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Thank you for giving us the opportunity to respond to the questions related to our article1Turpin W. et al.Gastroenterology. 2022; 163: 685-698Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar investigating the role of dietary patterns on microbiome composition and subclinical inflammation. As mentioned in the letter from Noviello et al,2Noviello D. et al.Gastroenterology. 2023; 164: 500-501Abstract Full Text Full Text PDF Scopus (1) Google Scholar other studies with fairly large sample sizes have identified that Western diets are associated with an increased risk of Crohn’s disease (CD). Notably, the Nurses Health Study I and II (245,112 participants) found that higher consumption of processed food significantly increased the risk of CD with a hazard ratio (HR) of 1.70 (95% confidence interval [CI], 1.23–2.35; P = .0008).3Lo C.H. et al.Clin Gastroenterol Hepatol. 2022; 20: e1323-e1337Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar This was replicated in the Prospective Urban Rural Epidemiology Study (116,087 participants) where a consumption of ≥5 servings per day of processed food increased the risk of CD with an HR of 1.82 (95% CI, 1.22–2.72) compared with <1 serving a day (P = .006).4Narula N. et al.BMJ. 2021; 374: n1554Crossref PubMed Scopus (95) Google Scholar Validating those findings in the Crohn’s and Colitis Canada Genetic, Environmental, Microbial (CCC-GEM) Project would strengthen previous studies’ findings. However, the CCC-GEM cohort was underpowered to detect an association between our dietary pattern with future risk of developing CD3Lo C.H. et al.Clin Gastroenterol Hepatol. 2022; 20: e1323-e1337Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,4Narula N. et al.BMJ. 2021; 374: n1554Crossref PubMed Scopus (95) Google Scholar with only 2289 participants (with baseline dietary data), of whom 53 had developed CD,2Noviello D. et al.Gastroenterology. 2023; 164: 500-501Abstract Full Text Full Text PDF Scopus (1) Google Scholar Despite sample size limitations, we observed that participants with a dietary pattern resembling a Western diet were more likely to develop CD (HR, 1.15; 95% CI, 0.67–1.96). Although not statistically significant, this analysis still showed that consuming a Western-like diet pattern (characterized by a higher consumption of processed food2Noviello D. et al.Gastroenterology. 2023; 164: 500-501Abstract Full Text Full Text PDF Scopus (1) Google Scholar) had the same direction of effect as previously described in the literature. With regard to antibiotic exposure as a major confounder when assessing the gut microbiome composition, we note that all CCC-GEM participants were healthy at the time of recruitment and were excluded if they had received antibiotic treatment within 3 months before recruitment into the study.1Turpin W. et al.Gastroenterology. 2022; 163: 685-698Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,5Lee S.H. et al.Gastroenterology. 2021; 161: 1540-1551Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Although the impact of antibiotics to the human microbiome can be long-lasting,6Jernberg C. et al.ISME J. 2007; 1: 56-66Crossref PubMed Scopus (750) Google Scholar we expect minimal confounding effects because of limited exposure to antibiotics in a healthy population at the time of recruitment. We recognize that smoking is a potential confounder of microbiota composition,7Benjamin J.L. et al.Inflamm Bowel Dis. 2012; 18: 1092-1100Crossref PubMed Scopus (156) Google Scholar and this was shown to be associated with elevated levels of fecal calprotectin.8Klingberg E. et al.Arthritis Res Ther. 2017; 19: 21Crossref PubMed Scopus (49) Google Scholar The CCC-GEM cohort, however, was composed of a relatively young population with a median age of 18.2 years (range, 6–350, with only 4.2% self-declaring as current smokers at the time of recruitment. Even when adjusting for current smoking status, we confirmed consistent findings that individuals consuming a dietary pattern that resembled a Western diet had higher levels of fecal calprotectin (P = .00029) when compared with individuals consuming a dietary pattern that resembled a Mediterranean-like diet. Finally, we assessed the distribution of antibody levels against microbial antigens across different dietary patterns as suggested by Noviello et al.2Noviello D. et al.Gastroenterology. 2023; 164: 500-501Abstract Full Text Full Text PDF Scopus (1) Google Scholar Unfortunately, the antimicrobial antibody data were only available in a small subset (ie, 272 participants) of the CCC-GEM cohort with food frequency questionnaire data collected.5Lee S.H. et al.Gastroenterology. 2021; 161: 1540-1551Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Nonetheless, the proportion of high antimicrobial antibody sum (≥2 positive antibodies) was higher in the Western-like dietary cluster (23.3%) vs other dietary clusters (15.4%; 1-sided P = .037). When adjusting for fecal calprotectin, the same direction of effect was observed but was not significant (1-sided P = .069). This is an interesting finding that might suggest an association between consumption of a Western-like diet with increased antimicrobial response and thus with possible dysregulation of immune homeostasis as previously discussed.9Christ A. et al.Immunity. 2019; 51: 794-811Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar Perhaps the dysregulation of gut barrier function might promote the translocation of bacteria or bacterial product. Unfortunately, the mechanisms of action of the Western-like diet in promoting this effect remain to be assessed. It would be important to assess the antimicrobial antibody data when available in the entire cohort to increase our statistical power. We thank Noviello et al2Noviello D. et al.Gastroenterology. 2023; 164: 500-501Abstract Full Text Full Text PDF Scopus (1) Google Scholar for their interest in our research findings and for their request for further analyses. We hope the prospective, healthy, at-risk CCC-GEM cohort provides insight into understanding the pathogenesis of CD that are not necessarily available from cross-sectional case-control studies. Environmental Protective and Risk Factors in an At-Risk Population of Subsequent Crohn’s DiseaseGastroenterologyVol. 164Issue 3PreviewWe read with great interest the article by Turpin et al1 who evaluated whether long-term dietary clusters (DCs) were associated with gut microbiome compositions as well as gut inflammation assessed by fecal calprotectin (FCP) in a cohort of healthy first-degree relatives of Crohn’s disease (CD) patients. They found that DC3 resembling the Mediterranean diet was associated with (a) a lower abundance of Ruminococcus, Dorea, and Campylobacter and an increase of Faecalibacterium and (b) a lower proportion of individuals with increased FCP at both cutoffs of 100 and 250 μg/g. Full-Text PDF