Toshifumi Ohkusa

Toshifumi Ohkusa is a Japanese academic and author. He is a special professor at Juntendo University Graduate School of Medicine.^[1]

Ohkusa is known for his works on microbial and pathogenic processes underlying gastrointestinal diseases. His works have been published in academic journals such as Gut, Gastroenterology and World Journal of Gastroenterology.^[2]

Ohkusa completed his MD degree from Tokyo Medical and Dental University in 1978. In 1986, he completed his PhD from the same institution.^[1]

Ohkusa began his academic career in 1986 as a research associate and instructor at the Tokyo Medical and Dental University, serving until 2001. Following this, he joined Juntendo University, where he was appointed assistant professor from 2001 to 2004. From 2005 to 2008, he worked as an associate professor there. Subsequently, he joined Jikei University Kashiwa Hospital, where he was a professor until 2017. Since 2017, he has been a special professor at Juntendo University Graduate School of Medicine.^[1]

Ohkusa's research has focused on investigating the microbial and pathogenic mechanisms of gastrointestinal diseases, particularly ulcerative colitis and Helicobacter pylori-related disorders, through his articles published in peer-reviewed journals.^[2]

In 1990 Ohkusa established a DSS-induced colitis model in mice, showing that acute and chronic colitis could be reliably reproduced, with associated mucosal damage, dysplasia, and altered intestinal microflora.^[3] His 1992 study in hamsters demonstrated that long-term DSS exposure led to dysplasia and adenocarcinoma, resembling human ulcerative colitis–associated cancer, while metronidazole prevented such changes.^[4] Combining DSS-induced colitis with azoxymethane pretreatment, his 1996 research showed that it resulted in multiple colorectal tumors, confirming that repeated mucosal injury and regeneration promoted tumorigenesis.^[5] His further research linked elevated fecal cholic acid levels with DSS-induced colitis and neoplasia, suggesting that bile acid metabolism contributes to colorectal tumor development.^[6] A 2002 study using repeated DSS cycles documented a progression from dysplasia to carcinoma, supporting a dysplasia–carcinoma sequence similar to that in ulcerative colitis patients.^[7] In 2003, he reported that Bifidobacterium longum administration reduced colitis severity in DSS-treated mice and helped maintain protective gut microflora, suggesting a therapeutic role for probiotics.^[8][9][10]

In 1995 Ohkusa reported that Helicobacter pylori infection was significantly more common in intestinal-type than diffuse-type early gastric cancer, suggesting a role in early intestinal-type carcinogenesis.^[11] In 1997, he described the disappearance of multiple hyperplastic gastric polyps one year after eradication therapy, alongside changes in endoscopic, histologic, and serologic findings.^[12] A 1998 randomized, controlled trial further demonstrated that most hyperplastic gastric polyps regressed after eradication, providing controlled evidence that eradication should be attempted before endoscopic removal.^[13] A subsequent retrospective study compared responder and non-responder cases, finding that persistent high gastrin levels contributed to polyp persistence despite similar improvements in gastric inflammation.^[14] Additionally, in 2001, he showed that eradication improved precancerous lesions, with regression of glandular atrophy and intestinal metaplasia over one year in successfully treated patients, while no histologic changes were seen in failures.^[15] Moreover, he also created a duodenal ulcer model caused by Helicobacter pylori infection.^[16] His later multicenter studies helped establish standard third-line and second-line eradication regimens in Japan.^{[17][18][19][20]}

Ohkusa's work demonstrated that the colonic mucosa in patients with UC was consistently invaded by small rods and cocci, suggesting that bacterial invasion of the mucosa may contribute to the persistence or aggravation of the disease.^[21] Building on this, his later studies identified Fusobacterium varium in the colonic mucosa of UC patients and showed that these bacteria elicited species-specific antibody responses. Immunohistochemical detection of F. varium was significantly higher in UC patients compared to controls, supporting its possible role as a pathogenic factor.^[22] Through subsequent experiments, he showed that Fusobacterium varium produced cytotoxic butyric acid, which damaged Vero cells, and when administered to mice, induced colonic lesions resembling ulcerative colitis, suggesting a pathogenic role.^[23] He also demonstrated that F. varium and other commensals invaded colonic epithelial cells and triggered secretion of proinflammatory cytokines, suggesting bacterial-epithelial interactions may contribute to inflammatory responses in ulcerative colitis.^[24] Additionally, he and his colleagues developed the nested culture method specifically to improve the detection of Fusobacterium varium from stool.^[25] Moreover, through genomic and transcriptomic analysis of a UC-associated F. varium strain, multiple virulence factors, including adhesion and secretion system genes, were identified with enhanced expression under specific conditions, suggesting pathogenic potential in intestinal inflammation.^{[26][27][28][29][30][31]}

Ohkusa reported on the role of Fusobacterium varium in ulcerative colitis (UC) and explored the potential of multi-drug antibiotic therapy as a treatment strategy. In 2005, he conducted a randomized, controlled pilot trial in which twenty patients with chronic active UC were assigned either to a two-week regimen of amoxicillin, tetracycline, and metronidazole or to a control group without antibiotics. The study reported significant improvements in clinical, endoscopic, and histological scores in the treatment group, along with reduced antibody titers and mucosal density of F. varium at both short- and long-term follow-up, with no serious drug-related toxicity observed.^[22] Later in 2010, he conducted a multicenter placebo-controlled trial and showed that the same antibiotic regimen improved clinical response, endoscopic scores, and steroid withdrawal rates in relapsing ulcerative colitis patients, with significant benefits at three and twelve months of follow-up.^[32] Later in 2011, he examined steroid-dependent ulcerative colitis patients and showed that the two-week antibiotic regimen achieved clinical improvement, remission, and substantial steroid withdrawal over twelve months.^[33] His later collaborative studies confirmed long-term benefits of antibiotic therapy and changes in gut microbiota.^{[34][35][36][37][38][39][40]}

Beyond colitis and H. pylori, Ohkusa has contributed to research on gastrointestinal microbiota, probiotics, and microbiota-targeted therapies, including their role in constipation, cancer immunotherapy, and aging-related diseases.^{[41][42][43][44][45][46][47][48][49][50][51][52][53][54]}

• Okayasu, I., Hatakeyama, S., Yamada, M., Ohkusa, T., Inagaki, Y., & Nakaya, R. (1990). A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology, 98(3), 694–702.
• Andreyev, H. J. N., Norman, A. R., Cunningham, D., Oates, J., Dix, B. R., Iacopetta, B. J., ... & Urosevic, N. (2001). Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II'study. British journal of cancer, 85(5), 692–696.
• Ohkusa, T., Fujiki, K., Takashimizu, I., Kumagai, J., Tanizawa, T., Eishi, Y., ... & Watanabe, M. (2001). Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Annals of internal medicine, 134(5), 380–386.
• Ohkusa, T., Okayasu, I., Ogihara, T., Morita, K., Ogawa, M., & Sato, N. (2003). Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis. Gut, 52(1), 79–83.
• Ohkusa, T., Koido, S., Nishikawa, Y., & Sato, N. (2019). Gut microbiota and chronic constipation: a review and update. Frontiers in medicine, 6, 19.