Injecting mice with microbial antigens via adjuvant CpG oligodeoxynucleotides (CpG-ODN) and/or curdlan, a dectin-1 agonist, can induce antigen-specific mucosal and systemic immune responses that impact disease development, according to a study published in Gastroenterology. The study findings support the development of vaccines to protect against microbe-associated intestinal disorders and disease.
Microbiome dysregulation has been associated with the development of a range of diseases including obesity and diabetes. The current study was designed to investigate a novel method for manipulating intestinal bacterial communities using microbial antigens to induce long-term, systemic, antigen-specific immunoglobulin (Ig)A and IgG responses within the desired mucosal tissues for the control of bacteria-related intestinal disorders.
Mice were injected with antigens (cholera toxin B-subunit [CTB], ovalbumin, or pneumococcal surface protein) combined with CpG-ODN and/or curdlan. Antigen-specific titers of IgG and IgA were measured in weekly blood and fecal samples, and antigen-specific splenic T-helper (Th)1 cells, Th17 cells, and memory B cells in the spleen and lymph nodes were collected and analyzed using ELISA.
The mice were given a nasal, oral, or vaginal ovalbumin boost 6 weeks after the initial immunization, and bronchial lavage, intestinal lamina propria, and vaginal swab samples were taken to collected and measured for antibodies and cytokines. Some mice were given intranasal Streptococcus pneumoniae or oral CTB, and the severity of pneumonia or diarrhea was later analyzed. Gnotobiotic mice were put on a high-fat diet 2 weeks after being gavaged with fecal matter containing an abundance of Clostridium ramosum (a commensal microbe associated with obesity and diabetes). Quantitative real-time polymerase chain reaction (PCR) was used to analyze intestinal tissues.
The fecal and serum samples of mice given 3 weeks of injections of antigens plus CpG-ODN and curdlan contained both antigen-specific IgA and IgG, and splenocytes produced interferon (IFN)G and interleukin (IL)17A. Following the ovalbumin boost, bronchial, lamina propria, and vaginal samples contained antigen-specific IgA. This immunization regimen prevented diarrhea from developing after CTB injections and inhibited lung colonization after injections of S pneumoniae. Obesity was effectively controlled in mice on high-fat diets that were immunized with C ramosum as compared with nonimmunized mice on the same high-fat diet.
Limitations to the study include being performed in an animal model, and human studies will be needed to prove efficacy, as well as to overcome issues such as the IFA emulsion, which was used to immunize the mice with C ramosum, because IFA is harmful to humans.
Investigators concluded, “The methods described in this study, albeit unconventional, warrant further practical investigations to assess their ability to target infectious mucosal pathogens as well as to treat various dysbiosis-related diseases.”
Fujimoto K, Kawaguchi Y, Shimohigoshi M, et al. Antigen-specific mucosal immunity regulates development of intestinal bacteria-mediated diseases [published online August 21, 2019]. Gastroenterology. doi: 10.1053/j.gastro.2019.08.021