Effect of Important Food Sources of Fructose-Containing Sugars on Inflammatory Biomarkers: A Systematic Review and Meta-Analysis of Controlled Feeding Trials

Abstract

Background: Fructose-containing sugars as sugar-sweetened beverages (SSBs) may increase inflammatory biomarkers. Whether this effect is mediated by the food matrix at different levels of energy is unknown. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials on the effect of different food sources of fructose-containing sugars on inflammatory markers at different levels of energy control.

Methods: MEDLINE, Embase, and the Cochrane Library were searched through March 2022 for controlled feeding trials ≥ 7 days. Four trial designs were prespecified by energy control: substitution (energy matched replacement of sugars); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced). The primary outcome was C-reactive protein (CRP). Secondary outcomes were tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Independent reviewers extracted data and assessed risk of bias. GRADE assessed certainty of evidence.

Results: We identified 64 controlled trials (91 trial comparisons, n = 4094) assessing 12 food sources (SSB; sweetened dairy; sweetened dairy alternative [soy]; 100% fruit juice; fruit; dried fruit; mixed fruit forms; sweetened cereal grains and bars; sweets and desserts; added nutritive [caloric] sweetener; mixed sources [with SSBs]; and mixed sources [without SSBs]) at 4 levels of energy control over a median 6-weeks in predominantly healthy mixed weight or overweight/obese adults. Total fructose-containing sugars decreased CRP in addition trials and had no effect in substitution, subtraction or ad libitum trials. No effect was observed on other outcomes at any level of energy control. There was evidence of interaction/influence by food source: substitution trials (sweetened dairy alternative (soy) and 100% fruit juice decreased, and mixed sources (with SSBs) increased CRP); and addition trials (fruit decreased CRP and TNF-α; sweets and desserts (dark chocolate) decreased IL-6). The certainty of evidence was moderate-to-low for the majority of analyses.

Conclusions: Food source appears to mediate the effect of fructose-containing sugars on inflammatory markers over the short-to-medium term. The evidence provides good indication that mixed sources that contain SSBs increase CRP, while most other food sources have no effect with some sources (fruit, 100% fruit juice, sweetened soy beverage or dark chocolate) showing decreases, which may be dependent on energy control.

Clinicaltrials: gov: (NCT02716870).

Keywords: CRP; food sources; fructose; fruit; fruit juice; inflammation; meta-analysis; sugar-sweetened beverages; sugars; systematic review.

Conflict of interest statement

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. L.C. was a Mitacs-Elevate post-doctoral fellow jointly funded by the Government of Canada and the Canadian Sugar Institute (September 2019–August 2021). She was previously (2010–2019) employed as a casual clinical coordinator at INQUIS Clinical Research, Ltd. (formerly Glycemic Index Laboratories, Inc.), a contract research organization. D.L. reports receiving a stipend from University of Toronto Department of Nutritional Sciences Graduate Student Fellowship, University of Toronto Fellowship in Nutritional Sciences, University of Toronto Supervisor’s Research Grant—Early Researcher Awards, and Dairy Farmers of Canada Graduate Student Fellowships; a scholarship from St. Michael’s Hospital Research Training Centre, and a University of Toronto School of Graduate Studies Conference Grant. S.A.-C. was funded by a CIHR Canadian Graduate Scholarships Master’s and Doctoral Award, the Loblaw Food as Medicine Graduate Award, the Ontario Graduate Scholarship (OGS), and the CIHR Canadian Graduate Scholarship Doctoral Award. She avoids consuming NSBs and SSBs. F.A.-Y. is a part-time Research Assistant at INQUIS Clinical Research, Ltd., a contract research organization. A.A. and A.C. have received funding from a Toronto 3D MSc Scholarship award. T.A.K. has received research support from the Canadian Institutes of Health Research (CIHR), the International Life Science Institute (ILSI), and National Honey Board. He has been an invited speaker at the Calorie Control Council Annual meeting for which he has received an honorarium. R.J.d.S. has served as an external resource person to the World Health Organization’s Nutrition Guidelines Advisory Group on trans fats, saturated fats, and polyunsaturated fats. The WHO paid for his travel and accommodation to attend meetings from 2012–2017 to present and discuss this work. He has presented updates of this work to the WHO in 2022. He has also done contract research for the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism, and Diabetes, Health Canada, and the World Health Organization for which he received remuneration. He has received speaker’s fees from the University of Toronto, and McMaster Children’s Hospital. He has held grants from the Canadian Institutes of Health Research, Canadian Foundation for Dietetic Research, Population Health Research Institute, and Hamilton Health Sciences Corporation as a principal investigator, and is a co-investigator on several funded team grants from the Canadian Institutes of Health Research. He has served as an independent director of the Helderleigh Foundation (Canada). He serves as a member of the Nutrition Science Advisory Committee to Health Canada (Government of Canada), and a coopted member of the Scientific Advisory Committee on Nutrition (SACN) Subgroup on the Framework for the Evaluation of Evidence (Public Health England). T.M.S.W. was previously part owner, and now is an employee of INQUIS and received an honorarium from Springer/Nature for being an Associate Editor of the European Journal of Clinical Nutrition. C.W.C.K. has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada (AAFC), Almond Board of California, Barilla, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd., the Peanut Institute, Pulse Canada and Unilever. He has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, WhiteWave Foods/Danone. He has received travel support and/or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd., Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate & Lyle, Unilever and White Wave Foods/Danone. He has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute and Oldways Preservation Trust. He is a founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the EASD and is a Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. D.J.A.J. has received research grants from Saskatchewan & Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Research Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg’s Company, Canada, Quaker Oats, Canada, Procter & Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut & Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI)and the Ontario Research Fund (ORF). He has received in-kind supplies for trials as a research support from the Almond board of California, Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker’s panel, served on the scientific advisory board and/or received travel support and/or honoraria from Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (Fare-Well), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan & Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter & Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael’s Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbohydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8)and his sister, Caroline Brydson, received funding through a grant from the St. Michael’s Hospital Foundation to develop a cookbook for one of his studies. He is also a vegan. J.L.S. has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS; formerly ILSI North America), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy “Checkoff” program), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Fund at the University of Toronto (a fund established by an inaugural donation from the Calorie Control Council). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, WhiteWave Foods/Danone, Nutrartis, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, and International Glutamate Technical Committee. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Phynova, and Inquis Clinical Research. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves or has served as an unpaid member of the Board of Trustees and an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. X.Y.Q., Q.L, S.B.M., V.L.C., and L.A.L. declare no relevant competing interests.

Figures

Figure 1

Flow of literature for the effect of food sources of fructose-containing sugars and inflammation; CRP = C-reactive protein; IL-6 = interleukin-6; TNF-α = tumor necrosis factor-alpha.

Figure 2

Summary plot for the effect of different food sources of fructose-containing sugars on CRP; Data are weighted mean differences (95% confidence intervals) for summary effects of individual food sources and total food sources on CRP. Analyses conducted by generic, inverse variance random effects models (at least five trials available) or fixed effects models (fewer than five trials available). Between-study heterogeneity was assessed by the Cochrane Q statistic, where PQ < 0.100 is considered statistically significant, and quantified by the I2 statistic, where I2 ≥ 50% is considered evidence of substantial heterogeneity. The effects of total fructose-containing sugars are denoted by the bolded lines with the effect estimates as diamonds. The effects of individual food sources are denoted by the non-bolded lines with the effect estimates as squares. Any statistically significant reductions are highlighted in green and significant increases in red. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as “High” certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome, and the black square with a white “2” indicates a double downgrade for each outcome. CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; MD= mean difference; N = number; SSB = sugar-sweetened beverages; a Since all included trials were randomized or non-randomized controlled trials, the certainty of the evidence was graded as high for all outcomes by default and then downgraded or upgraded based on pre-specified criteria. Criteria for downgrades included risk of bias (ROB) (downgraded if the majority of trials were considered to be at high ROB); inconsistency (downgraded if there was substantial unexplained heterogeneity [I2 ≥ 50%, PQ < 0.10]; indirectness (downgraded if there were factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results); imprecision (downgraded if the 95% confidence interval crossed the minimally important difference [MID] for harm or benefit set 0.5 mg/L for CRP [33,34,35]; and publication bias (downgraded if there is evidence of publication bias based on funnel plot asymmetry and/or significant Egger’s or Begg’s tests (p < 0.10) with confirmation by adjustment by Duval and Tweedie trim-and-fill analysis). Criteria for upgrades included a significant dose–response gradient; b For the interpretation of the magnitude, we used the MIDs (see a above) to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. We then used the MIDs to assess the importance of the magnitude of our point estimates using the effect size categories according GRADE guidance [47,54,56] as follows: large effect (≥5× MID); moderate effect (≥2× MID); small important effect (≥1× MID); and trivial/unimportant effect (<1 MID); * Where there was a significant interaction by food source in substitution trials, an influence of fruit in addition trials, and SSBs and/or mixed sources (with SSBs) were the sole food sources in subtraction and ad libitum trials, we performed the GRADE analysis for each individual food source.

Figure 3

Summary plot for the effect of different food sources of fructose-containing sugars on TNF-α; Data are weighted mean differences (95% confidence intervals) for summary effects of individual food sources and total food sources on TNF-α. Analyses conducted by generic, inverse variance random effects models (at least five trials available) or fixed effects models (fewer than five trials available). Between-study heterogeneity was assessed by the Cochrane Q statistic, where PQ < 0.100 is considered statistically significant, and quantified by the I2 statistic, where I2 ≥ 50% is considered evidence of substantial heterogeneity. The effects of total fructose-containing sugars are denoted by the bolded lines with the effect estimates as diamonds. The effects of individual food sources are denoted by the non-bolded lines with the effect estimates as squares. Any statistically significant reductions are highlighted in green and significant increases in red. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as “High” certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome, and the black square with a white “2” indicates a double downgrade for each outcome. CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; MD= mean difference; N = number; SSB = sugar-sweetened beverages; TNF-α = tumour necrosis factor-alpha; a Since all included trials were randomized or non-randomized controlled trials, the certainty of the evidence was graded as high for all outcomes by default and then downgraded or upgraded based on pre-specified criteria. Criteria for downgrades included risk of bias (ROB) (downgraded if the majority of trials were considered to be at high ROB); inconsistency (downgraded if there was substantial unexplained heterogeneity [I2 ≥ 50%, PQ < 0.10]; indirectness (downgraded if there were factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results); imprecision (downgraded if the 95% confidence interval crossed the minimally important difference [MID] for harm or benefit set at 0.28 pg/mL for TNF-α [36]; and publication bias (downgraded if there is evidence of publication bias based on funnel plot asymmetry and/or significant Egger’s or Begg’s tests (p < 0.10) with confirmation by adjustment by Duval and Tweedie trim-and-fill analysis). Criteria for upgrades included a significant dose–response gradient; b For the interpretation of the magnitude, we used the MIDs (see a above) to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. We then used the MIDs to assess the importance of the magnitude of our point estimates using the effect size categories according GRADE guidance [47,54,56] as follows: large effect (≥5× MID); moderate effect (≥2× MID); small important effect (≥1× MID); and trivial/unimportant effect (<1 MID); * Where there was an influence of fruit in addition trials, we performed the GRADE analysis for each individual food source.

Figure 4

Summary plot for the effect of different food sources of fructose-containing sugars on IL-6; Data are weighted mean differences (95% confidence intervals) for summary effects of individual food sources and total food sources on IL-6. Analyses conducted by generic, inverse variance random effects models (at least five trials available) or fixed effects models (fewer than five trials available). Between-study heterogeneity was assessed by the Cochrane Q statistic, where PQ < 0.100 is considered statistically significant, and quantified by the I2 statistic, where I2 ≥ 50% is considered evidence of substantial heterogeneity. The effects of total fructose-containing sugars are denoted by the bolded lines with the effect estimates as diamonds. The effects of individual food sources are denoted by the non-bolded lines with the effect estimates as squares. Any statistically significant reductions are highlighted in green and significant increases in red. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as “High” certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome, and the black square with a white “2” indicates a double downgrade for each outcome. CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; MD = mean difference; N = number; SSB = sugar-sweetened beverages; a Since all included trials were randomized or non-randomized controlled trials, the certainty of the evidence was graded as high for all outcomes by default and then downgraded or upgraded based on pre-specified criteria. Criteria for downgrades included risk of bias (ROB) (downgraded if the majority of trials were considered to be at high ROB); inconsistency (downgraded if there was substantial unexplained heterogeneity [I2 ≥ 50%, PQ < 0.10]; indirectness (downgraded if there were factors absent or present relating to the participants, interventions, or outcomes that limited the generalizability of the results); imprecision (downgraded if the 95% confidence interval crossed the minimally important difference [MID] for harm or benefit set at 0.18 pg/mL for IL-6 [37]; and publication bias (downgraded if there is evidence of publication bias based on funnel plot asymmetry and/or significant Egger’s or Begg’s tests (p < 0.10) with confirmation by adjustment by Duval and Tweedie trim-and-fill analysis). Criteria for upgrades included a significant dose–response gradient; b For the interpretation of the magnitude, we used the MIDs (see a above) to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. We then used the MIDs to assess the importance of the magnitude of our point estimates using the effect size categories according GRADE guidance [47,54,56] as follows: large effect (≥5× MID); moderate effect (≥2× MID); small important effect (≥1× MID); and trivial/unimportant effect (<1 MID); * Where there was a significant interaction by food source in addition trials, we performed the GRADE analysis for each individual food source.