muramidase and Colitis

It is a desirable and powerful strategy to precisely fabricate functional soft matter through self-assembly of molecular building blocks across a range of length scales. Proteins, nucleic acids, and polyphenols are the self-assemblers ubiquitous in nature. Assembly of proteins into flexible biocolloids, amyloid fibrils with high aspect ratio, has emerged as an unchallenged templating strategy for high-end technological materials and bio-nanotechnologies. We demonstrate the ability of these fibrils to support the deposition and self-assembly of polyphenols into hybrid nanofilaments and functional macroscopic hydrogels made thereof. The length scale of the substance that amyloid fibrils can attach with acting as the building templates was extended from nanometer down to sub-nanometer. Significantly increased loading capacities of polyphenols (up to 4.0 wt %) compared to that of other delivery systems and improved stability were realized. After oral administration, the hydrogels could transport from the stomach to the small intestine and finally to the gut (cecum, colon, rectum), with a long retention time in the colon. Oral administration of the hydrogels significantly ameliorated colitis in a mouse model, promoted intestinal barrier function, suppressed the pro-inflammatory mRNA expression, and very significantly (

Topics: Amyloid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Dextran Sulfate; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Muramidase; Nanoparticles; Polyphenols

The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and pathological conditions. However, little is known about the regulatory effect of intestinal microbiota on its recovery ability to repair damaged mucosal barrier. In this study, we established intestinal organoids and lamina propria lymphocytes (LPLs) co-cultured system, plus mice experiments, to explore the protective effect of Lactobacillus reuteri D8 on integrity of intestinal mucosa. We found that only live L. reuteri D8 was effective in protecting the morphology of intestinal organoids and normal proliferation of epithelial stained with EdU under TNF-α treatment, which was also further verified in mice experiments. L. reuteri D8 colonized in the intestinal mucosa and ameliorated intestinal mucosa damage caused by DSS treatment, including improvement of body weight, colon length, pathological change, and proliferation level. The repair process stimulated by L. reuteri D8 was also accompanied with increased numbers of Lgr5

Topics: Animals; Coculture Techniques; Colitis; Dextran Sulfate; Indoles; Interleukin-22; Interleukins; Intestinal Mucosa; Lactobacillus; Lymphocytes; Mice; Mice, Inbred C57BL; Mucous Membrane; Muramidase; Phosphorylation; Receptors, Aryl Hydrocarbon; Receptors, G-Protein-Coupled; Signal Transduction; STAT3 Transcription Factor; Stem Cells; Tumor Necrosis Factor-alpha

Beneficial microbes that target molecules and pathways, such as oxidative stress, which can negatively affect both host and microbiota, may hold promise as an inflammatory bowel disease therapy. Prior work showed that a five-strain fermented milk product (FMP) improved colitis in T-bet(-/-) Rag2(-/-) mice. By varying the number of strains used in the FMP, we found that Lactococcus lactis I-1631 was sufficient to ameliorate colitis. Using comparative genomic analyses, we identified genes unique to L. lactis I-1631 involved in oxygen respiration. Respiration of oxygen results in reactive oxygen species (ROS) generation. Also, ROS are produced at high levels during intestinal inflammation and cause tissue damage. L. lactis I-1631 possesses genes encoding enzymes that detoxify ROS, such as superoxide dismutase (SodA). Thus, we hypothesized that lactococcal SodA played a role in attenuating colitis. Inactivation of the sodA gene abolished L. lactis I-1631's beneficial effect in the T-bet(-/-) Rag2(-/-) model. Similar effects were obtained in two additional colonic inflammation models, Il10(-/-) mice and dextran sulfate sodium-treated mice. Efforts to understand how a lipophobic superoxide anion (O2 (-)) can be detoxified by cytoplasmic lactoccocal SodA led to the finding that host antimicrobial-mediated lysis is a prerequisite for SodA release and SodA's extracytoplasmic O2 (-) scavenging. L. lactis I-1631 may represent a promising vehicle to deliver antioxidant, colitis-attenuating SodA to the inflamed intestinal mucosa, and host antimicrobials may play a critical role in mediating SodA's bioaccessibility.

Topics: Animals; Colitis; Intestinal Mucosa; Lactococcus lactis; Mice; Muramidase; Reactive Oxygen Species; Superoxide Dismutase

Topics: Animals; Colitis; Lactococcus lactis; Muramidase; Superoxide Dismutase

Recent studies link endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) to inflammatory bowel disease. Altered eIF2α phosphorylation (eIF2α-P), a regulatory hub of the UPR, was observed in mucosal tissue of patients with inflammatory bowel disease. In this study, we examined the mechanistic role of eIF2α-P in intestinal epithelial cell (IEC) function and intestinal homeostasis in mice.. We generated mice with villin-Cre-mediated conditional expression of nonphosphorylatable Ser51Ala mutant eIF2α in IECs (AA mice). We analyzed AA mice under normal conditions and on challenge with oral infection of Salmonella Typhimurium or dextran sulfate sodium-induced colitis.. Loss of eIF2α-P did not affect the normal proliferation or differentiation of IECs. However, AA mice expressed decreased secretory proteins including lysozyme, suggesting eIF2α-P is required for Paneth cell function. The ultrastructure of AA Paneth cells exhibited a reduced number of secretory granules, a fragmented ER, and distended mitochondria under normal conditions. UPR gene expression was defective in AA IECs. Translation of Paneth cell specific messenger RNAs encoding lysozyme and cryptidins was significantly defective leading to the observed granule-deficient phenotype, which was associated with reduced ribosomal recruitment of these messenger RNAs to the ER membrane. Consequently, AA mice were more susceptible to oral Salmonella infection and dextran sulfate sodium-induced colitis.. We conclude eIF2α phosphorylation is required for the normal function of intestinal Paneth cells and mucosal homeostasis by activating UPR signaling and promoting messenger RNA recruitment to the ER membrane for translation.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Colitis; Dextran Sulfate; Disease Susceptibility; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Homeostasis; Interferon-gamma; Mice; Mice, Inbred C3H; Mice, Transgenic; Molecular Chaperones; Muramidase; Paneth Cells; Phosphorylation; Protein Biosynthesis; Ribosomes; RNA, Messenger; Salmonella Infections, Animal; Secretory Vesicles; Signal Transduction; Stress, Physiological; Unfolded Protein Response

Sickness behaviors, such as fatigue, mood alterations, and cognitive dysfunction, which result from changes in central neurotransmission, are prevalent in systemic inflammatory diseases and greatly impact patient quality of life. Although, microglia (resident cerebral immune cells) and cytokines (e.g., TNFα) are associated with changes in central neurotransmission, the link between peripheral organ inflammation, circulating cytokine signaling, and microglial activation remains poorly understood. Here we demonstrate, using cerebral intravital microscopy, that in response to liver inflammation, there is increased monocyte specific rolling and adhesion along cerebral endothelial cells (CECs). Peripheral TNFα-TNFR1 signaling and the adhesion molecule P-selectin are central mediators of these monocyte-CEC adhesive interactions which were found to be closely associated with microglial activation, decreased central neural excitability and sickness behavior development. Similar monocyte-CEC adhesive interactions were also observed in another mouse model of peripheral organ inflammation (i.e., 2,4-dinitrobenzene sulfonic acid-induced colitis). Our observations provide a clear link between peripheral organ inflammation and cerebral changes that impact behavior, which can potentially allow for novel therapeutic interventions in patients with systemic inflammatory diseases.

Topics: Alanine Transaminase; Animals; Cell Adhesion; Cerebral Cortex; Cholestasis; Colitis; Cytokines; Dinitrofluorobenzene; Disease Models, Animal; Endothelial Cells; Female; Hippocampus; Illness Behavior; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monocytes; Muramidase; P-Selectin; Pentylenetetrazole

Genetic polymorphisms of autophagy-related genes have been associated with an increased risk to develop inflammatory bowel disease (IBD). Autophagy is an elementary process participating in several cellular events such as cellular clearance and nonapoptotic programmed cell death. Furthermore, autophagy may be involved in intestinal immune homeostasis due to its participation in the digestion of intracellular pathogens and in antigen presentation. In the present study, the role of autophagy in the intestinal epithelial layer was investigated. The intestinal epithelium is essential to maintain gut homeostasis, and defects within this barrier have been associated with the pathogenesis of IBD. Therefore, mice with intestinal epithelial deletion of Atg7 were generated and investigated in different mouse models. Knockout mice showed reduced size of granules and decreased levels of lysozyme in Paneth cells. However, this was dispensable for gut immune homeostasis and had no effect on susceptibility in mouse models of experimentally induced colitis.

Topics: Animals; Autophagy; Autophagy-Related Protein 7; Biomarkers; Colitis; Cytoplasmic Granules; Disease Models, Animal; Gene Knockout Techniques; Homeostasis; Immunity, Innate; Immunohistochemistry; Intestinal Mucosa; Mice; Mice, Knockout; Microtubule-Associated Proteins; Muramidase; Paneth Cells

Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis.. The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice.. Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease.. AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.

Topics: Acute-Phase Proteins; Adaptor Protein Complex 1; Adaptor Protein Complex beta Subunits; Adaptor Protein Complex mu Subunits; alpha-Defensins; Animals; Antimicrobial Cationic Peptides; beta-Defensins; Cathelicidins; Cell Membrane; Cell Membrane Permeability; Colitis; Colon; Crohn Disease; Down-Regulation; Epithelial Cells; Homeostasis; Humans; Immunoglobulin A; Interleukin-17; Intestinal Mucosa; Lipocalin-2; Lipocalins; Mice; Mice, Knockout; Muramidase; Oncogene Proteins; Proteins; Receptors, Cytokine; Ribonuclease, Pancreatic; Ribonucleases; S100 Proteins; Signal Transduction; Th17 Cells; Tumor Necrosis Factor-alpha

Inflammatory bowel disease (IBD) is a chronic and recurring inflammation of the gastrointestinal tract, associated with a dysregulation of the mucosal immune system. There is an increasing prevalence of IBD; however, current pharmaceutical treatments are only moderately effective and have been associated with potential long-term toxicity. Lysozyme, a well-known antimicrobial protein found in large quantities in hen egg white, is a promising alternative for the treatment of IBD. A porcine model of dextran sodium sulfate (DSS)-induced colitis was used to examine the effect of hen egg lysozyme (HEL) supplementation on intestinal inflammation. Treatment with DSS resulted in weight loss, severe mucosal and submucosal inflammation, colonic crypt distortion, muscle wall thickening, down-regulation of mucin gene expression, and increased gastric permeability, but these symptoms were attenuated following supplementation with HEL and restored to basal levels observed in untreated control animals. Treatment with HEL also significantly reduced the local expression of pro-inflammatory cytokines TNF-alpha, IL-6, IFN-gamma, IL-8, and IL-17 while increasing the expression of the anti-inflammatory mediators IL-4 and TGF-beta, indicating that HEL may function as a potent anti-inflammatory and immunomodulator. Furthermore, the concomitant increases in TGF-beta and Foxp3 levels suggest that HEL may aid in restoring gut homeostasis by activating regulatory T cells, which are important in the regulation of the mucosal immune system. These results suggest that HEL is a promising novel therapeutic for the treatment of IBD.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Gene Expression; Intestinal Mucosa; Muramidase; Swine

Topics: Adult; Chronic Disease; Colitis; Enteritis; Female; Humans; Intestinal Secretions; Jejunum; Male; Middle Aged; Muramidase

Topics: Adult; Clinical Laboratory Techniques; Colitis; Endoscopy; Humans; Muramidase

The serum levels of lysozyme, serum electrophoresis, and serum immunoglobulins were determined prospectively in 101 patients with ulcerative colitis, ulcerative proctitis, Crohn's disease, or nonclassifiable nonspecific inflammatory bowel disease. Although the mean serum lysozyme concentration of patients with Crohn's disease (10.5 +/- 6.8 microgram/ml) and ulcerative colitis (9.6 +/- 4.1 microgram/ml) performed by a standardized lysoplate method was significantly greater than normal controls (6.0 +/- 1.5 microgram/ml), the results did not correlate with the diagnosis nor with the degree of disease activity. Individually separated protein fractions and serum immunoglobulins also did not correlate with the serum lysozyme levels. This study indicates that measurement of the level of serum lysozyme in individual patients is not helpful in determining the cause or degree of activity of nonspecific inflammatory bowel disease.

Topics: Adult; Blood Proteins; Colitis; Colitis, Ulcerative; Crohn Disease; Humans; Immunoglobulins; Middle Aged; Muramidase; Proctitis

Serum lysozyme activity was determined in the sera of 70 patients with inflammatory bowel disease by the lysoplate method. Serum lysozyme levels were significantly elevated only in patients with Crohn's disease of the small bowel. Patients with either granulomatous or ulcerative colitis had serum lysozyme values not different from normals, irrespective of activity of their disease.

Topics: Adult; Aged; Colectomy; Colitis; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; Middle Aged; Muramidase; Recurrence

Rectocolitis remains, at the present time, in spite of the large amount of work carried out, a condition of which the cause and the physiopathological mechanism are unknown: none of the theories proposed has been confirmed by the facts; none has made it possible to propose an effective therapeutic regimen. The diagnosis of haemorrhagic rectocolitis rests solely on an assembly of clinical, radiological, and anatomological findings, together with findings on progress of the disease; none of these findings taken separately being pathognomonic. Because of this it is essential in cases of inflammatory colic disorders to analyse critically these different elements before affirming the diagnosis that is often arrived at too easily. Different affections, even apart from Crohn's disease (parasitic, microbial, and iatrogenic affections, etc) may, in fact, give rise to radiological and clinical pictures close to those of haemorrhagic rectocolitis.

Topics: Autoimmune Diseases; Colitis; Colon; Crohn Disease; Diagnosis, Differential; Endoscopy; Gastrointestinal Hemorrhage; Genotype; Humans; Hypersensitivity; Infections; Intestinal Diseases, Parasitic; Intestinal Mucosa; Muramidase; Proctocolitis; Psychophysiologic Disorders; Radiography

Topics: Adult; Autoantibodies; Autoimmune Diseases; Chronic Disease; Colitis; Complement System Proteins; Female; Humans; Male; Middle Aged; Muramidase; Properdin

Topics: Allergy and Immunology; Amino Acids; Chromatography; Colitis; Colitis, Ulcerative; Diaminopimelic Acid; Fusobacterium; Immunodiffusion; Intestines; Mucous Membrane; Muramidase; Pimelic Acids; Rectum

Topics: Colitis; Colitis, Ulcerative; Humans; Muramidase

Topics: Adrenocorticotropic Hormone; Anti-Bacterial Agents; Capillaries; Colitis; Colitis, Ulcerative; Feces; Flavonoids; Humans; Muramidase; Psychosomatic Medicine

Topics: Anti-Infective Agents, Local; Antiviral Agents; Colitis; Colitis, Ulcerative; Dermatologic Agents; Humans; Muramidase

Topics: Anti-Infective Agents, Local; Antiviral Agents; Colitis; Colitis, Ulcerative; Dermatologic Agents; Humans; Muramidase

Topics: Colitis; Colitis, Ulcerative; Gastrointestinal Diseases; Humans; Muramidase; Peptic Ulcer

Topics: Anti-Infective Agents, Local; Colitis; Colitis, Ulcerative; Dermatologic Agents; Glycoside Hydrolases; Humans; Muramidase

Topics: Antiviral Agents; Colitis; Colitis, Ulcerative; Dermatologic Agents; Glycoside Hydrolases; Muramidase

Topics: Anti-Infective Agents, Local; Colitis; Colitis, Ulcerative; Dermatologic Agents; Glycoside Hydrolases; Muramidase

Topics: Colitis; Colitis, Ulcerative; Glycoside Hydrolases; Granulocytes; Humans; Muramidase

Topics: Adrenocorticotropic Hormone; Colitis; Colitis, Ulcerative; Crohn Disease; Dermatologic Agents; Feces; Ileitis; Muramidase

Topics: Antiviral Agents; Colitis; Colitis, Ulcerative; Humans; Muramidase

Topics: Colitis; Colitis, Ulcerative; Dermatologic Agents; Humans; Muramidase; Polysaccharide-Lyases

Topics: Adrenocorticotropic Hormone; Antiviral Agents; Colitis; Colitis, Ulcerative; Feces; Humans; Muramidase

Topics: Antiviral Agents; Colitis; Colitis, Ulcerative; Humans; Muramidase

Topics: Colitis; Colitis, Ulcerative; Food; Humans; Muramidase; Peptic Ulcer; Proteins; Ulcer