Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis

Abstract

Background: Bacteria are implicated in certain forms of model chronic colitis but the identity and role of bacteria in human ulcerative colitis (UC) are uncertain. Aims: To isolate pathogenic bacteria from inflamed mucosa of patients with UC, to examine whether the bacteria have a toxin to Vero cells, and to determine whether the toxin induces UC-like lesions in animals. Methods: Bacteria were isolated from UC patients and supernatants from cultures were filtered and tested for cytotoxicity to Vero cells. Bacterial cells producing the cytotoxic supernatants were examined by polymerase chain reaction for verotoxin genes. Culture supernatants of cytotoxic strains were examined by high performance liquid chromatography for organic acid concentrations. Mice were given enemas containing organic acid at the mean concentration in the supernatants of cytotoxic strains to ascertain whether colonic lesions appear in UC. Results: Only supernatants from cultures of Fusobacterium varium killed Vero cells. Bacterial cells lacked verotoxin genes. Bacterial culture supernatants contained high concentrations of n-butyric acid and the mean concentration (32 mmol/l) was cytotoxic to Vero cells. Twenty four hours after mice were given enemas containing either butyric acid or F varium culture supernatants, colonic ulcers with crypt abscesses, inflammatory cell infiltration, and apoptotic changes were observed. Conclusions: Butyric acid in culture supernatants from cultures of F varium caused UC-like lesions in mice. This study indicates that F varium may be one of the elusive pathogenic factors in UC.

The Role of Bacterial Infection in the Pathogenesis of Inflammatory Bowel Disease

“…We recently reported that culture supernatants from commensal bacteria (e.g., Fusobacterium varium) recovered from the inflamed mucosa of UC patients, induced UC-like lesions in mice (22,23). We have also observed that a combined antibiotic regimen directed against F. varium was effective in patients with active chronic UC (67).…”

Disruption of the p53-p53r2 DNA repair system in ulcerative colitis contributes to colon tumorigenesis

“…To our knowledge, this is the first such report for a series of organic acids. Although we earlier reported that butyric acid at 32 mM was cytotoxic to Vero cells and induced apoptosis, 17 induction of p53 and downstream molecules regulating G1 checkpoint and activation of p53-dependent DNA repair were here demonstrated at a lower concentration in colorectal carcinomas and in UC-Ca-derived cell lines in vitro (Figs. 4a and 4b).…”

“…16,17 These produce large amounts of organic acids, including short-chain fatty acids (SCFAs) and succinic acid. 18,19 SCFAs (such as butyrate, propionic acid and acetic acid) are important to maintain colonic functions, and butyrate, in particular, constitutes an energy supply for colonocytes and plays a central role in the homeostasis of the colonic mucosa.…”

Review of the gut microbiome and esophageal cancer: Pathogenesis and potential clinical implications

“…The normal gut microbiota carries out specific functions in host nutrient metabolism, xenobiotic and drug metabolism, structural integrity maintenance of the gut mucosal barrier, immunomodulation, and protection against pathogens 11, 12, 13, 14, 15. Recently, the gut microbiome has been shown to play a crucial role in health, as well as in diseases such as obesity,16 inflammatory bowel disease,17, 18 diabetes,19, 20 non‐alcoholic fatty liver disease,21, 22, 23 and several types of cancers 24, 25. Experimental evidence indicates that the human intestinal microbiome can influence tumor development and progression in the gastrointestinal tract by damaging DNA, activating oncogenic signaling pathways, producing tumor‐promoting metabolites, and suppressing the antitumor immune response 7, 25, 26, 27, 28, 29.…”