Dataset Information

Oral administration of human carbonic anhydrase I suppresses colitis in a murine inflammatory bowel disease model.

ABSTRACT: The incidence of inflammatory bowel disease (IBD) is increasing; hence, effective treatments are warranted. The therapeutic effect of human carbonic anhydrase I (hCA I) in IBD remains unknown. Therefore, we investigated whether oral tolerization to hCA I would induce antigen-specific protection from intestinal inflammation in vivo. Severe combined immunodeficient mice received hCA I, keyhole limpet hemocyanin (KLH), or phosphate-buffered saline (PBS) orally for 7 days. Colons and mesenteric lymph nodes (MLNs) were collected 4 weeks after cell transfer. Additionally, the mechanisms underlying the therapeutic effects were investigated. The comparison between the effects of well-established drugs and hCA I oral administration was investigated. Oral administration of hCA I ameliorated colitis remarkably. hCA I reached the cecum and ameliorated colitis more effectively than mesalazine and similarly to prednisolone. Compared with PBS treatment, hCA I treatment reduced interleukin (IL)-17a, IL-6, and retinoic acid-related orphan receptor gamma t (RORγt) expression in the colon or MLNs; moreover, hCA I markedly reduced IL-6, IL-17, and interferon-gamma (IFN-γ) levels in the MLN. Oral administration of hCA I induced immune tolerance and suppressed colitis in vivo. Thus, hCA I administration could be proposed as a new treatment option for IBD.

SUBMITTER: Tange K

PROVIDER: S-EPMC9606376 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Oral administration of human carbonic anhydrase I suppresses colitis in a murine inflammatory bowel disease model.

Tange Kazuhiro K Yagi Sen S Takeshita Eiji E Abe Masanori M Yamamoto Yasunori Y Tomida Hideomi H Kawamura Tomoe T Hanayama Masakazu M Matsuura Bunzo B Ikeda Yoshiou Y Hiasa Yoichi Y

Scientific reports 20221026 1

The incidence of inflammatory bowel disease (IBD) is increasing; hence, effective treatments are warranted. The therapeutic effect of human carbonic anhydrase I (hCA I) in IBD remains unknown. Therefore, we investigated whether oral tolerization to hCA I would induce antigen-specific protection from intestinal inflammation in vivo. Severe combined immunodeficient mice received hCA I, keyhole limpet hemocyanin (KLH), or phosphate-buffered saline (PBS) orally for 7 days. Colons and mesenteric lymp ...[more]

PMID: 36289244

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Project description:Inflammatory bowel diseases (IBDs) in humans are characterized in part by aberrant CD4-positive (CD4+) T-cell responses. Currently, identification of foci of inflammation within the gut requires invasive procedures such as colonoscopy and biopsy. Molecular imaging with antibody fragment probes could be used to noninvasively monitor cell subsets causing intestinal inflammation. Here, GK1.5 cys-diabody (cDb), an antimouse CD4 antibody fragment derived from the GK1.5 hybridoma, was used as a PET probe for CD4+ T cells in the dextran sulfate sodium (DSS) mouse model of IBD. Methods: The DSS mouse model of IBD was validated by assessing changes in CD4+ T cells in the spleen and mesenteric lymph nodes (MLNs) using flow cytometry. Furthermore, CD4+ T cell infiltration in the colons of colitic mice was evaluated using immunohistochemistry. 89Zr-labeled GK1.5 cDb was used to image distribution of CD4+ T cells in the abdominal region and lymphoid organs of mice with DSS-induced colitis. Region-of-interest analysis was performed on specific regions of the gut to quantify probe uptake. Colons, ceca, and MLNs were removed and imaged ex vivo by PET. Imaging results were confirmed by ex vivo biodistribution analysis. Results: An increased number of CD4+ T cells in the colons of colitic mice was confirmed by anti-CD4 immunohistochemistry. Increased uptake of 89Zr-maleimide-deferoxamine (malDFO)-GK1.5 cDb in the distal colon of colitic mice was visible in vivo in PET scans, and region-of-interest analysis of the distal colon confirmed increased activity in DSS mice. MLNs from colitic mice were enlarged and visible in PET images. Ex vivo scans and biodistribution confirmed higher uptake in DSS-treated colons (DSS, 1.8 ± 0.40; control, 0.45 ± 0.12 percentage injected dose [%ID] per organ, respectively), ceca (DSS, 1.1 ± 0.38; control, 0.35 ± 0.09 %ID per organ), and MLNs (DSS, 1.1 ± 0.58; control, 0.37 ± 0.25 %ID per organ). Conclusion:89Zr-malDFO-GK1.5 cDb detected CD4+ T cells in the colons, ceca, and MLNs of colitic mice and may prove useful for further investigations of CD4+ T cells in preclinical models of IBD, with potential to guide development of antibody-based imaging in human IBD.

Project description:ImportanceSome ophthalmologists may be reluctant to prescribe oral carbonic anhydrase inhibitors, given the potential for life-threatening systemic adverse reactions.ObjectiveTo conduct a population-based analysis of the safety of oral or topical carbonic anhydrase inhibitors in clinical care.Design, setting, and participantsThis matched longitudinal cohort study took place in Ontario, Canada. Consecutive patients older than 65 years who were prescribed an oral or topical carbonic anhydrase inhibitor in Ontario, Canada, between January 1, 1995, and January 1, 2020, were identified. Patients were matched 1-to-1 based on age, sex, and diabetes status. Time zero was defined as the date of the first identified prescription for the medication, and the primary analysis focused on the first 120 days of follow-up.Main outcomes and measuresThe primary end point was a severe complicated adverse event of either Stevens-Johnson syndrome, toxic epidermal necrolysis, or aplastic anemia.ResultsOverall, 128 942 matched patients initiated an oral or topical carbonic anhydrase inhibitor during the 25-year study period. The mean (SD) age was 75 (6.6) years, 71 958 (55.8%) were women, and 25 058 (19.4%) had a diagnosis of diabetes. The oral and topical carbonic anhydrase inhibitor groups had similar baseline demographics. Patients prescribed an oral carbonic anhydrase inhibitor had an absolute risk of a severe complicated adverse event of 2.90 per 1000 patients, whereas patients prescribed a topical carbonic anhydrase inhibitor had an absolute risk of 2.08 per 1000 patients. This difference was equivalent to a risk ratio of 1.40, with a number needed to harm of 1 in 1220 patients (95% CI, 1.12-1.74; P = .003). This generally low risk was replicated in multivariable regression controlling for confounding factors. Additional risk factors for a severe complicated adverse event included patients with more comorbidities and those with more frequent clinic contacts.Conclusions and relevanceThe risk of a serious adverse reaction following prescription of an oral or topical carbonic anhydrase inhibitor was low and similar between agents. Given the low risk of severe adverse reactions, this population-level analysis supports reconsidering the reluctance toward prescribing an oral carbonic anhydrase inhibitor.

Project description:Significant evidence supports a relationship between the gut microbiome, inflammation, host response, and health, including the finding that a number of disorders are associated with disruption of the microbiome. In these disorders, a number of dietary interventions (including prebiotics, live probiotics, or heat-killed microbes) have been proposed to be curative or preventative agents. The use of heat-killed microbes has a number of benefits over living organisms, including reduced infection risk in vulnerable individuals, extended shelf life and the potential for use in combination with antimicrobial agents. We previously reported that murine chow supplemented with 5% ADR-159, a heat-treated fermentate generated by two Lactobacillus strains, altered both behavior and the microbiome of male mice. Now we show that ADR-159 fed female mice also display a similar microbiome shift as determined by 16S rDNA analysis. In particular, we observed a reduction of levels of Turicibacter and Clostridium sensu stricto. These subtle changes in the bacterial component of the microbiome were mirrored by changes in the virome. Extended consumption of the ADR-159 diet had no negative effect on general health and lipocalin 2 levels (LCN2; a proxy for inflammation), but we observed increased IL-17f and decreased IL-12α expression in the colon and decreased short chain fatty acid levels in the ADR-159 fed animals. Four weeks into the diet, half of the animals were dosed with Citrobacter to determine the effect of ADR-159 on infection and on pathogen induced colitis. Overall, our results suggest that while the ADR-159 diet does not prevent Citrobacter infection, it had an effect on Citrobacter-induced inflammation. In contrast to animals fed standard chow, ADR-159 fed animals did not show a reduction of small intestine length and increase of colon crypt depth, which occurred in control mice. These microbiological, histological, and immunological results provide evidence to support the impact of heat-treated microorganisms and their metabolites on the murine microbiome and health.

Dataset Information

Oral administration of human carbonic anhydrase I suppresses colitis in a murine inflammatory bowel disease model.

Publications

Oral administration of human carbonic anhydrase I suppresses colitis in a murine inflammatory bowel disease model.

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