Diabetes Care 1 COMMENTARY

Fried Foods, Gut Microbiota, and Lu Qi Glucose Metabolism Diabetes Care | https://doi.org/10.2337/dci21-0033

Hot oil–based frying is a popular cooking the development of T2D could only be noted that several indices of glucose method that makes food more appealing detected in investigations in which the metabolism including the insulino- in texture and aromatic, thus improving cofounding was rigorously controlled, genic index (IGI), muscle insulin resis- palatability. Fried foods are considered such as randomized clinical trials. tance index (MIRI), and insulin levels unhealthy because frying may increase In addition, the potential mechanisms were improved during the interven- the energy density of foods and therefore underlying the observed adverse associ- tion in both groups, along with the energy intakes as well as deteriorate oils ations between fried foods and T2D reduction of energy intake. Compared through the process of oxidation and remain largely unknown; previous stud- with the control group, the 4-week hydrogenation, leading to a loss of unsat- ies suggest that a myriad of pathways intervention by fried foods group fl urated fatty acids such as linoleic and lin- such as weight gain, in ammation, and showed less improvement in IGI, olenic acids but increase in trans fatty lipid metabolism may be involved (1,2). MIRI, and area under the curve (AUC) acids, oil degradation, and advanced gly- In recent years, growing data suggest of insulin, and no difference in HbA1c, that the gut microbiota may play a key C-peptide, and AUC of glucose. The cation end products (1,2). In epidemio- role in linking dietary factors including authors concluded that fried meat intake logical studies, high intakes of fried foods fried foods and host’s health (8,9). Stud- impaired glucose homeostasis. have been associated with a variety of ies in humans and animal models indi- Among the secondary outcomes, the adverse health outcomes including type cate that fried food consumption or the group with fried meat intervention 2 diabetes (T2D), although the results are byproducts of frying and thermal proc- showed less reduction in biomarkers of not entirely consistent (3–6). The conflict- essing are related to the diversity and intestinal endotoxin and systemic inflam- ing findings are partly due to the diverse richness of the gut microbiota (10,11). mation and less increase in FGF21, a types of oil used in frying foods. For However, the randomized clinical trials hepatokine regulating satiety and sugar instance, null associations between fried assessing the effects of fried foods on intake (13). In addition, it was found foods and T2D risk were reported in pop- thegutmicrobiotaandthesubsequent that the fried meat group had a lower ulations with fried foods prepared using glucose metabolism are still lacking. gut microbiota richness than the control mainly olive oil, which is more resistant In this issue of Diabetes Care,Gao group; the overall microbial structure to oxidation than other common oils et al. (12) present the results from a ran- and composition as well as the micro- used for frying such as corn oil (4). In domized controlled feeding trial to test biota-predicted pathways relating to addition, the varying compositions of the the effects of fried meat intakes on glu- glucose homeostasis were also different foods being fried and frying conditions cose homeostasis. A total of 117 young between these two groups. Notably, the (temperature, duration) may also trigger overweight (BMI >24 kg/m2) adults ratio of Firmicutes and Bacteroidetes,a the heterogeneous results. An extra layer aged 18–35 years were randomized into traditional marker of T2D (14), was of complexity in the inconsistent observa- twogroups,whichwereprovidedisoca- higher in the intervention group than tions is introduced by various confound- loric meals with consistent foods and the control group. In addition, fried ing factors such as weight gain, high the Alternate Health Eating Index (AHEI) meat intervention led to significant blood pressure, and lipidemia, which are score >85, but different meat cooking shifts in fecal cometabolites, such as correlated with both fried food consump- methods—frying in the intervention decrease of butyric acid, valeric acid, tion and T2D risk (1,7). The causality of group and boiling, streaming, or dressing and indole-3-propionic acid and increase fried foods in glucose dysregulation and with sauce in the control group. It is of carnitine. Changes in these fecal

Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA Corresponding author: Lu Qi, [email protected] © 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license. See accompanying articles, pp. XXXX and XXXX. Diabetes Care Publish Ahead of Print, published online August 20, 2021 2 Commentary Diabetes Care

metabolites showed significant correla- and T2D, which have been evidenced by 3.LiuG,ZongG,WuK,etal.Meatcooking tions with changes in IGI, MIRI, intestinal the growing studies in the past 10 years methods and risk of type 2 diabetes: results from – three prospective cohort studies. Diabetes Care endotoxin lipopolysaccharides, FGF21, (15 18). Compelling data have shown – fl 2018;41:1049 1060 and in ammatory biomarkers, implying that the gut microbiota may affect host’s 4. Sayon-Orea C, Martinez-Gonzalez MA, Gea A, the compound mechanistic connections heath mainly through circulating metab- Flores-Gomez E, Basterra-Gortari FJ, Bes-Rastrollo between the gut microbiota and glucose olites (19). The gut microbiota takes a M. Consumption of fried foods and risk of homeostasis. The findings were further metabolic syndrome: the SUN cohort study. Clin critical part in the digestion of food – supported by the experiment in mice. fi Nutr 2014;33:545 549 ingredients, and a signi cant proportion 5. Qin P, Liu D, Wu X, et al. Fried-food consumption ThisstudybyGaoetal.hasseveral of the blood metabolome reacts to the and risk of overweight/obesity, type 2 diabetes major strengths. Randomized clinical tri- ingestion of foods. Therefore, circulating mellitus, and hypertension in adults: a meta- als are considered the gold standard to metabolites directly symbol the host- analysis of observational studies. Crit Rev Food Sci Nutr. 7 April 2021 [Epub ahead of print]. DOI: provide evidence for causality. In the microbiota-diet interactions (17,20). In study by Gao et al., the foods tested https://doi.org/10.1080/10408398.2021.1906626 addition, emerging evidence indicates 6. Cahill LE, Pan A, Chiuve SE, et al. Fried-food were carefully controlled and consistent that dietary interventions may significantly consumption and risk of type 2 diabetes and in the intervention and control groups, change circulating microbial metabolites coronary artery disease: a prospective study in 2 and randomization minimized the poten- and subsequently affect glucose metabo- cohorts of US women and men. Am J Clin Nutr tial confounding. Therefore, the observed 2014;100:667–675 lism (21,22). Thus, comprehensive analysis differences in the primary outcomes 7. Qi Q, Chu AY, Kang JH, et al. Fried food of circulating metabolome is called for in related to glucose homeostasis were consumption, genetic risk, and body mass index: the future randomized clinical trials. Fur- gene-diet interaction analysis in three US cohort likely caused by the distinct food proc- ther investigations are also warranted to studies. BMJ 2014;348:g1610 essing method–frying. Novel to this 8. Zinocker€ MK, Lindseth IA. The Western diet- assess the effects of fried foods by various study is the integration of profiling the microbiome-host interaction and its role in gut microbiome with quantitatively tar- typesofoil,aspriordatasuggestfoods metabolic disease. Nutrients 2018;10:10 geted bacterial metabolomics in the fecal fried in certain types of oil such as extra 9. Ward RE, Benninghoff AD, Hintze KJ. Food matrix and the microbiome: considerations for samples. Such analyses provide novel virgin olive oil may improve postprandial insulin response (23). The evidence from preclinical chronic disease studies. Nutr Res evidence for the roles of the microbial 2020;78:1–10 community in mediating the dietary the study by Gao et al. may contribute to 10. Partula V, Mondot S, Torres MJ, et al.; Milieu effects on glucose metabolism. In addi- draw more attention on the inclusion of Interieur Consortium. Associations between usual tion, the experiments in mice provided the healthy food processing methods diet and gut microbiota composition: results from fi in the dietary guidelines, beyond the the Milieu Interieur cross-sectional study. Am J extra proof to the ndings. The compre- – nutrients and food components. Food Clin Nutr 2019;109:1472 1483 hensive assessment of a broad range of 11. Zhou Z, Wang Y, Jiang Y, et al. Deep-fried oil biomarkers including intestinal endotoxin, processing is largely overlooked in the consumption in rats impairs glycerolipid metabolism, systemic inflammation, and others fur- current dietary recommendations. Notably, gut histology and microbiota structure. Lipids Health ther contribute to our understanding the beneficial effects of healthy foods such Dis 2016;15:86 of the complex bonds between fried as vegetables may be diminished during 12. GaoJ,GuoX,WeiW,etal.Theassociationof fried meat consumption with the gut microbiota meat, gut microbiota, and glucose frying at high temperature (24). Therefore, and fecal metabolites and its impact on glucose metabolism. the future dietary guidelines would take homoeostasis, intestinal endotoxin levels, and The study is subject to several poten- the food processing methods into account. systemic inflammation: a randomized controlled- tial limitations. Given the relatively short feeding trial. Diabetes Care 2021;44:XXXX–XXXX term of intervention, the study could not 13. Søberg S, Sandholt CH, Jespersen NZ, et al. FGF21 is a sugar-induced hormone associated evaluate the prolonged effect of fried L.Q. is supported by grants from the Funding. with sweet intake and preference in humans. Cell National Institutes of Health (NIH) National foods on glycemic homeostasis and T2D Metab 2017;25:1045–1053.e6 risk. Notably, the primary outcomes, Heart, Lung, and Blood Institute (HL071981, 14. Larsen N, Vogensen FK, van den Berg FW, including glucose and HbA1c, did not HL034594, HL126024), the NIH National Institute et al. Gut microbiota in human adults with type 2 of Diabetes and Digestive and Kidney Diseases diabetes differs from non-diabetic adults. PLoS differ between the intervention and (DK115679, DK091718, DK100383), the Fogarty control groups. This might be partly One 2010;5:e9085 International Center (TW010790), and Tulane 15. Qin J, Li Y, Cai Z, et al. A metagenome-wide due to the short intervention and rel- Research Centers of Excellence Awards. L.Q. was association study of gut microbiota in type 2 atively small sample size. The study a recipient of the American Heart Association diabetes. Nature 2012;490:55–60 participants are relatively young and Scientist Development Award (0730094N). L.Q. is 16. Karlsson FH, Tremaroli V, Nookaew I, et al. healthy; therefore, the generalizabil- also supported by NIH P30DK072476. Gut metagenome in European women with Duality of Interest. No potential conflicts of ity of the findings is constrained. In normal, impaired and diabetic glucose control. interest relevant to this article were reported. – addition, the ancillary nature and Nature 2013;498:99 103 17. Asnicar F, Berry SE, Valdes AM, et al. multiple testing in analyses justify Reference Microbiome connections with host metabolism cautions against making causal infer- 1. Gadiraju TV, Patel Y, Gaziano JM, DjousseL. and habitual diet from 1,098 deeply phenotyped ence on the findings of the bio- Fried food consumption and cardiovascular individuals. Nat Med 2021;27:321–332 markers and microbiome. health: a review of current evidence. Nutrients 18. Wang DD, Nguyen LH, Li Y, et al. The gut – The findings from the study by Gao 2015;7:8424 8430 microbiome modulates the protective association 2. Davis KE, Prasad C, Vijayagopal P, Juma S, between a Mediterranean diet and cardiometabolic et al. reemphasize the importance of Imrhan V. Advanced glycation end products, disease risk. Nat Med 2021;27:333–343 investigating the causal and mechanistic inflammation, and chronic metabolic diseases: links 19. Chen L, Wang D, Garmaeva S, et al.; Lifelines links between the diet, gut microbiota, in a chain? Crit Rev Food Sci Nutr 2016;56:989–998 Cohort Study. The long-term genetic stability and care.diabetesjournals.org Qi 3

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