (IBDND). We then assessed the effect of the microbiota on colitis and depression in mouse models of dextran sulfate sodium salt (DSS)-induced colitis and lipopolysaccharide (LPS)-induced depression. Furthermore, liquid chromatography-tandem mass spectrometry was used to analyse the microbiota-derived metabolites involved in gut-brain communication. Evans Blue tracer dye was used to assess blood-brain barrier (BBB) permeability. Results: Our results showed that the faecal abundance of Bacteroides vulgatus (B. vulgatus) was lower in patients with IBDD than in those with IBDND. In the DSS-induced colitis mouse model, the B. vulgatus group showed a significantly lower disease activity index score, lesser weight loss, and longer colon length than the DSS group. Moreover, B. vulgatus relieved depression-like behaviour in the DSS-induced colitis mouse model and in the LPS-induced depression mouse model. Furthermore, the key metabolite of B. vulgatus was p-hydroxyphenylacetic acid (4-HPAA), which was found to relieve intestinal inflammation and alleviate depression-like behaviours in mouse models. By increasing the expression of the tight junction protein claudin-5 in the vascular endothelium of the BBB, B. vulgatus and 4-HPAA play critical roles in gut-brain communication. Conclusion: B. vulgatus and B. vulgatus-derived 4-HPAA ameliorated intestinal inflammation and relieved depressive symptoms through the gut-brain axis. Thus, administration of B. vulgatus or 4-HPAA supplementation is a promising therapeutic strategy for treating IBD, particularly IBDD.

Evolving Trends and Burden of Inflammatory Bowel Disease in Asia, 1990-2019: A Comprehensive Analysis Based on the Global Burden of Disease Study.

BACKGROUND: Asia's inflammatory bowel disease (IBD) burden has rapidly increased recently, but the epidemiological trends in Asia remain unclear. We report IBD's incidence, prevalence, mortality, and Disability-Adjusted Life Years (DALY) in 52 Asian countries from 1990 to 2019. METHODS: Data from the Global Burden of Disease 2019 were analyzed for IBD burden across 52 countries, using metrics like incidence, prevalence, mortality rates, and DALY. The epidemiological trend of IBD from 1990 to 2019 was assessed with the Joinpoint and APC methods. Decomposition and frontier analyses examined factors behind IBD case and death changes. The NORPRED forecasted Asia's morbidity and mortality trends from 2019 to 2044. RESULTS: From 1990 to 2019, The incidence and prevalence of IBD increased in Asia, while mortality and DALY decreased. East Asia had the highest increase in disease burden. IBD incidence was highest among the 30-34 age group, with prevalence peaking in the 45-49 age group. In high-income regions, IBD peak age shifted to younger groups. Decompose analysis showed population growth as the primary factor for the increasing IBD cases in Asia. NORDPRED model predicted a continued IBD burden increase in Asia over the next 25 years. CONCLUSIONS: Between 1990 and 2019, ASIR and ASPR of IBD in Asia increased, while ASMR and ASDR decreased. Due to population growth and aging, the IBD burden is expected to rise over the next 25 years, particularly in East Asia.

Functional Phenotypes of Peritoneal Macrophages Upon AMD3100 Treatment During Colitis-Associated Tumorigenesis.

CXCL12 and its receptor CXCR4 are independent prognostic factors in colorectal cancer. AMD3100 is the most frequently used FDA-approved antagonist that targets the CXCL12-CXCR4 axis in clinical trials. We aimed to explore the role of AMD3100 and its effect on peritoneal macrophages' functional phenotypes during colitis-associated tumorigenesis. We treated AMD3100 in a colitis-associated colon cancer mouse model and evaluated its effect on tumorigenesis. The phagocytosis activities of peritoneal macrophages were measured by flow cytometry. The proportions of macrophages and M1/M2 subpopulations were investigated by flow cytometry, ELISA, and immunochemistry. Serum levels of pro-inflammatory and anti-inflammatory cytokines were measured by LEGENDplex™ kits. Transwell assay and qRT-PCR were performed to investigate the direct effect of CXCL12 on macrophages in vitro. We demonstrated that AMD3100 treatment reduced the inflammatory damages in the colonic mucosal and ameliorated tumor development in experimental mice. We found that the phagocytosis activities of peritoneal macrophages fluctuated during colitis-associated tumorigenesis. The proportions of peritoneal macrophages and M1/M2 subpopulations, together with their metabolite and cytokines, changed dynamically in the process. Moreover, AMD3100 regulated the functional phenotypes of macrophages, including reducing the recruiting activity, promoting polarization to the M1 subpopulation, and reducing IL-12 and IL-23 levels in serum. Our study contributes to understanding dynamic changes of peritoneal macrophages upon AMD3100 treatment during tumorigenesis and sheds light on the potential therapeutic target of AMD3100 and peritoneal macrophages against colitis-associated colon cancer.

miR-126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis-associated colorectal cancer.

Inflammatory bowel disease, characterised by chronic relapsing-remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR-126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR-126 in colitis-associated CRC (CAC) and its underlying mechanism. We detected downregulated miR-126 expression during colorectal tumorigenesis in the mouse CAC model and in specimens from patients with CRC. The deficiency of miR-126 in intestinal epithelial cells (IECs) exacerbated tumorigenesis in mice. We identified CXCL12 as a direct target of miR-126 in inhibiting the development of colitis and CAC. Moreover, miR-126 regulated the recruitment of macrophages via CXCL12 and decreased the levels of proinflammatory cytokines (IL-6, IL-12 and IL-23). In addition, IL-6 secreted by macrophages, which were regulated by cocultured transfected CRC cells, altered the proliferation and migration of colon cells. Our data suggest that miR-126 exerts an antitumour effect on CAC by regulating the crosstalk between IECs and macrophages via CXCL12-IL-6 signalling. Our study contributes to the understanding of cancer progression and suggests miR-126 as a potential therapy for CRC.

Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity.

BACKGROUND: Nucleus accumbens-1 (NAC-1) is highly expressed in a variety of tumors, including colon cancer, and is closely associated with tumor recurrence, metastasis, and invasion. AIM: To determine whether and how NAC-1 affects antitumor immunity in colon cancer. METHODS: NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression; tumor cells with or without knockdown of NAC-1 were treated with CD8+ T cells to test their cytocidal effect. The level of the immune checkpoint programmed death receptor-1 ligand (PD-L1) in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting. A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1. Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or control-shRNA were treated with OT-I mouse CD8+ T cells to determine the tumor response to immunotherapy. Immune cells in the tumor tissues were analyzed using flow cytometry. NAC-1, PD-L1 and CD8+ T cells in colon cancer specimens from patients were examined using immunohistochemistry staining. RESULTS: Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+ T cells in cell culture experiments. The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+ T cells was recapitulated in a colon cancer xenograft animal model. Furthermore, knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels, and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid. In a reporter gene assay, transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1, indicating that NAC-1 regulates PD-L1 expression at the transcriptional level. In addition, depletion of tumoral NAC-1 increased the number of CD8+ T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells. CONCLUSION: Tumor expression of NAC-1 is a negative determinant of immunotherapy.

Roseburia intestinalis stimulates TLR5-dependent intestinal immunity against Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder characterized by intestinal immune dysfunction. Multiple factors, including gut dysbiosis, are involved in the pathogenesis of CD. However, the effect of commensal bacteria on controlling the inflammatory response in individuals with CD remains unclear. METHODS: We detected Toll-like receptor 2 (TLR2), TLR4, and TLR5 expression in Roseburia intestinalis (R. intestinalis)-treated mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Then, we quantified the signs of colonic inflammation, the proportion of regulatory T cells (Tregs) and the expression of thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)-ß in TLR-5-deficient (Tlr5-/-) mice, bone marrow chimera mice (generated using wild-type (WT) and Tlr5-/- mice), and anti-TSLP/anti-TGFß-treated C57BL/6 mice with colitis induced by TNBS. In vitro, we used the lipopolysaccharide (LPS)-stimulated human intestinal epithelial cell line Caco-2 as an inflammatory colon cell model treated with or without the TLR5-siRNA intervention in the presence of R. intestinalis and incubated human monocyte-derived dendritic cells (DCs) with the supernatant of Caco-2 cells. Then, we cocultured human CD4+ T cells with the aforementioned DCs to determine the differentiation of Tregs. Additionally, samples from patients with CD were collected to analyse the correlation between TLR5/TSLP/TGFß expression and the percentage of R. intestinalis. FINDINGS: Here, we show that R. intestinalis inhibits the development of CD by increasing the differentiation of anti-inflammatory Tregs. Mechanistically, R. intestinalis stimulates TSLP production in intestinal epithelial cells (IECs) through TLR5 but not TLR2 or TLR4. TSLP produced by IECs specifically induces the secretion of interleukin-10 (IL-10) and TGFß from DCs, which is necessary for subsequent Treg differentiation. Consequently, the depletion of TLR5 (using Tlr5-/- mice) or inhibition of TSLP (using anti-TSLP neutralizing antibodies) attenuates the protective effect of R. intestinalis on experimental colitis in mice. Importantly, the expression of TSLP in patients with CD is positively correlated with the level of R. intestinalis. INTERPRETATION: These findings reveal the previously unknown mechanism of R. intestinalis-mediated intestinal immune regulation, which may provide the basis for new therapeutic strategies for CD. FUNDING: This work was funded by the National Natural Science Foundation of China (81670504 and 81970494), the Key Project of Research and Development Plan of Hunan Province (2019SK2041) and the Changsha Municipal Natural Science Foundation (kq2014258).

Roseburia intestinalis: A Beneficial Gut Organism From the Discoveries in Genus and Species.

Roseburia intestinalis is an anaerobic, Gram-positive, slightly curved rod-shaped flagellated bacterium that produces butyrate in the colon. R. intestinalis has been shown to prevent intestinal inflammation and maintain energy homeostasis by producing metabolites. Evidence shows that this bacterium contributes to various diseases, such as inflammatory bowel disease, type 2 diabetes mellitus, antiphospholipid syndrome, and atherosclerosis. This review reveals the potential therapeutic role of R. intestinalis in human diseases. Patients with inflammatory bowel disease exhibit significant changes in R. intestinalis abundance, and they may benefit a lot from modulations targeting R. intestinalis. The data reviewed here demonstrate that R. intestinalis plays its role in regulating barrier homeostasis, immune cells, and cytokine release through its metabolite butyrate, flagellin and other. Recent advancements in the application of primary culture technology, culture omics, single-cell sequencing, and metabonomics technology have improved research on Roseburia and revealed the benefits of this bacterium in human health and disease treatment.

Roseburia intestinalis­derived flagellin ameliorates colitis by targeting miR­223­3p­mediated activation of NLRP3 inflammasome and pyroptosis.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is a chronic, relapsing condition associated with the disorder of gut microbial communities. A previous study reported that levels of Roseburia intestinalis (R.I), a butyrate­producing bacterium, are significantly decreased in patients with IBD and exert an anti­inflammatory function in dextran sulfate sodium (DSS)­induced colitis. However, the role of R.I flagellin in UC and its underlying molecular mechanism are not yet fully understood. Therefore, a DSS­induced colitis model in C57Bl/6 mice and the LPS/ATP­induced THP­1 macrophages were treated with R.I flagellin, which were used to investigate the anti­inflammatory effects of R.I flagellin. The results demonstrated that R.I flagellin decreased colitis­associated disease activity index, colonic shortening and the pathological damage of the colon tissues in murine colitis models. Furthermore, R.I flagellin decreased the serum levels of proinflammatory cytokines and inhibited activation of the nucleotide­binding oligomerization segment­like receptor family 3 (NLRP3) inflammasome in murine colitis. R.I flagellin was also demonstrated to decrease the Gasdermin D to yield the N­terminal fragment membrane pore and inhibit inflammasome­triggered pyroptosis. In vitro analysis indicated that microRNA (miR)­223­3p was involved in the regulation of R.I flagellin on NLRP3 inflammasome activation. Taken together, the results of the present study demonstrated that R.I flagellin inhibited activation of the NLRP3 inflammasome and pyroptosis via miR­223­3p/NLRP3 signaling in macrophages, suggesting that R.I flagellin may be used as a novel probiotic product for the treatment of UC.

Systematic Review with Meta-Analysis: The Effects of Probiotics in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Probiotics was considered as a potential therapy for nonalcoholic fatty liver disease (NAFLD) without approval and comprehensive assessment in recent years, which call for a meta-analysis. METHODS: We performed electronic and manual searches including English and Chinese databases published before April 2019, with the use of mesh term and free text of "nonalcoholic fatty liver disease" and "probiotics." Clinical trials evaluating the efficacy of probiotic therapy in NAFLD patients were included according to the eligibility criteria. With the use of random effects models, clinical outcomes were presented as weighted mean difference (WMD) with 95% confidence interval (CI), while heterogeneity and meta-regression were also assessed. RESULTS: 28 clinical trials enrolling 1555 criterion proven NAFLD patients with the use of probiotics from 4 to 28 weeks were included. Overall, probiotic therapy had beneficial effects on body mass index (WMD: -1.46, 95% CI: [-2.44, -0.48]), alanine aminotransferase (WMD: -13.40, 95% CI: [-17.03, -9.77]), aspartate transaminase (WMD: -13.54, 95% CI: [-17.86, -9.22]), gamma-glutamyl transpeptidase (WMD: -9.88, 95% CI: [-17.77, -1.99]), insulin (WMD: -1.32, 95% CI: [-2.43, -0.21]), homeostasis model assessment-insulin resistance (WMD: -0.42, 95% CI: [-0.73, -0.12]), and total cholesterol (WMD: -15.38, 95% CI: [-26.50, -4.25]), but not in fasting blood sugar, lipid profiles, or tumor necrosis factor-alpha. CONCLUSION: The systematic review and meta-analysis support that probiotics are superior to placebo in NAFLD patients and could be utilized as a common complementary therapeutic approach.

A new colitis therapy strategy via the target colonization of magnetic nanoparticle-internalized Roseburia intestinalis.

The homeostasis process in the gut tissue of humans relies on intestinal bacteria. However, the intestine is a complex structural tissue with a huge superficial area, and thus the effective application of probiotics in the treatment of Crohn's disease (CD) is still challenging. Herein, we show the feasibility of probiotic target delivery and retention using magnetic iron oxide nanoparticle-internalized Roseburia intestinalis, which can be easily directed by a magnetic field in vitro and in vivo. Subsequently, the increased colonization of this core profitable flora not only resulted in a better therapy effect than traditional intragastric administration but also altered the bacterial composition, leading to a higher diversity in microbial taxa in rats with colitis. Our findings illustrate the exciting opportunities that nanotechnology offers for alternative strategies to modulate biological systems remotely and precisely, which represent a step towards the wireless magnetic manipulation of living biological entities in microbiology.