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Subtle modification, adding methoxy groups to the triptycene termini of a telechelic polydimethylsiloxane (PDMS), dramatically improves mechanical properties, forming a thermoplastic PDMS without the need for covalent cross-linking.

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson’s correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress–induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson’s correlation coefficient analysis revealed that AKK predominantly upregulated β-alanyl-3-methyl-l-histidine and edaravone to relieve depression. Furthermore, β-alanyl-3-methyl-l-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress–induced depressive symptoms in mice by regulating gut microbiota and metabolites. • AKK reduces depressive-like behaviors induced by chronic stress. • AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress. • Antidepressant effect of AKK correlates with the increase of β-alanyl-3-methyl-l-histidine and edaravone.

Bacterial meningitis (BM) is the main cause of the central nervous system (CNS) infection and continues to be an important cause of mortality and morbidity. Glutathione (GSH), an endogenous tripeptide antioxidant, has been proved to exert crucial role in reducing superoxide radicals, hydroxyl radicals and peroxynitrites. The purpose of this study is to expand the application scope of GSH via exploring its therapeutic effect on BM caused by Salmonella typhimurium SL1344 and then provide a novel approach for the treatment of BM. The results suggested that intragastric administration of GSH could significantly increase median survival and improve experimental autoimmune encephalomyelitis score of BM model mice. However, exogenous GSH did not affect the adhesion, invasion and cytotoxicity of SL1344 to C6, BV2 and primary microglia. Due to the contradiction between the therapeutic and bactericidal effects of GSH, the effect of GSH on blood-brain barrier (BBB) was investigated to explore its action target for the treatment of meningitis. GSH was found to repair the damage of BBB and then prevent the leakage of SL1344 from the brain to the blood circulation. The repaired BBB could also effectively reduce the entry of macrophages and neutrophils into the brain, and significantly reverse the microglia activation induced by SL1344. More importantly, exogenous GSH was proved to reduce mouse brain cell apoptosis by inhibiting the activation of caspase-8 followed by caspase-3, and reversing the up-regulation of ICAD and PARP-1 caused by SL1344.

Background Endoplasmic reticulum (ER) stress-related mucin depletion could be involved in the pathogenesis of inflammatory bowel disease (IBD). Akkermansia muciniphila (A. muciniphila), a symbiotic bacterium of the mucus layer, uses mucin as its sole energy source and shows potential in the treatment of colitis. However, the effects and underlying mechanisms of A. muciniphila on colonic epithelial ER stress in colitis are largely unknown. Methods Colitis was induced by adding 2.5% DSS in drinking water. Mice were orally administered A. muciniphila (3*10^7, 3*10^8 cfu/day) once daily for 10 days during DSS intervention. UHPLC high-resolution orbitrap mass spectrometry-based metabolomic analyses were performed on faeces. 16S rRNA sequencing were used to quantify and characterize the gut microbiota of mice and human. Colons were collected from mice and analyzed by histopathology, quantitative PCR and immunofluorescence. Colon biopsies from the patients with ulcerative colitis (UC) and controls were collected and analyzed by immunohistochemistry. Results Metabolite pathway enrichment analysis demonstrated that colitis-affected metabolites after A. muciniphila supplementation were mainly enriched in mineral absorption, bile secretion and protein digestion and absorption. P-hydroxyphenyl acetic acid, which showed the highest VIP scores, was significantly increased by A. muciniphila, and could cause ER stress. A. muciniphila supplementation changed the relative abundance and composition of intestinal microbiotaespecially a decrease inParasutterella, which showed the potential role in bile acid maintenance. A. muciniphila supplementation protected colon shortening, histological injury, intestinal inflammation and barrier damage in wild-type (WT) mice but not in farnesoid X receptor-null (FXR−/−) mice. Mechanistically, A. muciniphila supplementation activated FXR/SHP signaling, which directly increased X-box binding protein-1 splicing (XBP1s) and phosphorylated inositol requiring enzyme 1α (p-IRE1α) expression, and in turn formed XBP1s-SHP regulatory loop in response to ER stress. We further showed that the abundance of A. muciniphila in faeces from UC patients positively correlates with p-IRE1α expression. Conclusions Our results suggest that A. muciniphila supplementation alleviates DSS-induced colitis involvement of the IRE1α/XBP1 ER stress pathway via FXR/SHP axis activation.

Background Epidemiological evidences reveal that populations with psychological stress have an increased likelihood of respiratory viral infection involving influenza A virus (IAV) and SARS-CoV-2, but the mechanism remains elusive. Results By exploiting a chronic restraint stress (CRS) mouse model, we demonstrated that psychiatric stress substantially increased hosts’ vulnerability to viral pneumonia, concurrent with deregulated alveolar macrophages (AMs) and disturbed gut microbiome. The central importance of gut microbiome in stress-exacerbated viral pneumonia was confirmed by microbiome depletion and gut microbiome transplantation. In particular, stress exposure induced a decline in Lactobacillaceae abundance and hence γ-aminobutyric acid (GABA) level in mice. Microbial-derived GABA proved to be released in the peripheral and sensed by AMs via GABAAR, leading to enhanced mitochondrial metabolism and α-ketoglutarate (αKG) generation. The metabolic intermediator in turn served as the cofactor for the epigenetic regulator Tet2 to catalyze DNA hydroxymethylation, and promoted PPARγ-centered gene program underpinning survival, self-renewing, and immunoregulation of AMs. We thus uncover an unappreciated GABA/Tet2/PPARγ regulatory circuitry that was initiated by gut microbiome to instruct distant immune cells through a metabolic-epigenetic program. Accordingly, reconstitution with GABA-producing probiotics, or adoptive transferring of GABA-conditioned AMs, or resumption of pulmonary αKG level remarkably improved AMs homeostasis and alleviated severe pneumonia in stressed mice. Conclusions Together, our study identifies a microbiome-derived tonic signaling that is tuned by mental health status to imprint resident immune cells and defensive response in lungs. The findings are particularly significant for the subpopulation with psychiatric stress to combat critical respiratory viral infection.

The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18INK4C), CDKN1A (p21CIP1/WAF1), CDKN1C (p57KIP2) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer.

Hyperoside (HYP), a naturally occurring flavonoid compound, exerts multiple biological functions including myocardial protection, antiredox, and anti-inflammatory activities. However, the role of HYP on inflammatory bowel disease (IBD) and the underlying mechanism need to be further established. Here, we show that HYP treatment profoundly alleviated dextran sulfate sodium-induced ulcerative colitis in mice, characterized by reduced pathological scores, preserved tissue integrity, suppressed colonic inflammation, and balanced Th17/Treg response. Mechanistically, HYP was shown to restrain the expression of the E3 ubiquitin ligase, makorin ring finger protein 1 (MKRN1), which in turn promoted the ubiquitination and proteasomal degradation of peroxisome proliferator-activated receptor gamma (PPARγ), an essential regulator of Th17 and Treg differentiation. Consequently, HYP treatment enhanced PPARγ signaling and hence promoted Treg differentiation while suppressing Th17 cell development during colitis. Thus, our data indicate that HYP acts through the MKRN1/PPARγ axis to modulate the Th17/Treg axis and thereby confers protection against experimental colitis. The findings extend our understanding about HYP action and may provide a potential therapeutic target for IBD.

Jian Pi Qing Gan Yin (JPQGY) has been used clinically to relieve non-alcoholic fatty liver disease (NAFLD) in China for decades; however, the underlying mechanisms of JPQGY remain unclear.We evaluated the effects and mechanisms of JPQGY and hepatic steatosis caused by the middle stage of 13-week-high-fat-diet-induced NAFLD in mice.Different dosages of JPQGY (5.5, 11, and 22 g/kg/day) were administered to NAFLD mice simultaneously. Body weight, body mass index (BMI), and liver lipid- and inflammation-related serum indicators were measured enzymatically. Liver samples were stained with Oil Red O and hematoxylin and eosin (HE). Next, we performed a network pharmacology analysis and verified eight target genes mapping to NAFLD-related lipid metabolism pathways. The mRNA/protein expression was analyzed by real-time polymerase chain reaction (PCR) and western blotting.JPQGY significantly relieved histological damage (steatosis-inflammation-fibrosis), prevented the downregulation of AMPK and Pparα, and upregulated LXRα, Srebp-1c, F4/80, Nf-κb, and Cyp2e1 in the HFD-induced NAFLD mouse model.The present results suggest that chronic treatment with JPQGY ameliorated HFD-induced NAFLD in mice by targeting the first and second phases of hepatic steatosis by stimulating the AMPK/PPARα pathway and inhibiting the LXRα/Srebp1/Nf-κb pathway. Our findings provide evidence that supports the clinical use of this formula for high-fat diet-induced fatty liver disease.

Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.

Acute kidney injury (AKI) is a global public health hazard with high morbidity and mortality. Sepsis accounts for nearly half of all causes of AKI. Scientists have made a great effort to explore effective therapeutic agents with limited side effects in the treatment of AKI, but have had little success. With the development of gut flora study, Akkermansia muciniphila (A. muciniphila) has been proven to prevent different organs by regulating the inflammatory response. However, the reno-protective function is still unknown. Here, the AKI model was induced using lipopolysaccharide (LPS) in mice with or without pretreatment of A. muciniphila. Renal function and histological change were measured. Inflammatory factors were detected by ELISA and rt-PCR. TLR4/NF-κB signaling factors and NLRP3 inflammasome were tested by western blot and immunohistochemistry. Pretreatment of A. muciniphila markedly inhibited inflammatory response and ameliorated kidney histopathological changes. Furthermore, the TLR4, p-NF-κB p65, and downstream IκBα were notably activated in the model group and inhibited by A. muciniphila. A similar effect was found in the regulation of NLRP3 inflammasome. In conclusion, pretreatment with A. muciniphila could protect against LPS-induced AKI by inhibition of the TLR4/NF-κB pathway and NLRP3 inflammasome activation. It may be a new therapeutic strategy for AKI prevention and treatment in the future.

Background. The flower of Abelmoschus manihot (AM) has been widely used in the treatment of chronic inflammatory diseases, including ulcerative colitis. This paper aimed to confirm the therapeutic effect of AM on ulcerative colitis (UC) and explore its mechanism. Methods. Mouse models were induced by 2.5% dextran sulfate sodium (DSS) and treated with AM. UC signs, symptoms, colon macroscopic lesion scores, and disease activity index (DAI) scores were observed. Colon levels of interleukin- (IL-) 6, IL-1β, IL-18, IL-17, tumor necrosis factor- (TNF-) α, and IL-10 were quantified by ELISA. The colon protein expression levels of NLRP3, ASC, caspase 1 p10, β-arrestin1, ZO-1, occludin-1, and claudin-1 were examined by immunohistochemistry and western blotting. The mRNA levels of IL-1β, IL-18, NLRP3, ASC, and caspase 1 p10 in the colon were determined by real-time quantitative polymerase chain reaction (qPCR). Results. After treatment with AM, the mortality of mice, pathological damage to the colon, splenomegaly, and the spleen coefficient were decreased. AM reduced the levels of proinflammatory cytokines (IL-6, IL-1β, IL-18, IL-17, and TNF-α) and increased the level of IL-10. The mRNA expression levels of NLRP3, ASC, and caspase 1 in colon tissue were decreased by AM in a dose-dependent manner. In addition, AM also reduced the protein expression of NLRP3, ASC, caspase 1 p10, IL-1β, IL-18, and β-arrestin1 in the colon tissue of model mice. Western blot analysis confirmed that AM increased the expression of occludin-1, claudin-1, and ZO-1 in a dose-dependent manner. Conclusion. This study shows that AM has a significant therapeutic effect on mice with UC, and the mechanism may be related to the inhibition of the β-arrestin1/NLRP3 inflammasome signaling pathway and the protection of intestinal barrier function.

Colorectal cancer (CRC) is the third most common type of cancer. Here, we studied the inhibitory effect of IRAK1 and IRAK4 as a preventive strategy using a colitis-induced tumorigenesis mouse model. CRC clinical data were obtained from the Gene Expression Omnibus (GEO). An experimental inflammation-dependent CRC model was induced by treatment with azoxymethane (AOM) and then dextran sodium sulfate (DSS) in C57BL/6 mice. Mice were administered an IRAK1/4 inhibitor by intraperitoneal injection at 3 mg/kg twice each week for 9 weeks. The IRAK1/4 inhibitor attenuated histological changes and prevented tumor growth. Tumor-associated proteins, including p65 and Ki-67, were downregulated by the IRAK1/4 inhibitor in AOM/DSS-treated mice. Additionally, IRAK1/4 inhibitor administration effectively decreased the expression of inflammatory cytokines. Furthermore, we observed that IRAK1/4 inhibitor treatment attenuated colitis-induced tumorigenesis by inhibiting epithelial-mesenchymal transition. These observations indicate that inhibition of IRAK1 and IRAK4 may suppress experimental colitis-induced tumorigenesis by inhibiting inflammatory responses and epithelial-mesenchymal transition.

Purpose Total flavone of Abelmoschus manihot (TFA), the effective constituents extracted from Flos Abelmoschus Manihot, has been reported to inhibit inflammation. However, the effect of TFA on ulcerative colitis (UC) progression in patients with depression is unknown. The purpose of our research was to explore the anti-UC effects of TFA in the context of depression in mice with UC by regulating the gut microbiota to drive the intestinal barrier. Methods In this study, chronic stress (CS) and dextran sodium sulfate (DSS) were used to induce depression and UC, respectively, in C57BL/6J mice. Fecal microbiota transplantation (FMT) was used to evaluate how treating mice modeling UC and depression with TFA effected their gut microbiota. Results Our results showed that TFA effectively improved UC aggravated by CS. In addition, TFA treatment improved the depression-like phenotype, the disturbed gut microbiota, and the intestinal barrier function in CS mice. It is worth noting that FMT from the CS mice to the receptor group further aggravated the damage of the intestinal barrier and the disturbance of the gut microbiota in the recipient DSS mice, thus further aggravating UC, however, treatment of the intervention of TFA in the CS fecal microbiota transplant with TFA also played its therapeutic outcome. Conclusion Taken together, our results show that CS disrupts the gut microbiota, triggers intestinal barrier injury and aggravates DSS colitis, while TFA is a promising drug for the treatment of UC in patients with depression., Graphical Abstract

Inflammatory bowel diseases (IBDs) are characterized by chronic pathologies associated with extensive gut dysbiosis and intestinal inflammation. Hence, endeavors to improve the inflammatory pathology by manipulating gut microbiota are ongoing. Daphnetin (DAPH) is a coumarin derivative extracted from Daphne odora var with anti-inflammatory and immune-regulatory properties that has been widely used in treating inflammatory disorders. Herein, we showed that DAPH remarkably alleviated experimental colitis by reducing colonic inflammation, improving colonic integrity, and reestablishing immune and metabolic homeostasis in the inflicted intestines. Our analysis showed that DAPH modified the composition of gut microbiota and altered the metabolic profiles in dextran sulfate sodium-treated mice. In particular, this agent significantly elevated the abundance of short-chain fatty acid (SCFA)-producing gut microbiota, causatively related with the enhanced development of Treg cells and the reduced proinflammatory Th17 cell differentiation. More critically, the protective effect of DAPH was shown to be transmissible among colitic mice through cohousing or fecal microbiota transplantation, further substantiating the importance of SCFA-producing gut microbiota in DAPH action. We thus for the first time reveal the potential of DAPH in resetting the gut microbiome and reestablishing immune homeostasis in colitic mice, which may have clinical implications for treating IBD.-Ji, J., Ge, X., Chen, Y., Zhu, B., Wu, Q., Zhang, J., Shan, J., Cheng, H., Shi, L. Daphnetin ameliorates experimental colitis by modulating microbiota composition and Treg/Th17 balance.

Background The modified Si-Jun-Zi Decoction (SJZ), a Chinese medicine formula, is clinically used against multiple malignancies including colorectal cancer (CRC). This study aims to evaluate the effect of modified SJZ on CRC liver metastasis and identify the therapeutic mechanisms. Methods Human CRC cells with GFP fluorescence were transplanted into Balb/c nude mice spleens. Modified SJZ, 5-fluorouracil or the combined treatment was given for 3 weeks. CRC liver metastasis was measured by fluorescence imaging and plasma cytokines were analyzed. Furthermore, the effects of administration time and doses for the modified SJZ were investigated in nude mice. Results Modified SJZ could increase the survival rate and reduce CRC liver metastasis in the nude mice model. Plasma GM-CSF level was elevated. Three weeks of treatment with the modified SJZ at the full dose (45 g/kg) could significantly increase the number of macrophages but not neutrophils in the spleen. Conclusions These results indicate that modified SJZ can inhibit CRC liver metastasis by activating the innate immune system, providing a complementary and alternative therapy for CRC.

Background Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. Methods The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. Results Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). Conclusion It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect.

The total flavone of Abelmoschus manihot (TFA), a compound extracted from the flowers of Abelmoschus manihot (L.) Medic, has been widely used for the treatment of Crohn's disease, chronic glomerulonephritis and other diseases. The aim of this study was to investigate the effect of TFA on gut microbiota and intestinal barrier in dextran sulfate sodium (DSS) induced experimental colitis. C57BL/6J mice were treated with 2.5% DSS in drinking water to induce colitis. Mice were orally administrated with TFA (62.5mg/kg, 125mg/kg) or prednisone acetate (PAT, 2.5mg/kg) once daily for 7 days. Biological samples were collected for analysis of inflammation cytokines, gut microbiota and intestinal barrier integrity. TFA-H (125mg/kg) markedly attenuated DSS-induced colon shortening and histological injury in experimental colitis. The therapeutic effect was similar with PAT administration. TFA-H notably modulated the dysbiosis of gut microbiota induced by DSS and greatly enriched the Akkermansia muciniphila (A. muciniphila). Moreover, TFA-H remarkably ameliorated colonic inflammatory response and intestinal epithelial barrier dysfunction. Interestingly, TFA directly promotes the growth of A. muciniphila in vitro. Taken together, the results for the first time revealed that TFA, as a prebiotic of A. muciniphila, improved DSS-induced experimental colitis, at least partly through modulating gut microflora profile to maintain the colonic integrity and inhibit inflammation response.

The total flavone of Abelmoschus manihot (TFA), a compound extracted from the flowers of Abelmoschus manihot (L.) Medic, has been widely used for the treatment of Crohn's disease, chronic glomerulonephritis and other diseases. The aim of this study was to investigate the effect of TFA on the gut microbiota and intestinal barrier in dextran sulfate sodium (DSS)-induced experimental colitis. C57BL/6J mice were treated with 2.5% DSS in drinking water to induce colitis. Mice were orally administered TFA (62.5 mg/kg, 125 mg/kg) or prednisone acetate (PAT, 2.5 mg/kg) once daily for 7 days. Biological samples were collected for analysis of inflammatory cytokines, gut microbiota and intestinal barrier integrity. TFA-H (125 mg/kg) markedly attenuated DSS-induced colon shortening and histological injury in experimental colitis. The therapeutic effect was similar to that of PAT administration. TFA-H notably modulated the dysbiosis of gut microbiota induced by DSS and greatly enriched Akkermansia muciniphila (A. muciniphila). Moreover, TFA-H remarkably ameliorated the colonic inflammatory response and intestinal epithelial barrier dysfunction. Interestingly, TFA directly promotes the growth of A. muciniphila in vitro. Taken together, the results revealed for the first time that TFA, as a prebiotic of A. muciniphila, improved DSS-induced experimental colitis, at least partly by modulating the gut microflora profile to maintain colonic integrity and inhibit the inflammatory response.

Incorporation of microbiome data has recently become important for prevention, diagnosis, and treatment of colorectal cancer, and several species of bacteria were shown to be associated with carcinogenesis. However, the role of commensal fungi in colon cancer remains poorly understood. Here, we report that mice lacking the c-type lectin Dectin-3 (Dectin-3-/- ) show increased tumorigenesis and Candida albicans burden upon chemical induction. Elevated C. albicans load triggered glycolysis in macrophages and interleukin-7 (IL-7) secretion. IL-7 induced IL-22 production in RORγt+ (group 3) innate lymphoid cells (ILC3s) via aryl hydrocarbon receptor and STAT3. Consistently, IL-22 frequency in tumor tissues of colon cancer patients positively correlated with fungal burden, indicating the relevance of this regulatory axis in human disease. These results establish a C. albicans-driven crosstalk between macrophages and innate lymphoid cells in the intestine and expand our understanding on how commensal mycobiota regulate host immunity and promote tumorigenesis.

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for three weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson’s Correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression related molecular (corticosterone, dopamine and BDNF). Moreover, AKK altered chronic stress-induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated β-Alanyl-3-methyl-L-histidine and edaravone to relieve depression. Furthermore, β-Alanyl-3-methyl-L-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress-induced depressive symptoms in mice by regulating gut microbiota and metabolites. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 81873309). Declaration of Interests: There are no conflicts of interest to declare. Ethics Approval Statement: The experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine.

Additional file 5: Original data.

Background:Ulcerative colitis (UC) patients have a high incidence of mental disorders. The microbiota-gut-brain axis dysfunction is considered as one important pathogenesis of mental diseases. At present, little is known about how gut microbiota interact with the host in UC patients with depression and anxiety.Results: This prospective observational study enrolled 240 Chinese patients in two cohorts: the discovery cohort, including 69 active UC patients, 49 non-inflammatory bowel disease (IBD) depression and anxiety patients, and 62 healthy people, and the replication cohort of 60 active UC patients. About half of active UC patients showed symptoms of depression or anxiety. Through 16s rRNA sequencing, it was found that these UC patients accompanied with depression and anxiety had lower fecal microbial abundance with more Sellimonas , Eubacterium ventriosum group , Enterococcus , and Peptoclostridium , but less Prevotella_9 , Erysipelotrichaceae UCG_003 , Collinsella , and Dorea , compared with non-depressed/ anxious UC patients. Serum metabolome and proteome analysed using liquid chromatography/ mass spectrometry showed significantly increased glycochenodeoxycholate, stearoyllysophosphatidylcholine, and glyceryl stearates, while decreased 2'-deoxy-D-ribose and a set of immunoglobulin protein in the serum of UC patients with depression and anxiety. Through integration of multiple statistical analyses and multi-omics correlation analyses, we revealed a highly connected and comprehensive network, centring on Prevotella_9 and 1-stearoyl-sn-glycerol, composed of these bacteria, metabolites and proteins associated with UC-specific depression and anxiety.Conclusion: This study has identified a highly connected multi-omics network, composed of a set of gut microbiota, serum metabolites and proteins, specifically related to depression and anxiety in active UC. This network might influence host's mental state through mediating the effect of gut inflammation on synapse pruning in the central nervous system.

Mycobiota are inseparable from human health, shaking up the unique position held by bacteria among microorganisms. What is surprising is that this seemingly small species can trigger huge changes in the human body. Dysbiosis and invasion of mycobiota are confirmed to cause disease in different parts of the body. Meanwhile, our body also produces corresponding immune changes upon mycobiota infection. Several recent studies have made a connection between intestinal mycobiota and the human immune system. In this review, we focus on questions related to mycobiota, starting with an introduction of select species, then we summarize the typical diseases caused by mycobiota in different parts of the human body. Moreover, we constructed a framework for the human anti-fungal immune system based on genetics and immunology. Finally, the progression of fungal detection methods is also reviewed.

There are trillions and trillions of microorganisms in the human gut, and these microorganisms and their metabolites are closely related to human health. Recent studies have found that the abundance of Akkermansia muciniphila is decreased in many diseases. Supplementation of A. muciniphila is used to treat many diseases, suggesting it as a probiotic. Herbal medicines are considered as valuable asset of traditional Chinese medicine. Recent studies have revealed traditional Chinese medicine as a potential prebiotic agent for the treatment of many diseases. Hence, in this review, we aimed to provide a plausible mechanistic basis for the interactions between herbal medicines and A. muciniphila, and therapeutic benefits on this interaction in various illnesses.

Background. Dehydrocostus lactone (DL), one of the main active constituents in Aucklandia lappa Decne. (Muxiang), reported to have anti-inflammatory, antiulcer, and immunomodulatory properties. However, the effect of DL on ulcerative colitis (UC) has not been reported. To analyze the anti-inflammatory potential role of DL in UC, we provide a mechanism for the pharmacological action of DL. Methods. The experimental model of UC was induced by using oral administration of 2% dextran sulfate sodium (DSS) with drinking water in BALB/c mice. Mesalazine (Mes, 0.52 g/kg/d), DL-high doses (DL-H, 20 mg/kg/d), DL-middle doses (DL-M, 15 mg/kg/d), DL-low doses (DL-L, 10 mg/kg/d) were gavaged once a day from day 4 to day 17. Disease activity index (DAI) was calculated daily. On day 18, mice were rapidly dissected and the colorectal tissues were used to detect the levels of UC-related inflammatory cytokines (TNF-α, IL-1β, MCP-1, MPO, SOD, IL-6, IL-17, and IL-23), IL-6/STAT3 inflammatory signaling pathway (iNOS, COX2, IL-6, GP130, L-17, and IL-23), and colorectal mucosal barrier-related regulatory factors (MUC2, XBP1s, and α-defensins) by ELISA or qRT-PCR. Results. DL reduced the colorectal inflammation histological assessment, decreased UC-related inflammatory cytokines (TNF-α, IL-1β, MCP-1, MPO, SOD, IL-6, IL-17, and IL-23), downregulated IL-6/STAT3 inflammatory signaling pathway (iNOS, COX2, IL-6, GP130, L-17, and IL-23), repaired the key colorectal mucosal barrier protein-MUC2, and inhibited the downstream pathway (XBP1s and α-defensin). Conclusions. DL possessed the potential of anti-inflammatory effect to treated colitis. The protective mechanism of DL may involve in reducing inflammation and improving colorectal barrier function via downregulating the IL-6/STAT3 signaling.

Aim Published outcomes following ligation of the intersphincteric fistula tract (LIFT) for high transsphincteric fistulas (HTFs) are equivocal probably because most trials are small and comprise mixed patient populations. The aim of this study was to highlight the long-term efficacy of LIFT for HTFs in a large homogeneous sample and to determine the risk factors that contribute to non-healing resulting in failure and recurrence. Method A retrospective study was performed which assessed patients with HTFs treated by LIFT without prior loose setons from September 2012 to December 2017. Continence function was evaluated by the Wexner incontinence scale and anal manometry. Quality of life was assessed by using the faecal incontinence quality of life (FIQL) scale with four domains: lifestyle, coping, depression and embarrassment. Results Seventy patients with HTFs underwent 71 LIFT procedures. The primary healing rate was 81.7% with a median follow-up duration of 16.5 (range 4.5-68) months. The healing rates of mature and immature fistulas were 83.7% and 77.3%, respectively. Two patients suffered failure with an unhealed intersphincteric wound. Recurrence occurred in 11 patients. Incontinence of flatus, present in four patients before surgery, improved postoperatively. Two patients undergoing LIFT combined with fistulotomy complained of flatus incontinence after surgery. No significant differences between preoperative and postoperative Wexner score, maximum resting pressure and maximum squeeze pressure were detected. The FIQL was improved in lifestyle, coping and depression. No risk factor for non-healing was found. Conclusion LIFT has a promising long-term outcome for HTFs, with negligible impairment on continence and improved quality of life.

Background Evidence concerning the effect of faecal microbiota transplantation [FMT] in Clostridium difficile infection [CDI] patients with inflammatory bowel disease [IBD] has not been firmly established. Therefore, we performed a systematic review and meta-analysis to evaluate FMT treatment outcomes in patients with IBD treated for CDI. Methods An electronic search of four databases was conducted until November 1, 2017. Cohort studies of FMT efficacy and safety in CDI patients with IBD were included. Pooled effect sizes were calculated with 95% confidence intervals [CI] using a random-effects model. Results Nine cohort studies comprising a total of 346 CDI patients with IBD were included. The initial cure rate was 81% [95% CI = 76%-85%] and the overall cure rate was up to 89% [95% CI = 83%-93%], both with no significant heterogeneity. The recurrence rate was 19% [95% CI = 13%-27%] with moderate heterogeneity [Cochran's Q, p = 0.19; I2 = 33%]. There was no significant difference in the CDI cure rate after FMT in patients with and without IBD (risk ratio [RR] = 0.92; 95% CI = 0.81-1.05; Cochran's Q, p = 0.06; I2 = 53%). Subgroup analysis revealed a similar CDI treatment effects after FMT in patients with Crohn's disease and in those with ulcerative colitis [p = 0.1804]. Four studies reported adverse events of IBD flares. Conclusions FMT is an effective therapy for CDI in patients with IBD. Well-designed randomised controlled trials and well-conducted microbiological studies are needed to validate its efficacy and safety.

Inflammatory bowel diseases (IBDs) are characterized by chronic pathologies associated with extensive gut dysbiosis and intestinal inflammation. Hence, endeavors to improve the inflammatory pathology by manipulating gut microbiota are ongoing. Daphnetin (DAPH) is a coumarin derivative extracted from

Flos Abelmoschus manihot is widely used as traditional drug in China. Abelmoschus manihot (AM) extracted from Flos Abelmoschus manihot that has been applied for treating chronic inflammatory diseases. Here we showed that AM significantly alleviated DSS-induced colitis in mice. AM modified gut microbiota composition, increased microbial diversity, and in particularly, elevated the abundance of short chain fatty acids (SCFAs)-producing gut microbiota in colitic mice. Consequently, levels of SCFAs especially butyrate and acetate were increased upon AM treatment, which, primarily through peroxisome proliferator-activated receptor gamma (PPARγ) pathway, led to the enhanced Treg generation and the suppressed Th17 development. Together, we herein provide the first evidences to support that AM, a natural plant-derived complex, can potentially reset gut microbiome and metabolism, resume immune and tissue homeostasis, and hence prevent colitis, which may provide a new perspective on IBD pathogenesis and suggest a novel microbiota-targeting therapy for inflammatory gut diseases.

1. Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn’s disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug.2. Although the systemic TSA exposures were low (AUC0–t approximately 330 ng*h/ml) in both the normal and colitis models after oral administration TSA 20 mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies.3. Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher p...

This study aimed to explore cell surface biomarkers related to cancer stem cells (CSCs) and their role in the tumorigenesis of colon cancer. Various colon cancer cell lines were screened for CD133 and CD44 expression. CD44(high)/CD133(high) and CD44(low)/CD133(low) cells were separately isolated by Fluorescence-Activated Cell Sorting (FACS). The cell proliferation, colony formation, cell cycle characteristics, and tumorigenic properties in CD44(high)/CD133(high) and CD44(low)/CD133(low) cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression profiles of stem cell-related genes were examined by RT-PCR. With HCT-116 cells, flow cytometry analysis revealed that CD44(high)/CD133(high) cells had higher proliferation potency than CD44(low)/CD133(low) cells. Compared to CD44(low)/CD133(low) cells, CD44(high)/CD133(high) cells had more stem cell-related genes, and displayed increased tumorigenic ability. In summary, CD44(high)/CD133(high) cells isolated from HCT-116 cells harbor CSC properties that may be related to the tumor growth of colon cancer. These results suggest that CD44 and CD133 could be strong markers of colorectal cancer stem cells.

Background Colorectal cancer (CRC) has a high incidence and mortality rate worldwide. Colitis-associated CRC (CAC) is used for describing the relationship between inflammation and CRC. No chemopreventive agents have been found to be both effective and safe in CRC. Therefore, the prevention and treatment of CAC are extremely urgent. Wu Mei Wan (WMW) has been used for the clinical treatment of enteritis with a remarkable efficacy. Here, we aim to investigate the underlying mechanism of WMW in the prevention of CAC. Methods The AOM/DSS-induced CAC mouse model was used, and the mice were divided into normal control (NC), AOM/DSS model control (MC), and AOM/DSS plus WMW (WMW). The weight of mice, the score of DAI, survival rate, number of tumors and sample collection were performed at the end of the 14th week. Histopathological examination was performed using Hematoxylin–Eosin (HE) staining. Tumor cell proliferation was indicated by the expression of PCNA, and p65 and p-STAT3 were detected by immunohistochemistry. Serum IL-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). The expression of p65, IL-6 and p-STAT3 in the colon was detected by Western Blot. Intestinal flora was analyzed by 16S rDNA sequencing. Results WMW improved the survival rate of mice in the MC group and also attenuated CAC symptoms such as abnormal clinical colitis and pathological changes to intestinal tissue by reducing DAI score, tumor formation, tumor volume, and grade of tumorigenesis. WMW also reduced the proliferation of tumor cells in colon tissues. WMW decreased the expression of p65, IL-6, and p-STAT3 in colon tumors of CAC mice. WMW decreased Bacteroidetes and increased Firmicutes at the phylum level, while decreasing bacteroidales_s24-7_group and increasing the number of Lachnospiraceae at the family level. Conclusion WMW attenuates CAC by regulating the balance between “tumor-promoting bacteria” and “tumor-suppressing bacteria” and the NF-kB/IL-6/STAT3 pathway. WMW has the potential to be a safe and effective chemopreventive drug but further clinical evidence is necessary.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. However, the molecular mechanisms of CRC pathogenesis are not fully understood. In this study, we report the characterization of LYAR (Ly-1 antibody reactive clone) as a key regulator of the migration and invasion of human CRC cells. Immunohistochemistry analysis demonstrated that LYAR is expressed at a higher level in metastatic CRC tissues. We found that LYAR promoted the migratory and invasive capabilities of CRC cells. Gene expression profile analysis of CRC cells showed that LGALS1, which encodes the galectin-1 protein, was a potential target of LYAR. The ChIP assay and gene reporter assays indicated that LYAR directly bound to the LGALS1 promoter. The ectopic expression of galectin-1 partially restored the mobile potential of LYAR knocked-down cells, which suggests that galectin-1 contributed to the LYAR-promoted cell migration and invasion of CRC cells. Thus, this study revealed a novel mechanism by which the transcription factor LYAR may promote tumor cell migration and invasion by upregulating galectin-1 gene expression in CRC.