  Citation: Milesi, G.; Rangan, A.; Grafenauer, S. Whole Grain Consumption and Inflammatory Markers: A Systematic Literature Review of Randomized Control Trials. Nutrients 2022, 14, 374. https://doi.org/10.3390/nu14020374 Academic Editors: Marinangeli Christopher P. F. and Rosa Casas Received: 14 December 2021 Accepted: 11 January 2022 Published: 16 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Review Whole Grain Consumption and Inflammatory Markers: A Systematic Literature Review of Randomized Control Trials Genevieve Milesi 1 , Anna Rangan 1 and Sara Grafenauer 2,3, * 1 Nutrition and Dietetics Group, Sydney Nursing School, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Camperdown, NSW 2006, Australia; gmil2280@uni.sydney.edu.au (G.M.); anna.rangan@sydney.edu.au (A.R.) 2 Grains & Legumes Nutrition Council, Mount Street, North Sydney, NSW 2060, Australia 3 School of Medicine & Health, University of New South Wales, Randwick, NSW 2052, Australia * Correspondence: s.grafenauer@unsw.edu.au Abstract: Whole grain foods are rich in nutrients, dietary fibre, a range of antioxidants, and phyto- chemicals, and may have potential to act in an anti-inflammatory manner, which could help impact chronic disease risk. This systematic literature review aimed to examine the specific effects of whole grains on selected inflammatory markers from human clinical trials in adults. As per the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol, the online databases MEDLINE, Embase, Cochrane, CINAHL, and Scopus were searched from inception through to 31 August 2021. Random- ized control trials (RCTs) ≥ 4 weeks in duration, reporting ≥1 of the following: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were included. A total of 31 RCTs were included, of which 16 studies recruited overweight/obese individuals, 12 had pre-existing conditions, two were in a healthy population, and one study included participants with prostate cancer. Of these 31 RCTs, three included studies with two intervention arms. A total of 32 individual studies measured CRP (10/32 were significant), 18 individual studies measured IL-6 (2/18 were significant), and 13 individual studies measured TNF (5/13 were significant). Most often, the overweight/obese population and those with pre-existing conditions showed significant reductions in inflammatory markers, mainly CRP (34% of studies). Overall, consumption of whole grain foods had a significant effect in reducing at least one inflammatory marker as demonstrated in 12/31 RCTs. Keywords: whole grain; refined grain; inflammation; inflammatory markers; C-reactive protein; tumor necrosis factor; interlukin-6 1. Introduction Whole grains are defined by Food Standards Australia and New Zealand (FSANZ), to be ‘ ... intact, dehulled, ground, cracked or flaked grains where the components– endosperm, germ and bran are present in substantially the same proportions as they exist in the intact grain’ and includes wholemeal [1]. More recently, a consensus definition of whole grain as a food and as an ingredient was published with the aim of assisting in nutri- tion education and food labeling, but this also provides useful guidance for research [2]. Foods containing whole grains are both higher in nutrients and dietary fiber, as compared to refined grain alternatives, and in observational studies, diets higher in whole grains positively impact chronic disease, such as type 2 diabetes mellitus [3], cardiovascular dis- ease (CVD) [4], certain cancers [4] including colorectal cancer [5–8], and other influencing risk factors, such as weight [9], and markers for CVD, such as triglyceride and choles- terol levels [10]. In addition, the nutrient bundle within whole grains contains potential anti-inflammatory properties, which is of importance as elevated levels of inflammatory biomarkers are linked to an increase in chronic disease risk [2,3]. The benefits of whole grain foods, including pseudo grains, quinoa, buckwheat, and amaranth, have been known for several decades, and included in the Australian Dietary Guidelines since 1979 [11]. Nutrients 2022, 14, 374. https://doi.org/10.3390/nu14020374 https://www.mdpi.com/journal/nutrients