Alteration of Colonic Bacterial and Fungal Composition and Their Inter- and Intra-Kingdom Interaction in Patients with Adenomas with Low-Grade Dysplasia.

Colorectal cancer (CRC) develops from pre-cancerous cellular lesions in the gut epithelium and mainly originates from specific types of colonic adenomas with dysplasia. However, gut microbiota signatures among sampling sites in patients with colorectal adenomas with low-grade dysplasia (ALGD) and normal control (NC) remain uncharacterized. To characterize gut microbial and fungal profiles in ALGD and normal colorectal mucosa tissues. We used 16S and ITS1-2 rRNA gene sequencing and bioinformatics analysis on the microbiota of ALGD and normal colorectal mucosa from 40 subjects. Bacterial sequences in the ALGD group showed an increase in Rhodobacterales, Thermales, Thermaceae, Rhodobacteraceae, and several genera, including Thermus, Paracoccus, Sphingobium, and Pseudomonas, compared to the NC group. Fungal sequences in the ALGD group showed an increase in Helotiales, Leotiomycetes, and Basidiomycota, while several orders, families, and genera, including Verrucariales, Russulales, and Trichosporonales, were decreased. The study found various interactions between intestinal bacteria and fungi. The bacterial functional analysis showed increased glycogen and vanillin degradation pathways in the ALGD group. Meanwhile, the fungal functional analysis showed a decrease in pathways related to the biosynthesis of gondoate and stearate, as well as degradation of glucose, starch, glycogen, sucrose, L-tryptophan, and pantothenate, and an increase in the octane oxidation pathway in the ALGD group. The mucosal microbiota in ALGD exhibits altered fungal and microbial composition compared to the NC mucosa, potentially contributing to the development of intestinal cancer by regulating specific metabolic pathways. Therefore, these changes in microbiota and metabolic pathways may be potential markers for diagnosing and treating colorectal adenoma and carcinoma.

SegPC-2021: A challenge & dataset on segmentation of Multiple Myeloma plasma cells from microscopic images.

Multiple Myeloma (MM) is an emerging ailment of global concern. Its diagnosis at the early stages is critical for recovery. Therefore, efforts are underway to produce digital pathology tools with human-level intelligence that are efficient, scalable, accessible, and cost-effective. Following the trend, a medical imaging challenge on "Segmentation of Multiple Myeloma Plasma Cells in Microscopic Images (SegPC-2021)" was organized at the IEEE International Symposium on Biomedical Imaging (ISBI), 2021, France. The challenge addressed the problem of cell segmentation in microscopic images captured from the slides prepared from the bone marrow aspirate of patients diagnosed with Multiple Myeloma. The challenge released a total of 775 images with 690 and 85 images of sizes 2040×1536 and 1920×2560 pixels, respectively, captured from two different (microscope and camera) setups. The participants had to segment the plasma cells with a separate label on each cell's nucleus and cytoplasm. This problem comprises many challenges, including a reduced color contrast between the cytoplasm and the background, and the clustering of cells with a feeble boundary separation of individual cells. To our knowledge, the SegPC-2021 challenge dataset is the largest publicly available annotated data on plasma cell segmentation in MM so far. The challenge targets a semi-automated tool to ensure the supervision of medical experts. It was conducted for a span of five months, from November 2020 to April 2021. Initially, the data was shared with 696 people from 52 teams, of which 41 teams submitted the results of their models on the evaluation portal in the validation phase. Similarly, 20 teams qualified for the last round, of which 16 teams submitted the results in the final test phase. All the top-5 teams employed DL-based approaches, and the best mIoU obtained on the final test set of 277 microscopic images was 0.9389. All these five models have been analyzed and discussed in detail. This challenge task is a step towards the target of creating an automated MM diagnostic tool.

Polymersome-mediated cytosolic delivery of cyclic dinucleotide STING agonist enhances tumor immunotherapy.

Cyclic dinucleotides (CDNs) as stimulator of interferon genes (STING) agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy. The efficacy of these CDNs is, however, reduced greatly by their fast clearance, poor cell uptake and inefficient cytosolic transportation. Here, we report that reduction-responsive biodegradable chimaeric polymersomes (CPs) markedly enhance tumor retention and cytosolic delivery of a synthetic CDN, ADU-S100, and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes, giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control. The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation, which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge. The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.

Immunotherapy of Malignant Glioma by Noninvasive Administration of TLR9 Agonist CpG Nano-Immunoadjuvant.

Immunotherapy with toll like receptor 9 (TLR9) agonist CpG ODN offers an emergent strategy to treat life-threatening malignant glioma. CpG is typically applied invasively by intracranial and intrathecal administration which induces not only poor compliance and lessened potency but also possibly strong adverse effects and immunotoxicity. Here, it is reported that immunotherapy of murine LCPN glioma is greatly boosted by polymersome-steered intravenous and intranasal brain delivery of CpG. CpG is efficiently loaded in apolipoprotein E peptide-directed polymersomes to give blood-brain barrier permeable and glioma and cervical lymph node-homing CpG nano-immunoadjuvant (t-NanoCpG) which strongly stimulates the maturation of dendritic cells, antigen cross-presentation, and production of proinflammatory cytokines in vivo. Intriguingly, both intravenous and intranasal administration of t-NanoCpG brings about significant survival benefits in murine LCPN glioma-bearing mice while free CpG and nontargeted CpG nano-immunoadjuvant (NanoCpG) afford modest therapeutic effects. Moreover, combination of t-NanoCpG with radiotherapy further boosts the immunotherapeutic effects leading to more improved survival rate of mice. This intelligent brain-permeable nano-immunoadjuvant provides a new, minimally invasive and highly potent strategy for immunotherapy of glioma.

Micellar paclitaxel boosts ICD and chemo-immunotherapy of metastatic triple negative breast cancer.

Triple negative breast cancer (TNBC) with easy metastasis, "cold" tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed. Chemo-immunotherapy deemed as a potential treatment for TNBC is however confronted by low TNBC selectivity, pronounced systemic toxicity, and limited immunogenic cell death (ICD) induction. Here, employing clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle we constructed α5ß1 integrin-targeted micellar paclitaxel (ATN-MPTX) to elicit strong and selective ICD and chemo-immunotherapy of TNBC. ATN-MPTX exhibited evident targetability and prominent uptake in α5ß1 integrin-positive 4 T1 cells and induced significantly stronger ICD than free PTX and non-targeted MPTX. The therapeutic studies in 4 T1 TNBC model demonstrated that ATN-MPTX caused superior tumor accumulation and treatment efficacy to all controls. Of note, ATN-MPTX plus nano-STING agonist further augmented the immunotherapeutic effects by increasing secretion of proinflammatory cytokines and CD4+ and CD8+ T cells in the tumor and spleen while reducing Treg, leading to significantly improved inhibition of 4 T1 primary tumor and more interestingly mitigated lung metastases. This strong and selective ICD induction of ATN-MPTX renders it an interesting tool to enhance chemo-immunotherapy of TNBC.

Fecal microbiota profiling in irritable bowel syndrome and inflammatory bowel disease patients with irritable bowel syndrome-type symptoms.

BACKGROUND: The intestinal microbiota is thought to be involved in the occurrence of inflammatory bowel disease in remission with irritable bowel syndrome (IBS)-type symptoms, but the specific distinct profile of these bacteria remains unclear. This cross-sectional study aims to investigate the fecal microbiota profiling in patients with these diseases. METHODS: Fecal samples from 97 subjects, including Crohn's disease patients in remission with IBS-type symptoms (CDR-IBS+) or without IBS-type symptoms (CDR-IBS-), ulcerative colitis patients in remission with IBS-type symptoms (UCR-IBS+) or without IBS-type symptoms (UCR-IBS-), IBS patients and healthy controls, were collected and applied 16S ribosomal DNA (rDNA) gene sequencing. The V4 hypervariable regions of 16S rDNA gene were amplified and sequenced by the Illumina MiSeq platform. The differences in the sample diversity index in groups were analyzed with R software. RESULTS: The richness of the intestinal microbiota in the CDR-IBS group was markedly lower than those in the control and IBS groups based on the analysis of observed species and the Chao index (P < 0.05). The observed species index in the CDR-IBS+ group was higher than that in the CDR-IBS- group (median index: 254.8 vs 203, P = 0.036). No difference was found in alpha diversity between UCR patients with IBS-type symptoms and those without related symptoms. At the genus level, the number of Faecalibacterium in CDR patients with IBS-type symptoms increased significantly, while Fusobacterium decreased versus those without such symptoms (mean relative abundance of Faecalibacterium: 20.35% vs 5.18%, P < 0.05; Fusobacterium: 1.51% vs 5.2%, P < 0.05). However, compared with the UCR-IBS- group, the number of Faecalibacterium in the UCR-IBS+ group decreased, while the number of Streptococcus increased, but there was no significant difference in the genus structure. The abundance and composition of the microbiota of IBS patients were not distinct from those of healthy controls. CONCLUSIONS: The IBS-type symptoms in CD patients in remission may be related to an increase in Faecalibacterium and a decrease in Fusobacterium. The IBS-type symptoms in UC patients in remission cannot be explained by changes in the abundance and structure of the intestinal microbiota.

Small, Smart, and LDLR-Specific Micelles Augment Sorafenib Therapy of Glioblastoma.

Targeted molecular therapy, for example, with sorafenib (SF) is considered as a new and potent strategy for glioblastoma (GBM) that remains hard to treat today. Several clinical trials with SF, as monotherapy or combination therapy with current treatments, have not met the clinical endpoints, likely as a result of the blood-brain barrier (BBB) and inferior GBM delivery. Here, we designed and explored small, smart, and LDLR-specific micelles to load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake. LDLR-mSF with 2.5% ApoE peptide functionality based on poly(ethylene glycol)-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate exhibited nearly quantitative SF loading, small size (24 nm), high colloidal stability, and glutathione-activated SF release. The in vitro and in vivo studies certified that LDLR-mSF greatly enhanced BBB permeability and U-87 MG cell uptake and caused 10.6- and 12.9-fold stronger anti-GBM activity and 6.0- and 2.5-fold higher GBM accumulation compared with free SF and non-LDLR mSF controls, respectively. The treatment of an orthotopic human GBM tumor model revealed that LDLR-mSF at a safe dosage of 15 mg of SF/kg significantly retarded tumor progression and improved the survival rate by inducing tumor cell apoptosis and inhibiting tumor angiogenesis. These small, smart, and LDLR-specific micelles provide a potential solution to enhance targeted molecular therapy of GBM.

Faecalibacterium prausnitzii Attenuates DSS-Induced Colitis by Inhibiting the Colonization and Pathogenicity of Candida albicans.

SCOPE: Intestinal commensal microbiota interactions play critical roles in the inflammatory bowel disease (IBD) development. Candida albicans (CA) can aggravate intestinal inflammation; however, whether Faecalibacterium prausnitzii (FP) can antagonize CA is unknown. METHODS AND RESULTS: CA are co-cultured with bacteria (FP and Escherichia coli (EC)), bacterial supernatant, and bacterial medium, respectively. Then, the CA hyphae-specific genes' expression and CA cells' morphology are investigated. The Nod-like receptor pyrin-containing protein 6 (NLRP6) inflammasome, inflammatory cytokines, and antimicrobial peptides (AMPs) production are evaluated in intestinal epithelial cells pre-treated with bacteria, bacterial med, and bacterial supernatant and exposed without or with CA. Both bacteria significantly prohibit CA numbers, while only FP and FP supernatant prohibit the transformation and virulence factors (extracellular phospholipase, secreted aspartyl proteinase, and hemolysin) secretion of CA in a co-culture system compared with media controls. Further, FP and FP supernatant promote the production of the NLRP6 inflammasome, interleukin (IL)-1ß, IL-18, and antibacterial peptides (ß-defensin (BD)-2 and BD-3) and inhibit in vitro and in vivo CA growth and pathogenicity, and alleviate DSS-colitis in mice, while EC do not show the similar effect. CONCLUSION: FP improve intestinal inflammation by inhibiting CA reproduction, colonization, and pathogenicity and inducing AMP secretion in the gut. This study uncovers new relationships between intestinal microbes and fungi in IBD patients.

Selective transferrin coating as a facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer in vivo.

Brain metastases are a most disturbing situation for breast cancer patients as there is basically no adequate treatment available. Any potential drug formulation has to be able to cross the blood-brain barrier (BBB) and specific to metastatic brain tumors without causing unacceptable adverse effects. Here, we developed transferrin-functionalized chimeric polymersomes carrying siRNA against polo-like kinase 1 (Tf@TBP-CPs-siPLK1) for treating brain metastatic MDA-MB 231 triple negative breast cancer (TNBC) xenografts in mice. To facilitate the loading of siPLK1, chimaeric polymersomes (CPs) were designed with spermine in the watery core and transferrin-binding peptide (TBP) at the surface, enabling attachment of transferrin after the siRNA loading step and thereby circumventing interference of transferrin with siRNA loading. Tf@TBP-CPs-siPLK1 encapsulating 3.8 wt% siRNA had a mean size of about 50 nm and a neutral zeta potential in phosphate buffer (PB). By virtue of the presence of transferrin, Tf@TBP-CPs demonstrated greatly (ca. 5-fold) enhanced internalization in MDA-MB 231 cells and transcytosis in the endothelial (bEnd.3) monolayer model in vitro as well as markedly improved accumulation in the orthotopically xenografted MDA-MB 231 tumor in the brain in vivo compared with control CPs lacking transferrin, supporting that transferrin mediates efficient BBB penetration and high specificity towards MDA-MB 231 cells. As a result, Tf@TBP-CPs-siPLK1 effectively inhibited tumor progression and prolonged the lifespan of the mice significantly. Selective transferrin coating appears to be a particularly facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer.

Characterization of fungal and bacterial dysbiosis in young adult Chinese patients with Crohn's disease.

Intestinal microbiota dysbiosis has been described in inflammatory bowel disease (IBD), but data from China are limited. In this study, we performed molecular analysis of the fecal microbial community from 20 healthy Chinese subjects and 25 patients with Crohn's disease (CD), and evaluated associations with bacterial and fungal compositions. Decreased richness and diversity of bacterial composition was observed in the CD group compared with healthy (H) subjects. Significant structural differences in bacterial (but not fungal) composition among healthy controls and CD patients were found. A reduction in Firmicutes and Actinobacteria abundance, and overrepresentation of Proteobacteria were observed in the CD patients compared with the H group. The Escherichia-Shigella genus was overrepresented in the CD group, whereas Faecalibacterium, Gemmiger, Bifidobacterium, Romboutsia, Ruminococcus, Roseburia, and Fusicatenibacter abundance were decreased in the CD group compared with H subjects. Differences in fungal microbiota between the H and CD groups were observed at the genus rather than at the phylum level. The Candida genus was overrepresented in the CD (active disease) group compared with the H group, whereas no difference between CD (remission) and H groups was observed. Aspergillus, unclassified_Sordariomycetes, and Penicillium genera had greater representation in the H subjects compared with the CD group. Bacterial and fungal intra- and inter-kingdom correlations were observed between the H and CD groups. Therefore, fecal bacterial and fungal microbiome communities differed considerably between H and CD patients, and between Chinese and Western populations. The role of gut microbiota in homeostasis and in gastrointestinal disorders should be investigated further.

MiR-124a Mediates the Impairment of Intestinal Epithelial Integrity by Targeting Aryl Hydrocarbon Receptor in Crohn's Disease.

Growing evidence suggested that microRNAs (miRNAs) contributed to the progression of Crohn's disease (CD), but the exact physiological functions of many miRNAs in CD patients still remain illusive. In this study, we explore the potent pathogenicity of miRNAs in CD. Expressions of miRNAs and aryl hydrocarbon receptor (AHR) protein were determined in the colitic colon of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mice and CD patients. Colitis was induced in wild-type (WT), miR-124a overexpression (miR-124a-Nju), and AHR knockout (AHR-/-) mice. Intestinal barrier function was evaluated in colitis mice and Caco2 monolayers. There was a negative relationship between miR-124a and AHR protein in inflamed colons from CD patients. MiR-124a-Nju and AHR-/- mice treated with TNBS had more severe intestinal inflammation than WT mice. Both miR-124a-Nju mice and AHR-/- mice underwent evident intestinal barrier destruction, and anti-miR-124a administration could reverse this dysfunction in miR-124a-Nju mice but not in AHR-/- mice. In vitro studies revealed that miR-124a mimics downregulated the expression of AHR and tight junction proteins and induced hyperpermeability by increasing miR-124a expression, which was abrogated by miR-124a inhibitor and AHR antagonist FICZ. This study suggests that miR-124a can induce intestinal inflammation and cause intestinal barrier dysfunction by supressing AHR.

Candida albicans SC5314 inhibits NLRP3/NLRP6 inflammasome expression and dampens human intestinal barrier activity in Caco-2 cell monolayer model.

Candida albicans is an opportunistic fungal pathogen that colonizes human gastro-intestinal mucosal tissues. Its effect on the immune response in intestinal epithelial cells and on the intestinal mucosal barrier are not yet fully understood. In this study, we investigated Caco-2 cells, a monolayer model of intestinal epithelial cells, with or without treatment with C. albicans SC5314 (CA) or heat-inactivated CA (CA-inact). RNA sequencing was conducted, and the mRNA and protein levels of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) or NLRP6/ASC/caspase-1 inflammasome signaling pathway components, inflammatory cytokines (interleukin-18 [IL-18] and IL-1ß), anti-microbial peptides (AMPs; ß-defensin-2 [BD-2], BD-3, and LL-37), and tight junction proteins (occludin and zona occludens-1 [ZO-1]) were examined by real-time PCR, western blotting, and/or immunofluorescence microscopy. Lactase dehydrogenase (LDH) activity in the Caco-2 cell supernatant were measured by enzyme kinetics analysis. Our results showed that the NOD-like receptor signaling pathway participates in the CA- and CA-inact-infected Caco-2 cells, as shown by microarray analysis of total mRNA expression. The expression of NLRP3, NLRP6, ASC, BD-2, BD-3, occludin, and ZO-1 were significantly decreased in Caco-2 cells infected with CA and CA-inact compared to that in the untreated control. IL-1ß expression was decreased in the Caco-2 cells in both the CA- and CA-inact-infected groups compared to that in the control. Caspase-1 and IL-18 levels were not markedly affected by CA or CA-inact in Caco-2 cells. Our findings indicate that CA can inhibit the NLRP3 and NLRP6 pathways and dampen human intestinal mucosal barrier activity by decreasing the production of AMPs and tight junction proteins, independent of CA activity.

Dually Active Targeting Nanomedicines Based on a Direct Conjugate of Two Purely Natural Ligands for Potent Chemotherapy of Ovarian Tumors.

Actively targeted nanomedicines have promised to revolutionize cancer treatment; however, their clinical translation has been limited by either low targetability, use of unsafe materials, or tedious fabrication. Here, we developed CD44 and folate receptor (FR) dually targeted nanoparticulate doxorubicin (HA/FA-NP-DOX) based on a direct conjugate of two purely natural ligands, hyaluronic acid and folic acid (FA), for safe, highly specific, and potent treatment of ovarian tumors in vivo. HA/FA-NP-DOX had a small size and high DOX loading, wherein the particle size decreased from 115, 93, to 89 nm with increasing degree of substitution of FA from 6.4, 8.5, to 11.1, while increased from 80, 93, to 103 nm with increasing DOX loading from 15.0, 23.1, to 31.4 wt %. Interestingly, HA/FA-NP-DOX exhibited excellent lyophilization redispersibility and long-term storage stability with negligible drug leakage while it released 91% of DOX in 48 h at pH 5.0. Cellular studies corroborated that HA/FA-NP-DOX possessed high selectivity to both CD44 and FR, resulting in strong killing of CD44- and FR-positive SKOV-3 ovarian cancer cells while low toxicity against CD44- and FR-negative L929 fibroblast cells. In vivo studies revealed a long elimination half-life of 5.6 h, an elevated tumor accumulation of 12.0% ID/g, and an effective inhibition of the SKOV-3 ovarian tumor for HA/FA-NP-DOX, leading to significant survival benefits over free DOX·HCl and phosphate-buffered saline controls. These dually targeted nanomedicines are simple and safe, providing a potentially translatable treatment for CD44- and FR-positive malignancies.

Alterations in the mucosa-associated fungal microbiota in patients with ulcerative colitis.

BACKGROUND: Fungi colonize the human gut and might play a key role in the pathogenesis of ulcerative colitis (UC). However, studies on the fungal composition in the gut (especially adhering to the intestinal mucosa) of UC patients is limited. RESULTS: The number of fungi decreased significantly in inflamed mucosa compared with that in HS mucosa. Fifteen major genera were examined, among which Wickerhamomyces, unidentified genus of Saccharomycetales, Aspergillus, Sterigmatomyces, and Candida showed increasing trends, whereas Exophiala, Alternaria, Emericella, Epicoccum, Acremonium, Trametes, and Penicillium showed decreasing trends in UC patients compared to the HS. The pro-inflammatory cytokines (IL-Iß, TNF-α, INF-γ, IL-6, IL-17A, and IL-23) were up-regulated in the UC group. The genera Wickerhamomyces, Nigrospora, and Penicillium were positively correlated, while Sporobolomyces and Trametes were negatively correlated with the expression of several colonic pro-inflammatory cytokines and the Baron and/or Mayo score. CONCLUSIONS: Our study confirms the alteration of the colonic fungal microbiota in the UC patients, which might be associated with mucosal inflammation and pathogenesis of UC. Further studies need to identify the roles of different intestinal fungi in detail, and to determine the mechanism of the host-fungal interaction underlying the development of UC. METHODS: Mucosal samples of inflamed descending colon from 14 active UC patients and 15 healthy subjects (HS) were analyzed by high-throughput sequencing to compare the fungal microbiota. The expressions of pro-inflammatory cytokines (IL-Iß, TNF-α, INF-γ, IL-6, IL-17A, and IL-23) in intestinal mucosal tissues were examined. The Baron and Mayo scores of UC patients were evaluated, and the correlation between intestinal fungal composition and intestinal inflammatory status was analyzed.

Chemopreventive effects of 5-aminosalicylic acid on inflammatory bowel disease-associated colorectal cancer and dysplasia: a systematic review with meta-analysis.

BACKGROUND AND AIMS: The chemopreventive effect of 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease (IBD) has been widely studied; however, the results remain conflicting. The aim of this study was to systematically review the literature and update evidence concerning effects of 5-ASA on the risk of colorectal cancer (CRC) and dysplasia (Dys) in patients with ulcerative colitis (UC) or Crohn's disease (CD). RESULTS: 5-ASA showed a chemopreventive effect against CRC/Dys in IBD patients (OR = 0.58, 95% CI: 0.45-0.75). However, this effect was significant only in clinical-based studies (OR = 0.51; 95% CI: 0.39-0.65), but not in population-based studies (OR = 0.71; 95% CI: 0.46-1.09). Moreover, this effect was noticeable in patients with UC (OR = 0.46, 95% CI: 0.34-0.61), but not in CD (OR = 0.66, 95% CI: 0.42-1.03), and on the outcome of CRC (OR = 0.54, 95% CI: 0.39-0.74), but not Dys (OR = 0.47; 95% CI: 0.20-1.10). In IBD patients, mesalazine dosage ≥ 1.2 g/day showed greater protective effects against CRC/Dys than dosages < 1.2 g/day. However, Sulphasalazine therapy did not show any noticeable protective function regardless of the dosage administered. MATERIALS AND METHODS: We performed a systematic review with a meta-analysis of 26 observational studies involving 15,460 subjects to evaluate the risks of developing CRC and Dys in IBD patients receiving 5-ASA treatment. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each evaluation index. CONCLUSIONS: 5-ASA has a chemopreventive effect on CRC (but not Dys) in IBD patients. Moreover, UC patients can benefit more from 5-ASA than CD patients. Mesalazine maintenance dosage ≥ 1.2 g/day is an effective treatment for reducing CRC risk in IBD patients.

Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis.

Intestinal fungi are increasingly believed to greatly influence gut health. However, the effects of fungi on intestinal inflammation and on gut bacterial constitution are not clear. Here, based on pyrosequencing method, we reveal that fungal compositions vary in different intestinal segments (ileum, cecum, and colon), prefer different colonization locations (mucosa and feces), and are remarkably changed during intestinal inflammation in dextran sulfate sodium (DSS)-colitis mouse models compare to normal controls: Penicillium, Wickerhamomyces, Alternaria, and Candida are increased while Cryptococcus, Phialemonium, Wallemia and an unidentified Saccharomycetales genus are decreased in the guts of DSS-colitis mice. Fungi-depleted mice exhibited aggravated acute DSS-colitis associated with gain of Hallella, Barnesiella, Bacteroides, Alistipes, and Lactobacillus and loss of butyrate-producing Clostridium XIVa, and Anaerostipes compare with normal control. In contrast, bacteria-depleted mice show attenuated acute DSS-colitis. Mice with severely chronic recurrent DSS-colitis show increased plasma (1,3)-ß-D-glucan level and fungal translocation into the colonic mucosa, mesenteric lymph nodes and spleen. This work demonstrate the different roles of fungi in acute and chronic recurrent colitis: They are important counterbalance to bacteria in maintaining intestinal micro-ecological homeostasis and health in acutely inflamed intestines, but can harmfully translocate into abnormal sites and could aggravate disease severity in chronic recurrent colitis.

Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has recently been considered to be under the influence of the gut microbiota, which might exert toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. In this study, the composition of the gut microbiota in NAFLD patients and healthy subjects was determined via 16S ribosomal RNA Illumina next-generation sequencing. Among those taxa displaying greater than 0.1% average abundance in all samples, five genera, including Alistipes and Prevotella, were significantly more abundant in the gut microbiota of healthy subjects compared to NAFLD patients. Alternatively, Escherichia, Anaerobacter, Lactobacillus and Streptococcus were increased in the gut microbiota of NAFLD patients compared to healthy subjects. In addition, decreased numbers of CD4+ and CD8+ T lymphocytes and increased levels of TNF-α, IL-6 and IFN-γ were detected in the NAFLD group compared to the healthy group. Furthermore, irregularly arranged microvilli and widened tight junctions were observed in the gut mucosa of the NAFLD patients via transmission electron microscopy. We postulate that aside from dysbiosis of the gut microbiota, gut microbiota-mediated inflammation of the intestinal mucosa and the related impairment in mucosal immune function play an important role in the pathogenesis of NAFLD.

Faecalibacterium prausnitzii inhibits interleukin-17 to ameliorate colorectal colitis in rats.

BACKGROUND AND AIMS: It has been shown that Faecalibacterium prausnitzii (F. prausnitzii), one of the dominant intestinal bacterial flora, may protect colonic mucosa against the development of inflammation and subsequent inflammatory bowel disease (IBD), with the underlying mechanisms being unclear. METHODS: The impacts of F. prausnitzii and its metabolites on IL-23/Th17/IL-17 pathway markers were determined in human monocytes and a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid. F. prausnitzii and its culture medium (containing complete metabolites) were used to treat the rats in vivo, as well as rat splenocytes and human monocytes in vitro. Inflammatory cytokines were measured in colon tissue, plasma and cell culture medium. RESULTS: The culture supernatant of F. prausnitzii increased plasma anti-Th17 cytokines (IL-10 and IL-12)and suppressed IL-17 levels in both plasma and colonic mucosa, with ameliorated colonic colitis lesions. This inhibition of IL-17 release has also been observed in both rat splenocytes and human venous monocytes in vitro. The culture supernatant of F. prausnitzii also suppressed Th17 cell differentiation induced by cytokines (TGF-ß and IL-6) and bone marrow-derived dendritic cells (BMDCs) in vitro. The metabolites of F. prausnitzii in the culture supernatant exert a stronger anti-inflammatory effect than the bacterium itself. F. prausnitzii protected the colon mucosa against the development of IBD by its metabolites, suggesting a promising potential for the use of F. prausnitzii and its metabolic products in the treatment of IBD.

Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis.

BACKGROUND AND AIMS: Faecalibacterium prausnitzii (F. prausnitzii) is a common anaerobic bacteria colonized in the human gut and inflammatory bowel disease (IBD) patients are usually lack of F. prausnitzii. The aims of this study were to evaluate the anti-inflammatory and immunomodulatory capacity of F. prausnitzii by comparing it with Bifidobacterium longum (B. longum) in both cellular and animal experiments. METHODS: Human peripheral blood mononuclear cells (PBMCs) and 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colitis rat models were treated with F. prausnitzii, B. longum, F. prausnitzii supernatant or F. prausnitzii medium, respectively. Interleukin (IL)-10, TGF-ß1 and IL-12p70 in human PBMCs culture supernatant and rat blood serum were detected. The frequency of CD25(+)Foxp3(+)Treg in human PBMCs, rat PBMCs and rat splenocytes were investigated. Besides, the T-bet, GATA-3, ROR-γt and Foxp3 mRNA in human PBMCs, histopathologic characteristics of the intestinal mucosal and weight loss in the rat models were examined. RESULTS: F. prausnitzii, B. longum and F. prausnitzii supernatant clearly facilitated the induction of IL-10 and TGF-ß1, while induced relatively mild production of IL-12p70 in both cellular and animal models. The F. prausnitzii, B. longum and supernatant differed in their capacity to induce T-bet, GATA-3 and ROR-γt mRNA expression in human PBMCs (both bacterial strains inhibited the expression of ROR-γt while supernatant inhibited the T-bet and GATA-3). However, all of them induced the Foxp3 and Treg production and ameliorated the TNBS-induced colitis. In addition, F. prausnitzii supernatant exhibited the supreme anti-inflammatory capacity. CONCLUSIONS: F. prausnitzii and its unidentified metabolites in the supernatant are promising candidates in treating IBD, and further research remains necessary to elucidate the safety, efficacy, optimum and mechanism of this bacterium in the clinical practice.