Understanding the Role of PUFAs in Crohn’s Disease

Abstract

See “PUFA-induced metabolic enteritis as a fuel for Crohn’s disease,” by Schwärzler J, Mayr L, Vila AV, et al, on page 1690.The pathogenesis of inflammatory bowel disease (IBD) remains to be fully elucidated. Nevertheless, accumulating evidence points toward the role of diet as a key modifiable risk factor for both the development of IBD and for maintaining disease activity. A recurrent finding is the pro-inflammatory effect of a Western diet, which is characterized by decreased intake of dietary fiber and increased consumption of refined sugars, animal protein, total fat, and ultraprocessed foods.1Khalili H. Chan S.S.M. Lochhead P. et al.The role of diet in the aetiopathogenesis of inflammatory bowel disease.Nat Rev Gastroenterol Hepatol. 2018; 15: 525-535Crossref PubMed Scopus (111) Google Scholar Recently, 2 large prospective cohort studies reported an increased risk of Crohn’s disease in individuals with higher consumption of ultraprocessed foods.2Narula N. Wong E.C.L. Dehghan M. et al.Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study.BMJ. 2021; 374: n1554Crossref PubMed Scopus (41) Google Scholar,3Lo CH, Khandpur N, Rossato SL, et al. Ultra-processed foods and risk of crohn's disease and ulcerative colitis: a prospective cohort study [published online ahead of print August 28, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.08.031.Google Scholar Emulsifiers are food additives frequently used in food processing with potential proinflammatory effects.4Chassaing B. Koren O. Goodrich J.K. et al.Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.Nature. 2015; 519: 92-96Crossref PubMed Scopus (1052) Google Scholar In a recent controlled feeding study in humans, supplementation with carboxymethylcellulose led to alterations in intestinal microbiota and a decrease in short-chain fatty acids.5Chassaing B. Compher C. Bonhomme B. et al.Randomized controlled-feeding study of dietary emulsifier carboxymethylcellulose reveals detrimental impacts on the gut microbiota and metabolome.Gastroenterology. 2022; 162: P743-P756Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Increased fat consumption has also been associated with intestinal inflammation.6Agus A. Denizot J. Thévenot J. et al.Western diet induces a shift in microbiota composition enhancing susceptibility to adherent-invasive E. coli infection and intestinal inflammation.Sci Rep. 2016; 6: 19032Crossref PubMed Scopus (241) Google ScholarIn this issue of Gastroenterology, Schwärzler et al7Schwärzler J. Mayr L. Vila A.V. et al.PUFA-induced metabolic enteritis as a fuel for Crohn's disease.Gastroenterology. 2022; 162: 1690-1704Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar explored the concept of polyunsaturated fatty acids (PUFA)-induced intestinal inflammation. In an elegant translational work, the authors used 2 murine models to link PUFA intake to endoplasmic reticulum (ER) stress–driven enteritis, patient-derived organoids to link PUFAs to epithelial cytokine expression, and 2 independent cohorts of patients with Crohn’s disease to link PUFA intake to disease activity. In X-box binding protein 1 (XPB1)–/–IEC mice, exposure to a PUFA-enriched Western diet for 3 months led to severe enteritis, although this was not observed in wild-type mice or XPB1–/–IEC mice on a low-fat diet or a standard Western diet. In a second murine model, the glutathione peroxidase 4 (GPX4)+/-IEC mice, the authors confirmed previous findings that GPX4 protects from ER stress induced by exposure to PUFAs and showed that both omega-3 and omega-6 PUFA can induce intestinal inflammation in Gpx4+/-IEC mice. Interestingly, intestinal microbiota seem to play a role in the PUFA-induced enteritis, as treatment with antibiotic lead to a decrease in intestinal inflammation.One of the strengths of the study is its translational aspect. Small intestinal organoids derived from healthy controls and patients with Crohn’s disease were exposed to omega-3 and omega-6 PUFAs. Increased interleukin-8 and tumor necrosis factor–α expression was only observed in organoids from patients with Crohn’s disease with impaired GPX4 expression. Finally, the estimated intake of PUFAs correlated with disease activity in a cohort of patients with Crohn’s disease. Recognizing the limitations of questionnaire-based estimation of PUFA intake, the authors used an independent cohort and measured fecal omega-3 and omega-6 PUFAs concentration as a surrogate marker of PUFA intake, confirming their initial observation that PUFA intake is correlated with disease activity.The link between PUFA intake and Crohn’s disease has been studied in the past and has generated conflicting results. So have serum PUFA levels been linked to disease activity in Crohn’s disease.8Scoville E.A. Allaman M.M. Adams D.W. et al.Serum polyunsaturated fatty acids correlate with serum cytokines and clinical disease activity in Crohn's disease.Sci Rep. 2019; 9: 2882Crossref PubMed Scopus (26) Google Scholar In contrast, in a large prospective cohort study, no association was seen between PUFA intake and risk of Crohn’s disease.9Ananthakrishnan A.N. Khalili H. Konijeti G.G. et al.Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.Gut. 2014; 63: 776-784Crossref PubMed Scopus (279) Google Scholar Adding another layer of complexity, in 2 randomized controlled trials (EPIC trials) supplementation of omega-3 PUFA was not effective in the prevention of relapse in patients with Crohn’s disease in clinical remission.10Feagan B.G. Sandborn W.J. Mittmann U. et al.Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials.JAMA. 2008; 299: 1690-1697Crossref PubMed Scopus (228) Google Scholar The supplementation of omega-3 PUFA did not result in higher relapse rates compared with placebo, a finding that could be expected if omega-3 PUFA are indeed the fuel for Crohn’s disease enteritis. This raises the question of whether the pro-inflammatory effect of omega-3 PUFA will be proven in future nutrition intervention trials. The present study provides possible explanations for these conflicting results, as the authors nicely demonstrate that the detrimental effect of PUFAs depends on the GPX4 activity of the host and not solely in the measured or estimated intake. The same group has previously shown that expression of GPX4 is decreased in intestinal epithelial cells of patients with Crohn’s disease compared with healthy controls or patients with ulcerative colitis. GPX4 is an enzyme that protects cells from membrane lipid peroxidation and subsequent cell damage or death. Interestingly, PUFAs can induce enteritis in Gpx4-deficient cells.11Mayr L. Grabherr F. Schwärzler J. et al.Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.Nat Commun. 2020; 11: 1775Crossref PubMed Scopus (59) Google Scholar In this perspective, it would be interesting to measure GPX4 activity in samples from patients included in the EPIC trials. Could GPX4 expression explain why these trials were negative? Future individualized and host-tailored dietary intervention trials will be needed to solidly proof PUFA restriction improves disease activity in Crohn’s disease.Performing high-quality randomized controlled trials with dietary interventions is challenging, although vital for the advancement of dietary research in IBD.12Staudacher H.M. Irving P.M. Lomer M.C.E. et al.The challenges of control groups, placebos and blinding in clinical trials of dietary interventions.Proc Nutr Soc. 2017; 76: 203-212Crossref PubMed Scopus (62) Google Scholar The IBD community has been fortunate to see several dietary intervention studies being published in recent years, including the Crohn’s disease exclusion diet,13Levine A. Wine E. Assa A. et al.Crohn’s disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial.Gastroenterology. 2019; 157: 440-450.e8Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar the FACES (Food and Crohn's Disease Exacerbation Study) study,14Albenberg L. Brensinger C.M. Wu Q. et al.A diet low in red and processed meat does not reduce rate of crohn's disease flares.Gastroenterology. 2019; 157: 128-136.e5Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and the DINE-CD (Trial of Specific Carbohydrate and Mediterranean Diets to Induce Remission of Crohn's Disease) trial.15Lewis J.D. Sandler R.S. Brotherton C. et al.A randomized trial comparing the specific carbohydrate diet to a Mediterranean diet in adults with Crohn's disease.Gastroenterology. 2021; 161: 837-852.e9Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Yet, we are still lacking an evidence-based efficient dietary intervention to treat patients with IBD. Ongoing randomized controlled trials (eg, NCT04946448, NCT02843100, and NCT04431700) will hopefully fill this gap, while mechanistic studies, such as the one from Schwärzler et al,7Schwärzler J. Mayr L. Vila A.V. et al.PUFA-induced metabolic enteritis as a fuel for Crohn's disease.Gastroenterology. 2022; 162: 1690-1704Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar remain crucial to further understand and tailor our dietary interventions. See “PUFA-induced metabolic enteritis as a fuel for Crohn’s disease,” by Schwärzler J, Mayr L, Vila AV, et al, on page 1690. See “PUFA-induced metabolic enteritis as a fuel for Crohn’s disease,” by Schwärzler J, Mayr L, Vila AV, et al, on page 1690. See “PUFA-induced metabolic enteritis as a fuel for Crohn’s disease,” by Schwärzler J, Mayr L, Vila AV, et al, on page 1690. The pathogenesis of inflammatory bowel disease (IBD) remains to be fully elucidated. Nevertheless, accumulating evidence points toward the role of diet as a key modifiable risk factor for both the development of IBD and for maintaining disease activity. A recurrent finding is the pro-inflammatory effect of a Western diet, which is characterized by decreased intake of dietary fiber and increased consumption of refined sugars, animal protein, total fat, and ultraprocessed foods.1Khalili H. Chan S.S.M. Lochhead P. et al.The role of diet in the aetiopathogenesis of inflammatory bowel disease.Nat Rev Gastroenterol Hepatol. 2018; 15: 525-535Crossref PubMed Scopus (111) Google Scholar Recently, 2 large prospective cohort studies reported an increased risk of Crohn’s disease in individuals with higher consumption of ultraprocessed foods.2Narula N. Wong E.C.L. Dehghan M. et al.Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study.BMJ. 2021; 374: n1554Crossref PubMed Scopus (41) Google Scholar,3Lo CH, Khandpur N, Rossato SL, et al. Ultra-processed foods and risk of crohn's disease and ulcerative colitis: a prospective cohort study [published online ahead of print August 28, 2021]. Clin Gastroenterol Hepatol https://doi.org/10.1016/j.cgh.2021.08.031.Google Scholar Emulsifiers are food additives frequently used in food processing with potential proinflammatory effects.4Chassaing B. Koren O. Goodrich J.K. et al.Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.Nature. 2015; 519: 92-96Crossref PubMed Scopus (1052) Google Scholar In a recent controlled feeding study in humans, supplementation with carboxymethylcellulose led to alterations in intestinal microbiota and a decrease in short-chain fatty acids.5Chassaing B. Compher C. Bonhomme B. et al.Randomized controlled-feeding study of dietary emulsifier carboxymethylcellulose reveals detrimental impacts on the gut microbiota and metabolome.Gastroenterology. 2022; 162: P743-P756Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Increased fat consumption has also been associated with intestinal inflammation.6Agus A. Denizot J. Thévenot J. et al.Western diet induces a shift in microbiota composition enhancing susceptibility to adherent-invasive E. coli infection and intestinal inflammation.Sci Rep. 2016; 6: 19032Crossref PubMed Scopus (241) Google Scholar In this issue of Gastroenterology, Schwärzler et al7Schwärzler J. Mayr L. Vila A.V. et al.PUFA-induced metabolic enteritis as a fuel for Crohn's disease.Gastroenterology. 2022; 162: 1690-1704Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar explored the concept of polyunsaturated fatty acids (PUFA)-induced intestinal inflammation. In an elegant translational work, the authors used 2 murine models to link PUFA intake to endoplasmic reticulum (ER) stress–driven enteritis, patient-derived organoids to link PUFAs to epithelial cytokine expression, and 2 independent cohorts of patients with Crohn’s disease to link PUFA intake to disease activity. In X-box binding protein 1 (XPB1)–/–IEC mice, exposure to a PUFA-enriched Western diet for 3 months led to severe enteritis, although this was not observed in wild-type mice or XPB1–/–IEC mice on a low-fat diet or a standard Western diet. In a second murine model, the glutathione peroxidase 4 (GPX4)+/-IEC mice, the authors confirmed previous findings that GPX4 protects from ER stress induced by exposure to PUFAs and showed that both omega-3 and omega-6 PUFA can induce intestinal inflammation in Gpx4+/-IEC mice. Interestingly, intestinal microbiota seem to play a role in the PUFA-induced enteritis, as treatment with antibiotic lead to a decrease in intestinal inflammation. One of the strengths of the study is its translational aspect. Small intestinal organoids derived from healthy controls and patients with Crohn’s disease were exposed to omega-3 and omega-6 PUFAs. Increased interleukin-8 and tumor necrosis factor–α expression was only observed in organoids from patients with Crohn’s disease with impaired GPX4 expression. Finally, the estimated intake of PUFAs correlated with disease activity in a cohort of patients with Crohn’s disease. Recognizing the limitations of questionnaire-based estimation of PUFA intake, the authors used an independent cohort and measured fecal omega-3 and omega-6 PUFAs concentration as a surrogate marker of PUFA intake, confirming their initial observation that PUFA intake is correlated with disease activity. The link between PUFA intake and Crohn’s disease has been studied in the past and has generated conflicting results. So have serum PUFA levels been linked to disease activity in Crohn’s disease.8Scoville E.A. Allaman M.M. Adams D.W. et al.Serum polyunsaturated fatty acids correlate with serum cytokines and clinical disease activity in Crohn's disease.Sci Rep. 2019; 9: 2882Crossref PubMed Scopus (26) Google Scholar In contrast, in a large prospective cohort study, no association was seen between PUFA intake and risk of Crohn’s disease.9Ananthakrishnan A.N. Khalili H. Konijeti G.G. et al.Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.Gut. 2014; 63: 776-784Crossref PubMed Scopus (279) Google Scholar Adding another layer of complexity, in 2 randomized controlled trials (EPIC trials) supplementation of omega-3 PUFA was not effective in the prevention of relapse in patients with Crohn’s disease in clinical remission.10Feagan B.G. Sandborn W.J. Mittmann U. et al.Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials.JAMA. 2008; 299: 1690-1697Crossref PubMed Scopus (228) Google Scholar The supplementation of omega-3 PUFA did not result in higher relapse rates compared with placebo, a finding that could be expected if omega-3 PUFA are indeed the fuel for Crohn’s disease enteritis. This raises the question of whether the pro-inflammatory effect of omega-3 PUFA will be proven in future nutrition intervention trials. The present study provides possible explanations for these conflicting results, as the authors nicely demonstrate that the detrimental effect of PUFAs depends on the GPX4 activity of the host and not solely in the measured or estimated intake. The same group has previously shown that expression of GPX4 is decreased in intestinal epithelial cells of patients with Crohn’s disease compared with healthy controls or patients with ulcerative colitis. GPX4 is an enzyme that protects cells from membrane lipid peroxidation and subsequent cell damage or death. Interestingly, PUFAs can induce enteritis in Gpx4-deficient cells.11Mayr L. Grabherr F. Schwärzler J. et al.Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.Nat Commun. 2020; 11: 1775Crossref PubMed Scopus (59) Google Scholar In this perspective, it would be interesting to measure GPX4 activity in samples from patients included in the EPIC trials. Could GPX4 expression explain why these trials were negative? Future individualized and host-tailored dietary intervention trials will be needed to solidly proof PUFA restriction improves disease activity in Crohn’s disease. Performing high-quality randomized controlled trials with dietary interventions is challenging, although vital for the advancement of dietary research in IBD.12Staudacher H.M. Irving P.M. Lomer M.C.E. et al.The challenges of control groups, placebos and blinding in clinical trials of dietary interventions.Proc Nutr Soc. 2017; 76: 203-212Crossref PubMed Scopus (62) Google Scholar The IBD community has been fortunate to see several dietary intervention studies being published in recent years, including the Crohn’s disease exclusion diet,13Levine A. Wine E. Assa A. et al.Crohn’s disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial.Gastroenterology. 2019; 157: 440-450.e8Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar the FACES (Food and Crohn's Disease Exacerbation Study) study,14Albenberg L. Brensinger C.M. Wu Q. et al.A diet low in red and processed meat does not reduce rate of crohn's disease flares.Gastroenterology. 2019; 157: 128-136.e5Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and the DINE-CD (Trial of Specific Carbohydrate and Mediterranean Diets to Induce Remission of Crohn's Disease) trial.15Lewis J.D. Sandler R.S. Brotherton C. et al.A randomized trial comparing the specific carbohydrate diet to a Mediterranean diet in adults with Crohn's disease.Gastroenterology. 2021; 161: 837-852.e9Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Yet, we are still lacking an evidence-based efficient dietary intervention to treat patients with IBD. Ongoing randomized controlled trials (eg, NCT04946448, NCT02843100, and NCT04431700) will hopefully fill this gap, while mechanistic studies, such as the one from Schwärzler et al,7Schwärzler J. Mayr L. Vila A.V. et al.PUFA-induced metabolic enteritis as a fuel for Crohn's disease.Gastroenterology. 2022; 162: 1690-1704Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar remain crucial to further understand and tailor our dietary interventions. PUFA-Induced Metabolic Enteritis as a Fuel for Crohn’s DiseaseGastroenterologyVol. 162Issue 6PreviewPolyunsaturated fatty acids enriched in a Western diet trigger metabolic gut inflammation in susceptible mice and elicit an inflammatory response from Crohn’s epithelium, and their intake correlates with a poor disease course. Full-Text PDF Open Access