A 7.5-year-old, 4.7-kg, indoor, neutered male Oriental Shorthair cat was presented to the Queen Mother Hospital for Animals for the investigation of mixed bowel diarrhoea with a progressive 8-month history of haematochezia, mucoid diarrhoea, tenesmus and vocalisation. Defecation frequency had increased from twice to ⩾5 times daily. Before the onset of colitis, the cat had a 4-year history of small-bowel diarrhoea, with large volumes of liquid faeces. Prior treatments, including 4 weeks of anti-inflammatory oral glucocorticoids, a single subcutaneous injection of cefovecin, multiple 2-week courses of oral metronidazole and frequent 3-day courses of oral fenbendazole prescribed predominately for the chronic small-bowel diarrhoea, had not improved the clinical signs. Therapeutic limited-ingredient novel protein and hydrolysed protein diets were not trialled and the cat received a commercial over-the-counter complete diet. The cat had a WSAVA body condition score of 5/9 with normal muscling. The remainder of the physical examination was unremarkable, and the cat was hospitalised for further investigations. Haematology and serum biochemistry revealed a mild mature neutrophilia (13.04 × 109/l [reference interval (RI) 2.5–12.5 ×109]) and hypercholesterolemia (4.39 mmol/l [RI 2.2–4]). Serum cobalamin concentrations without prior supplementation were supranormal (>1200 ng/l [RI >200]) and T4 concentration was not supportive of hyperthyroidism (31.5 nmol/l [RI 19–65]). Feline immunodeficiency virus antibody and feline leukaemia virus antigen testing were negative. A McMaster faecal egg count did not detect endoparasites or coccidial oocysts; neither Giardia species nor Cryptosporidium species were identified. A faecal sample submitted for Tritrichomonas foetus polymerase chain reaction (PCR) before referral had returned negative. Transabdominal ultrasound identified a diffuse 4.5-mm thickening of the colonic wall and a severe, focal narrowing at the distal aspect of the descending colon. There was no abdominal lymphadenopathy, and the remainder of the gastrointestinal tract was unremarkable. Gastroduodenal and ileocolic endoscopy (Olympus GIF-XP260N) was performed under general anaesthesia. The stomach, duodenum and ileum were grossly unremarkable. The colon was short in length (20 cm), friable and oedematous with severe, diffuse ulceration and haemorrhage (). The focal narrowing identified during transabdominal ultrasonography was not visualised. Gastric, duodenal and ileal biopsies were histologically unremarkable. Ten colonic biopsy specimens were collected using 2.2-mm oval fenestrated biopsy forceps. Nine specimens were placed free-floating in 10% formalin, and embedded in paraffin blocks for histopathology. One colonic biopsy specimen collected in a sterile sample pot and moistened with sterile 0.9% saline was submitted for aerobic and anaerobic culture. Histopathology was consistent with multifocal, severe pyogranulomatous and ulcerative colitis with numerous PAS+ macrophages and distortion of the lamina propria by florid granulation tissue (). Culture recorded by matrix-assisted laser desorption/ionisation revealed a moderate growth of E coli that was sensitive to marbofloxacin (minimum inhibitory concentration [MIC] ⩽0.5). FISH was performed on formalin-fixed, paraffin-embedded colonic biopsy specimens using specific Campy-lobacter, E coli and eubacterial probes, revealing abundant, multiplying clusters of E coli and fewer clusters of Campylobacter jejuni and Clostridial species. An 8-week course of oral marbofloxacin (4 mg/kg q24 h) was prescribed with five consecutive days of oral fenbendazole (50 mg/kg q24h). The cat was also transitioned onto a therapeutic hydrolysed protein diet (Pro Plan Veterinary Diets HA Hypoallergenic Dry Cat Food; Purina) over 5 days. A partial CR (⩽40% improvement as reported by the owner) was described 2 weeks into therapy, characterised by improved faecal consistency and reduced frequency of haematochezia and tenesmus. As multiple therapies were simultaneously implemented, it is not possible to definitively confirm which therapy was most effective. Five months later, the cat was re-referred with a complete clinical relapse typified by haematochezia and tenesmus, without any reported small-bowel diarrhaea. Strict adherence to the advised hydrolysed protein diet was confirmed; however, trials with alternative therapeutic diets were declined by the owner. The primary-care practice had prescribed 10 days of oral metronidazole (26.6 mg/kg q12h) followed by 8 days of oral sulfasalazine (13.3 mg/kg q12h), without improvement. Haematology and serum biochemistry remained unremarkable. Serum cobalamin and TT4 concentrations were 1050.0 ng/l (RI >200) and 13.9 nmol/l (RI 19–65), respectively. Feline specific pancreatic lipase immunoreactivity and trypsin-like immunoreactivity concentrations were unremarkable at 1.5 µg/l (RI 0.1–3.5) and 71.0 µg/l (RI 12.1–82), respectively. A repeat faecal McMaster egg count did not detect endoparasites or coccidial oocysts. Sedation was performed to facilitate colonic washing and the retrieval of faeces for T foetus-PCR testing, which returned negative. Transabdominal ultrasonography confirmed persistent and diffuse colonic-wall thickening (3.5 mm). Repeat gastric and ileal endoscopic biopsies were histologically unremarkable. Duodenal histopathology was consistent with mild, mixed inflammation. Colonoscopy did not identify ulceration or haemorrhage (). Ten colonic biopsy specimens were obtained and processed in a manner identical to that described in the initial investigation above. Histopathology was consistent with a CIE describing a moderate lymphoplasmacytic, neutrophilic and eosinophilic colitis without a histiocytic component (). A profuse growth of marbofloxacin-sensitive E coli (MIC ⩽0.5) was cultured from a colonic biopsy specimen, with a sensitivity pattern identical to that of the initial diagnosis. FISH was repeated in a manner identical to that of the initial investigation, with additional Salmonella-species-specific probes. Individual and localised clusters of E coli, Salmonella and Clostridial species were detected within the tissue. Campylobacter species were not detected. Oral marbofloxacin (4 mg/kg q24h) was prescribed, but discontinued after 2 weeks due to lack of clinical improvement. An IDEXX feline microbiota dysbiosis index was performed on a single faecal sample, which was inconsistent with a shift in the overall intestinal microbiota (dysbiosis index −2.5 log DNA [RI <0]). Therefore, additional empirical therapy, predominantly with diet, was initially prioritised over faecal microbiota transplant.