cefoxitin and Colitis

Topics: Anti-Bacterial Agents; Cefoxitin; Colitis; Colon; Escherichia coli; Female; Gentamicins; Humans; Intestines; Male; Mannitol; Metronidazole; Prospective Studies; Rectum; Surgical Wound Infection

Core 1- and core 3-derived mucin-type O-linked oligosaccharides (O-glycans) are major components of the colonic mucus layer. Defective forms of colonic O-glycans, such as the Thomsen-nouveau (Tn) antigen, frequently are observed in patients with ulcerative colitis and colorectal cancer, but it is not clear if they contribute to their pathogenesis. We investigated whether and how impaired O-glycosylation contributes to the development of colitis-associated colorectal cancer using mice lacking intestinal core 1- and core 3-derived O-glycans.. We generated mice that lack core 1- and core 3-derived intestinal O-glycans (DKO mice) and analyzed them, along with mice that singly lack intestinal epithelial core 1 O-glycans (IEC C1galt1(-/-) mice) or core 3 O-glycans (C3Gnt(-/-) mice). Intestinal tissues were collected at different time points and analyzed for levels of mucin and Tn antigen, development of colitis, and tumor formation using imaging, quantitative polymerase chain reaction, immunoblot, and enzyme-linked immunosorbent assay techniques. We also used cellular and genetic approaches, as well as intestinal microbiota depletion, to identify inflammatory mediators and pathways that contribute to disease in DKO and wild-type littermates (controls).. Intestinal tissues from DKO mice contained higher levels of Tn antigen and had more severe spontaneous chronic colitis than tissues from IEC C1galt1(-/-) mice, whereas spontaneous colitis was absent in C3GnT(-/-) and control mice. IEC C1galt1(-/-) mice and DKO mice developed spontaneous colorectal tumors, although the onset of tumors in the DKO mice occurred earlier (age, 8-9 months) than that in IEC C1galt1(-/-) mice (15 months old). Antibiotic depletion of the microbiota did not cause loss of Tn antigen but did reduce the development of colitis and cancer formation in DKO mice. Colon tissues from DKO mice, but not control mice, contained active forms of caspase 1 and increased caspase 11, which were reduced after antibiotic administration. Supernatants from colon tissues of DKO mice contained increased levels of interleukin-1β and interleukin-18, compared with those from control mice. Disruption of the caspase 1 and caspase 11 genes in DKO mice (DKO/Casp1/11(-/-) mice) decreased the development of colitis and cancer, characterized by reduced colonic thickening, hyperplasia, inflammatory infiltrate, and tumors compared with DKO mice.. Impaired expression of O-glycans causes colonic mucus barrier breach and subsequent microbiota-mediated activation of caspase 1-dependent inflammasomes in colonic epithelial cells of mice. These processes could contribute to colitis-associated colon cancer in humans.

Topics: Animals; Antigens, Tumor-Associated, Carbohydrate; Colitis; Colorectal Neoplasms; Gastrointestinal Microbiome; Glycosylation; Intestinal Mucosa; Mice; Mice, Knockout; Mucins; Polysaccharides

Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.

Topics: Animals; Antigens, Tumor-Associated, Carbohydrate; Base Sequence; Colitis; Colon; Disease Models, Animal; DNA Primers; Galactosyltransferases; Humans; Intestinal Mucosa; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular Chaperones; Mutation; Polysaccharides

Hamster flora introduced into germfree mice reduced the cecum to conventional size, suppressed populations of Escherichia coli and Clostridium difficile to the same degree that mouse flora did, and corrected the hypocellularity that is characteristic of the small bowel of germfree mice. A highly toxigenic strain of C. difficile readily induced cecitis in germfree and antibiotic-treated conventional mice, and histological examination frequently revealed pseudomembranes. Toxins A and B were both detected in ceca of animals with colitis. Gnotobiotic mice provide a model in which to study the role of the indigenous microflora in protecting against antibiotic-associated colitis.

Topics: Animals; Anti-Bacterial Agents; Cecum; Cefoxitin; Clostridium; Colitis; Cricetinae; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Germ-Free Life; Male; Mesocricetus; Mice

Hamsters given the new penicillin temocillin, either orally or by injection, did not develop antibiotic-associated colitis, whereas animals given the control antibiotics cefoxitin or clindamycin developed the disease, which is characterized by marked hemorrhagic cecitis and high cecal levels of Clostridium difficile cytotoxin.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Cefoxitin; Clindamycin; Clostridium; Colitis; Cricetinae; Feces; Gastrointestinal Hemorrhage; Injections, Subcutaneous; Mesocricetus; Penicillins

The studies reported here were designed to ascertain whether or not the new beta-lactam antibiotic, temocillin, would produce antibiotic-associated colitis in the hamster. The experiments were controlled with clindamycin and cefoxitin, which are known to induce antibiotic-associated colitis experimentally and clinically. All three antibiotics were administered to groups of animals both parenterally and orally. Clindamycin, at 1 mg/hamster, caused a slow onset of antibiotic-associated colitis by both routes, with death occurring at between 4 and 8 days. 80 to 100% of the animals had diarrhoea and showed signs of haemorrhage and caecal distension, with the caecal contents being Clostridium difficile toxin-positive. The onset of antibiotic-associated colitis after administration of cefoxitin was less marked at the 1 mg parenteral dose, with only 40% of the hamsters showing signs of colitis. At the higher doses of cefoxitin, colitis was more severe and the animals exhibited dramatic weight loss, with death occurring at between 3 and 5 days. The majority of animals had diarrhoea and were C. difficile toxin-positive; 60 to 80% also showed signs of haemorrhage and caecal distension. In contrast, the hamsters receiving temocillin remained healthy with no signs of diarrhoea, and showed consistent weight gain. No pathological abnormalities were observed and the caecal contents were toxin-negative. These results suggest that temocillin therapy in humans is unlikely to cause significant disturbance of the gastrointestinal flora.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Cecum; Cefoxitin; Clindamycin; Colitis; Cricetinae; Injections, Subcutaneous; Male; Penicillins