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Background & Aims: Crohn's disease patients can be characterized by antibody responses against Crohn's disease-related bacterial sequence, Escherichia coli outer membrane porin C, Saccharomyces cerevisiae (oligomannan), and neutrophil nuclear antigens. Our aim was to determine whether expression of antibodies against Crohn's disease-related bacterial sequence and Escherichia coli outer membrane porin C is associated with distinct phenotypic manifestations. Methods: Sera from 303 patients were tested for antibodies to the Crohn's disease-related bacterial sequence (I2), anti-Escherichia coli outer membrane porin C, anti-Saccharomyces cerevisiae, and perinuclear antineutrophil cytoplasmic antibodies and for 3 Crohn's disease-associated variants of the NOD2 gene (R702W, G908R, and 1007fs) and compared with clinical data. Results: Patients expressing I2 were more likely to have fibrostenosing Crohn's disease (64.4% vs. 40.7%; P < 0.001) and to require small bowel surgery (62.2% vs. 37.4%; P < 0.001). Patients with anti-Escherichia coli outer membrane porin C were more likely to have internal perforating disease (50.0% vs. 30.7%; P = 0.001) and to require small bowel surgery (61.4% vs. 44.2%; P = 0.003). Anti-Crohn's disease-related bacterial sequence was independently associated with fibrostenosis (P = 0.027) and small bowel surgery (P = 0.01), whereas anti-Escherichia coli outer membrane porin C was independently associated with internal perforations (P < 0.006). Patients positive for I2, anti-Escherichia coli outer membrane porin C, and anti-Saccharomyces cerevisiae were the most likely to have undergone small bowel surgery (72.0%; odds ratio, 8.6; P < 0.001) compared with patients without reactivity (23.0%). When the presence and magnitude of antibody responses were considered, 90% of patients with small bowel disease who required surgery had high levels of I2, Escherichia coli outer membrane porin C, and oligomannan antibodies, compared with only 18.2% with low-titer responses (P < 0.001). Conclusions: I2 and anti-Escherichia coli outer membrane porin C are associated with Crohn's disease phenotypes, and patients with the highest level of serum reactivity toward an increasing number of microbiota have the greatest frequency of strictures, internal perforations, and small bowel surgery.