Dysregulation of the microbiome has been associated with development of complex diseases such as obesity and diabetes. However, no method has been developed to control disease-associated commensal microbes. We investigated whether immunization with microbial antigens, using CpG oligodeoxynucleotides (CpG-ODN) and/or curdlan as adjuvants, induces systemic antigen-specific immunoglobulin (Ig)A and IgG production and affects development of diseases in mice. C57BL/6 mice were given intramuscular injections of antigens (ovalbumin, cholera toxin (CT) B-subunit, or PspA) combined with CpG-ODN and/or curdlan. Blood and fecal samples were collected weekly and antigen-specific IgG and IgA titers were measured. Lymph nodes and spleens were collected and analyzed by ELISA for antigen-specific splenic T-helper (Th)1 cells, Th17 cells, and memory B cells. Six weeks after primary immunization, mice were given a oral, nasal, or vaginal boost of ovalbumin; intestinal lamina propria, bronchial lavage, and vaginal swab samples were collected and antibodies and cytokines were measured. Some mice were also given oral CT or intranasal Streptococcus pneumoniae and the severity of diarrhea or pneumonia was analyzed. Gnotobiotic mice were gavaged with fecal material from obese individuals, which had a high abundance of Clostridium ramosum (a commensal microbe associated with obesity and diabetes), and were placed on a high-fat diet 2 weeks after immunization with C. ramosum. Intestinal tissues were collected and analyzed by quantitative real-time PCR. Serum and fecal samples from mice given injections of antigens in combination with CpG-ODN and curdlan for 3 weeks contained antigen-specific IgA and IgG, and splenocytes produced IFNG and IL17A. Lamina propria, bronchial, and vaginal samples contained antigen-specific IgA following the ovalbumin boost. This immunization regimen prevented development of diarrhea following injection of CT, and inhibited lung colonization by S. pneumoniae. In gnotobiotic mice colonized with C. ramosum and placed on a high-fat diet, the mice that had been immunized with C. ramosum became less obese than the non-immunized mice. Injection of mice with microbial antigens and adjuvant induces antigen-specific mucosal and systemic immune responses. Immunization with S pneumoniae antigen prevented lung infection by this bacteria, and immunization with C ramosum reduced obesity in mice colonized with this microbe and placed on a high-fat diet. This immunization approach might be used to protect against microbe-associated disorders of intestine. Copyright 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.