The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PAPERCLIP:

ObjectiveTo identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).MethodsCohorts of male and female patients with AS and age‐ and sex‐matched healthy control subjects were selected, and the levels of serum cytokines (interferon‐γ [IFNγ], tumor necrosis factor α, interleukin‐17A [IL‐17A], and IL‐6) were examined by enzyme‐linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.ResultsThe frequency of IL‐17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS‐associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex‐related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS.ConclusionThe results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex‐related differences in the clinical features of AS and could provide a rationale for sex‐specific treatment of AS.

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IntroductionMismatch repair (MMR) is an evolutionary conserved DNA repair pathway that is required to repair mutations that arise through DNA replication or other processes. 1,2 MutS homologue 2 (Msh2) dimerizes with either Msh6 or Msh3 to recognize single base-pair mismatches or mismatches caused by insertion/deletions, respectively. 2 After binding to the mismatch, Msh2 hydrolyzes ATP, which induces a change in the heterodimer that allows for the recruitment of downstream repair factors such as MutL homologue 1, postmeiotic segregation 2, and exonuclease 1 (Exo1). 3,4 Because of Msh2's essential role in repairing DNA mutations, Msh2 Ϫ/Ϫ mice have 5-fold, 11-fold, and 15-fold greater mutation frequencies in the brain, small intestine, and thymus, respectively, 5 and are predisposed to cancer. [6][7][8] During an immune response, Ig genes undergo somatic hypermutation (SHM) to produce high-affinity antibodies. SHM is initiated by activation-induced cytidine deaminase (AID), 9 which deaminates cytidine molecules within the V region to produce dU:dG mispairs. [10][11][12] The dU:dG mismatch is recognized by the Msh2/Msh6 heterodimer, but instead of repairing this mutation, MMR produces mutations. [13][14][15][16][17][18] Mice deficient in Msh2, Msh6, postmeiotic segregation 2, MutL homologue 1, or Exo1 have an approximately 2-fold decrease in overall mutation frequency at the V region. 13,14,[16][17][18] In particular, there is an approximately10-fold decrease in mutations at A:T base pairs at the V region in MSH2-deficient mice, whereas the mutation frequency at G:C base pairs is unaltered. [15][16][17][18][19] These results indicate that the MMR pathway is required to produce mutations at A:T base pairs in the V region. MMR proteins have also been implicated in mutagenic processes that cause disease, including trinucleotide-repeat diseases. 20 Two sets of recent results suggest the possibility that the MMR system is generally defective in germinal center (GC) B cells.Ouchida et al 21 reported that GC B cells have a generally greater mutation rate than other cells, as measured by the frequency of mutations on a lacZ transgene. Liu et al 22 found that in Msh2 mutant mice, the mutation frequency of AID-sensitive genes was either lower or only slightly greater than in wild-type (WT) cells; they argued that the Msh2-dependent pathway was not functioning normally in GC cells. Together, these results would fit a simple unified model in which the expression of a GC/B cell-specific factor commandeers MMR and transforms this DNA repair pathway into a mutagenic pathway.An alternative explanation is that the MMR pathway is only mutagenic at sites mutated by AID, which would argue against a factor that disrupts global MMR function in GC B cells. To explore this issue, we examined the impact of Msh2-deficiency at a lacI transgene that is not mutated by AID in GC B cells. Our results indicate that Msh2 efficiently repairs lacI mutations in all cell populations examined, including GC B cells. Thus, MMR functions normally in GC ...