• E-cadherin
• bacteria
• disease pathogenesis
• epithelial barrier
• homeostasis
• infection
• inflammation

• Cadherins/metabolism
• Humans
• Inflammation/metabolism
• Bacterial Infections/metabolism
• Bacterial Infections/immunology
• Bacterial Infections/microbiology
• Animals
• Adherens Junctions/metabolism
• Homeostasis
• Epithelial Cells/microbiology
• Epithelial Cells/metabolism
• Epithelium/microbiology
• Epithelium/metabolism

• R01 DE031046 NIDCR NIH HHS
• R21 CA294025 NCI NIH HHS

• 3-MA
• Autophagy
• Goblet cells
• Muc2
• Nano-selenium
• Small intestine

• Animals
• Female
• Goblet Cells/metabolism
• Sequestosome-1 Protein/metabolism
• Selenium/pharmacology
• Selenium/metabolism
• Chickens/metabolism
• Autophagy
• Intestine, Small/metabolism

• Trefoil factor 3
• biomarkers
• kidney
• kidney disease
• neonates

• B.SUB.23.254 Medical University of Bialystok

• Chronic kidney disease
• Gut-kidney axis
• Renal tubular epithelial cell
• Signaling
• Trefoil factor 3

Mucinous adenocarcinoma (MAC) is a unique clinicopathological subtype of colorectal cancer, which is characterized by extracellular mucinous components that comprise at least 50% of the tumor tissue. The clinical characteristics, molecular features, response to chemo-/radiotherapy, and prognosis of MAC are different from that of non-MAC (NMAC). MAC is more common in the proximal colon, with larger volume, higher T-stage, a higher proportion of positive lymph nodes, poorer tumor differentiation, and a higher proportion of peritoneal implants compared to NMAC. Although biopsy is the main diagnostic method for MAC, magnetic resonance imaging is superior in accuracy, especially for rectal carcinoma. The aberrant expression of mucins, including MUC1, MUC2 and MUC5AC, is a notable feature of MAC, which may be related to tumor invasion, metastasis, inhibition of apoptosis, and chemo-/radiotherapy resistance. The genetic origin of MAC is mainly related to BRAF mutation, microsatellite instability, and the CpG island methylator phenotype pathway. In addition, the poor prognosis of rectal MAC has been confirmed by various studies, and that of colonic MAC is still controversial. In this review, we summarize the epidemiology, clinicopathological characteristics, molecular features, methods of diagnosis, and treatments of MAC in order to provide references for further fundamental and clinical research.

• Mucinous adenocarcinoma
• Colorectal cancer
• Mucin
• Microsatellite instability
• Magnetic resonance imaging
• Treatment

• microbiome
• gastrointestinal models

• Animals
• Biomarkers
• Cell Line
• Cytokines/metabolism
• Gastrointestinal Microbiome
• Homeostasis
• Humans
• Intestinal Mucosa/metabolism
• Lipid Peroxidation
• Oxygen/metabolism
• Reactive Oxygen Species/metabolism

• R01 EB021908 NIBIB NIH HHS
• R01 GM098117 NIGMS NIH HHS
• NIH/NIBIB
• Division of Integrative Organismal Systems

• Mucin-2
• goblet cells
• immunomodulation
• intestinal peptides
• probiotics

• bacteria
• epithelium
• mucin
• ulcerative colitis

• Animals
• Bacteria/genetics
• Colitis/chemically induced
• Colitis/genetics
• Colitis/microbiology
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/microbiology
• Colitis, Ulcerative/pathology
• Colon/metabolism
• Colon/microbiology
• Dextran Sulfate
• Disease Models, Animal
• Homeostasis
• Humans
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Mice
• Mucin 5AC/metabolism
• Protective Factors
• RNA, Ribosomal, 16S

• R01 DK111856 NIDDK NIH HHS
• R03 DK114545 NIDDK NIH HHS
• K01 DK099485 NIDDK NIH HHS
• R01 HL080396 NHLBI NIH HHS
• R01 HL130938 NHLBI NIH HHS
• National Institutes of Health
• Crohn's and Colitis Foundation

Enteric viral co-infections, infections involving more than one virus, have been reported for a diverse group of etiological agents, including rotavirus, norovirus, astrovirus, adenovirus, and enteroviruses. These pathogens are causative agents for acute gastroenteritis and diarrheal disease in immunocompetent and immunocompromised individuals of all ages globally. Despite virus–virus co-infection events in the intestine being increasingly detected, little is known about their impact on disease outcomes or human health. Here, we review what is currently known about the clinical prevalence of virus–virus co-infections and how co-infections may influence vaccine responses. While experimental investigations into enteric virus co-infections have been limited, we highlight in vivo and in vitro models with exciting potential to investigate viral co-infections. Many features of virus–virus co-infection mechanisms in the intestine remain unclear, and further research will be critical.

• co-infection
• co-infection models
• enteric virus
• viral pathogenesis

Primary sclerosing cholangitis (PSC) is a common indication for liver transplantation (LT). Up to 25% of patients experience recurrence of PSC (rPSC) after LT, which is associated with significant morbidity and mortality. To date, it is not possible to predict which patients are at risk for rPSC. The aetiology of PSC is complex and is speculated to involve translocation of intestinal bacteria to the liver, because of its frequent co‐occurrence with inflammatory bowel diseases (IBD). Here, we investigate whether the mucosal intestinal microbiome of PSC patients (n = 97) at time of first LT can identify those patients who will develop rPSC. 16S gene sequencing of bacterial DNA isolated from formalin‐fixed paraffin‐embedded biopsies showed that PSC patients with Crohn’s disease (n = 15) have a reduced microbial diversity and that inflammation of the mucosa is associated with beta‐diversity changes and feature differences. No differences in alpha‐ or beta diversity were observed between patients with rPSC (n = 14) and without rPSC (n = 83). However, many over‐represented bacterial features were detected in patients with rPSC, while surprisingly, those without recurrence of disease were characterized by an increased presence of the Gammaproteobacteria Shigella. This pilot study warrants further investigation into bacterial differences between rPSC and non‐rPSC patients.

• liver transplantation
• microbiome
• primary sclerosing cholangitis
• recurrent disease

• gut-on-a-chip
• gut-organoids
• human-based methods
• infectious diseases
• microbiota
• nutrition
• third-generation sequencing

• Biomedical Research/methods
• Communicable Disease Control/methods
• Communicable Diseases
• Gastrointestinal Microbiome/physiology
• Humans
• Nutritional Physiological Phenomena/physiology
• Nutritional Status/physiology
• Technology/methods

• MUC2
• MUC4
• MUC5AC
• Mucins
• colon and colorectal cancer
• glycans
• inflammatory bowel disease

• R01 CA206444 NCI NIH HHS
• RO1 CA183459 NIH HHS
• CA210637 NIH HHS
• R44 CA224619 NCI NIH HHS
• P50 CA127297 NIH HHS
• RO1CA206444 NIH HHS
• P50 CA127297 NCI NIH HHS
• UO1 CA200466 NIH HHS
• P01 CA217798 NCI NIH HHS
• R01 CA183459 NCI NIH HHS
• PO1 CA217798 NIH HHS
• R01 CA210637 NCI NIH HHS
• R43 CA235984 NCI NIH HHS

• Digestive tract
• Food ingredients
• Functional foods
• Intestinal mucosa
• Mucins
• Probiotic bacteria

Dose-dependent toxicity and acquired resistance are two major challenges limiting the efficacious treatment of mammary carcinoma (MC) with doxorubicin. Herein, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity and acquired resistance of estrogen receptor positive (ER+) MC cells to doxorubicin. Doxorubicin treatment of ER+MC cells increased TFF3 expression. The depletion of TFF3 by siRNA or inhibition with a small molecule TFF3 inhibitor (AMPC) synergistically enhanced the efficacy of doxorubicin in ER+MC through the suppression of doxorubicin-induced AKT activation and enhancement of doxorubicin-induced apoptosis. Elevated expression of TFF3 and increased activation of AKT were also observed using a model of acquired doxorubicin resistance in ER+MC cells. AMPC partially re-sensitized the doxorubicin resistant cells to doxorubicin-induced apoptosis. Indeed, doxorubicin resistant ER + MC cells exhibited increased sensitivity to AMPC as a single agent compared to doxorubicin sensitive cells. In vivo, AMPC attenuated growth of doxorubicin sensitive ER+MC xenografts whereas it produced regression of xenografts generated by doxorubicin resistant ER+MC cells. Hence, TFF3 inhibition may improve the efficacy and reduce required doses of doxorubicin in ER+MC. Moreover, inhibition of TFF3 may also be an effective therapeutic strategy to eradicate doxorubicin resistant ER+MC.

• PI3K/AKT
• acquired resistance
• apoptosis
• dose-dependent toxicity
• doxorubicin
• mammary carcinoma
• trefoil factor 3 (TFF3)

The gut microbiome is extremely important for maintaining homeostasis with host intestinal epithelial, neuronal, and immune cells and this host-microbe interaction is critical during times of stress or disease. Environmental, nutritional, and cognitive stress are just a few factors known to influence the gut microbiota and are thought to induce microbial dysbiosis. Research on this bidirectional relationship as it pertains to health and disease is extensive and rapidly expanding in both in vivo and in vitro/ex vivo models. However, far less work has been devoted to studying effects of host-microbe interactions on acute stressors and performance, the underlying mechanisms, and the modulatory effects of different stressors on both the host and the microbiome. Additionally, the use of in vitro/ex vivo models to study the gut microbiome and human performance has not been researched extensively nor reviewed. Therefore, this review aims to examine current evidence concerning the current status of in vitro and ex vivo host models, the impact of acute stressors on gut physiology/microbiota as well as potential impacts on human performance and how we can parlay this information for DoD relevance as well as the broader scientific community. Models reviewed include widely utilized intestinal cell models from human and animal models that have been applied in the past for stress or microbiology research as well as ex vivo organ/tissue culture models and new innovative models including organ-on-a-chip and co-culture models.

• DoD
• ex vivo
• in vitro
• intestine
• physiology
• stress

• Escherichia coli Nissle 1917
• Lactobacillus rhamnosus GG
• cytokine
• intestinal immune response
• mucins

• goblet cell
• gut infections
• inflammatory bowel disease
• microbes
• mucus

• cytokine
• goblet cell
• mucus
• spirochete
• swine

• TFF3
• cancer stem cells
• chemoresistance
• hepatocellular carcinoma
• oncogenic

• Animals
• Antibiotics, Antineoplastic/pharmacology
• Apoptosis/drug effects
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Proliferation/drug effects
• Cell Transformation, Neoplastic/drug effects
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Doxorubicin/pharmacology
• Drug Resistance, Neoplasm
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Prognosis
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Survival Rate
• Trefoil Factor-3/metabolism
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

Shigella dysenteriae (S.dysenteriae) the causative agent of bacillary dysentery invades the human colonic epithelium resulting in severe intestinal inflammatory response and epithelial destruction. However, the mechanism by which S.dysenteriae infection regulates proinflammatory cytokines during intestinal inflammation is still obscure. In this study, we evaluated whether the interaction of β-catenin and NF-κB regulates proinflammatory cytokines TNF-α and IL-8 by modulating GSK-3β activity during S.dysenteriae infection in rat ileal loop model. Here we demonstrated that S.dysenteriae infection stimulate β-catenin degradation which in turn decreased the association between NF-κB and β-catenin. Also, we showed that S.dysenteriae infection increased GSK-3β kinase activity which in turn phosphorylates β-catenin for its degradation by ubiquitination and upregulates IL-8 through NF-κB activation thereby leading to inflammation. Thus these findings revealed the role of β-catenin/ NF-κB and GSK-3β in modulating the inflammatory response during bacterial infection and also showed that β-catenin acts as a critical regulator of inflammation.

• Animals
• Cytokines/metabolism
• Dysentery, Bacillary/metabolism
• Dysentery, Bacillary/pathology
• Humans
• Inflammation/metabolism
• Inflammation Mediators/metabolism
• NF-kappa B/metabolism
• Rats
• Shigella dysenteriae/isolation & purification
• Signal Transduction
• beta Catenin/metabolism

To investigate β-catenin-mediated bacterial elimination during Pseudomonas aeruginosa infection of macrophage-like RAW264.7 cells.

Cell viability and catenin beta 1 (CTNNB1) expression in RAW264.7 cells following P. aeruginosa infection versus uninfected cells, were detected by cell counting kit-8 assay and β-catenin Western blots. RAW264.7 cells with CTNNB1 overexpression were established with β-catenin lentivirus using flow cytometry and clonogenic limiting dilution assays. Bacterial killing was measured by plate counts; phagocytosis and nitric oxide (NO) were measured by flow cytometry; and reactive oxygen species (ROS) were measured using Griess reaction. Autophagy was determined by microtubule-associated protein 1 light chain 3 alpha-phosphatidylethanolamine conjugate (LC3-II) protein levels and formation of LC3 puncta, using Western blot and immunofluorescence staining.

Following P. aeruginosa infection, RAW264.7 cell β-catenin levels were reduced in a time- and multiplicity of infection-dependent manner. CTNNB1 overexpression was associated with increased P. aeruginosa elimination, but had no effect on RAW264.7 cell phagocytosis, ROS and NO. CTNNB1 overexpression reduced LC3-II levels and formation of LC3 puncta, suggesting autophagy inhibition. Rapamycin/starvation-induced autophagy resulted in reduced bacterial killing following P. aeruginosa infection.

β-catenin may promote bacterial killing via suppression of P. aeruginosa-induced macrophage autophagy.

• Pseudomonas aeruginosa
• autophagy
• bacterial killing
• β-catenin

Tumour necrosis factor-α (TNF-α) is a double-edged cytokine associated with pathogenesis of inflammatory-related cancers being also able to induce cancer cell death. In the process of tumour development or metastasis, cancer cells can become resistant to TNF-α. In trefoil factor 3 (TFF3) overexpressing colorectal adenocarcinoma cells (HT-29/B6), we observed enhanced resistance against TNF-α/interferon gamma-induced apoptosis. TFF3 is a secreted small peptide that supports intestinal tissue repair but is also involved in intestinal tumour progression and scattering. We hypothesised that TFF3 rescues intestinal epithelial cancer cells from TNF-α-induced apoptosis by involving regulatory RNA networks. In silico-based expression analysis revealed TFF3-mediated regulation of selected microRNAs as well as long non-coding RNAs (lncRNAs), whereas miR-491-5p was identified to target the lncRNA ‘psoriasis susceptibility-related RNA gene induced by stress’ (PRINS). RNA interference-based gain- and loss-of-function experiments examined miR-491-PRINS axis to exert the TFF3-mediated phenotype. Chemical inhibition of selected pathways showed that phosphatidylinositol 3-kinase/AKT accounts for TFF3-mediated downregulation of miR-491-5p and accumulation of PRINS. Moreover, we showed that PRINS colocalises with PMAIP1 (NOXA) in nuclei of HT-29/B6 possessing inhibitory effects. Immunoprecipitation experiments proved molecular interaction of PMAIP1 with PRINS. Our study provides an insight into RNA regulatory networks that determine resistance of colorectal cancer cells to apoptosis.

• Bone marrow mesenchymal stem cells
• Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1
• Glycogen synthase kinase-3β
• Osteogenic differentiation
• Type 2 diabetes mellitus

• ARNTL Transcription Factors/metabolism
• Animals
• Biomarkers/metabolism
• Cell Differentiation
• Cell Proliferation
• Cellular Microenvironment
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Type 2/pathology
• Glycogen Synthase Kinase 3 beta/antagonists & inhibitors
• Glycogen Synthase Kinase 3 beta/metabolism
• Male
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/pathology
• Osteogenesis
• Rats
• Wnt Signaling Pathway

Shigella is a pathovar of Escherichia coli comprising four groups, Shigella flexneri, Shigella sonnei, Shigella dysenteriae, and Shigella boydii, each of them, with the exception of S.sonnei, comprising several serotypes. Shigella accounts for the majority of dysentery causing infections occurring world-wide each year. Recent advancements in the Shigella field have led to a better understanding of the molecular mechanisms underlying host epithelial cell invasion and immune cell function manipulation, mainly using S. flexneri as a model. Host-cell invasion is the final step of the infection process, as Shigella's virulence strategy relies also on its ability to survive hostile conditions during its journey through the gastro-intestinal tract, to compete with the host microbiota and to cross the intestinal mucus layer. Hence, the diversity of the virulence strategies among the different Shigella species has not yet been deeply investigated, which might be an important step to understand the epidemiological spreading of Shigella species worldwide and a key aspect for the validation of novel vaccine candidates. The recent development of high-throughput screening and sequencing methods will facilitate these complex comparison studies. In this review we discuss several of the major avenues that the Shigella research field has taken over the past few years and hopefully gain some insights into the questions that remain surrounding this important human pathogen.

• Shigella
• diversity
• microbiota
• mucus
• virulence

• HT-29
• Immunomodulation
• Lactobacillus casei
• NF-κB
• PBMCs
• Probiotics
• TFF3

Mucosal epithelial cells in the intestine act as the first line of host defense against pathogens by increasing mucin production for clearance. Despite this fact, the underlying molecular mechanisms by which Shigella dysenteriae transduce mucin gene expression remain poorly defined. The goal of this study was to determine the role of Bone morphogenetic protein (BMP) pathway in mucin gene expression during S. dysenteriae infection. In this study we demonstrate that S. dysenteriae activates BMP signaling to induce MUC2 and MUC5AC gene expression in rat ileal loop model and in vitro. We also observed that BMP pathway regulates CDX2 expression which plays a critical role in induction of MUC2 gene during S. dysenteriae infection. In SMAD4 silenced cells S. dysenteriae infection did not abrogate MUC2 and MUC5AC gene expression whereas in CDX2 silenced cells it induces differential expression of MUC5AC gene. These results suggest that SMAD4-CDX2 induces MUC2 gene expression whereas SMAD4 directly influences differential expression of MUC5AC gene. Altogether, our results show that during S. dysenteriae infection the BMP pathway modulates inflammatory transcription factors CDX2 and SMAD4 to induce MUC2 and MUC5AC gene expression which plays a key role in the regulation of host mucosal defense thereby paving a cue for therapeutic application.

• Animals
• Bone Morphogenetic Proteins/metabolism
• CDX2 Transcription Factor
• Cell Line
• Disease Models, Animal
• Dysentery, Bacillary/genetics
• Dysentery, Bacillary/metabolism
• Dysentery, Bacillary/microbiology
• Gene Expression Regulation
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Humans
• Ileitis/genetics
• Ileitis/metabolism
• Ileitis/microbiology
• Male
• Mucin 5AC/biosynthesis
• Mucin 5AC/genetics
• Mucins/biosynthesis
• Mucins/genetics
• Rats
• Shigella dysenteriae
• Signal Transduction
• Smad4 Protein/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Transcription, Genetic

Fermented dairy products are the usual carriers for the delivery of probiotics to humans, Bifidobacterium and Lactobacillus being the most frequently used bacteria. In this work, the strains Bifidobacterium animalis subsp. lactis IPLA R1 and Bifidobacterium longum IPLA E44 were tested for their capability to modulate immune response and the insulin-dependent glucose homeostasis using male Wistar rats fed with a standard diet. Three intervention groups were fed daily for 24 days with 10% skimmed milk, or with 10⁹ cfu of the corresponding strain suspended in the same vehicle. A significant increase of the suppressor-regulatory TGF-β cytokine occurred with both strains in comparison with a control (no intervention) group of rats; the highest levels were reached in rats fed IPLA R1. This strain presented an immune protective profile, as it was able to reduce the production of the proinflammatory IL-6. Moreover, phosphorylated Akt kinase decreased in gastroctemius muscle of rats fed the strain IPLA R1, without affecting the glucose, insulin, and HOMA index in blood, or levels of Glut-4 located in the membrane of muscle and adipose tissue cells. Therefore, the strain B. animalis subsp. lactis IPLA R1 is a probiotic candidate to be tested in mild grade inflammation animal models.

• deoxynivalenol
• fumonisin B1
• intestinal epithelia
• mucins
• nivalenol
• zearalenone

• Bacterial killing
• Corneal infection
• Inflammation
• β-Catenin