Identification of Commensal Species Positively Correlated with Early Stress Responses to a Compromised Mucus Barrier

Background: Our aims were (1) to correlate changes in the microbiota to intestinal gene expression before and during the development of colitis in Muc2(-/-) mice and (2) to investigate whether the heterozygote Muc2(+/-) mouse would reveal host markers of gut barrier stress. Methods: Colon histology, transcriptomics, and microbiota profiling of faecal samples was performed on wild type, Muc2(+/-), and Muc2(-/-) mice at 2, 4, and 8 weeks of age. Results: Muc2(-/-) mice develop colitis in proximal colon after weaning, resulting in inflammatory and adaptive immune responses, and expression of genes associated with human inflammatory bowel disease. Muc2(+/-) mice do not develop colitis, but produce a thinner mucus layer. The transcriptome of Muc2(+/-) mice revealed differential expression of genes participating in mucosal stress responses and exacerbation of a transient inflammatory state around the time of weaning. Young wild type and Muc2(+/-) mice have a more constrained group of bacteria as compared with the Muc2(-/-) mice, but at 8 weeks the microbiota composition is more similar in all mice. At all ages, microbiota composition discriminated the groups of mice according to their genotype. Specific bacterial clusters correlated with altered gene expression responses to stress and bacteria, before colitis development, including colitogenic members of the genus Bacteroides. Conclusions: The abundance of Bacteroides pathobionts increased before histological signs of pathology suggesting they may play a role in triggering the development of colitis. The Muc2(+/-) mouse produces a thinner mucus layer and can be used to study mucus barrier stress in the absence of colitis.