Association of gut microbiota and inflammatory markers in obese patients with type 2 diabetes mellitus: post hoc analysis of a synbiotic interventional study.

Bioscience of Microbiota, Food and Health Vol. 41 (3), 103–111, 2022 Full Paper Association of gut microbiota and inflammatory markers in obese patients with type 2 diabetes mellitus: post hoc analysis of a synbiotic interventional study Yukiko SUGAWARA1, Akio KANAZAWA1*, Masanori AIDA5, Yasuto YOSHIDA5, Yuichiro YAMASHIRO6 and Hirotaka WATADA1-4 1Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan 2Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan 3Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan 4Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan 5Food Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan 6Probiotics Research Laboratory, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Received December 2, 2021; Accepted January 26, 2022; Published online in J-STAGE February 16, 2022 Chronic inflammation caused by gut dysbiosis is associated with the pathophysiology of metabolic disease. Synbiotics are useful for ameliorating gut dysbiosis; however, it remains unclear what types of bacteria act as key markers for synbiotic-driven improvement of chronic inflammation. Here, we performed a post hoc analysis of a 24-week randomized controlled study using synbiotics to investigate the association between gut microbiota and inflammatory markers. We characterized the responders who showed lower interleukin-6 (IL-6) levels in response to synbiotic supplementation among 86 obese patients with type 2 diabetes mellitus. In our baseline analysis, the relative abundances of Bifidobacterium adolescentis and Alistipes onderdonkii correlated positively with IL-6, lipopolysaccharide binding protein (LBP), and high-sensitivity C-reactive protein (Hs-CRP) levels. The relative abundance of Eubacterium rectale correlated positively with LBP and Hs-CRP levels, and that of Bacteroides thetaiotaomicron correlated positively with LBP levels. Based on our responder analysis, patients with higher body mass indices (over 30 kg/m2 on average), low abundances of Bacteroides caccae and Parabacteroides merdae at baseline and 24 weeks, and minimal changes in the relative abundance of E. rectale and Shannon index from baseline showed decreased IL-6 levels compared with baseline. However, glycemic control in responders was unchanged. In conclusion, we identified four bacterial species (B. adolescentis, A. onderdonkii, E. rectale, and B. thetaiotaomicron) related to chronic inflammation and predictive markers (B. caccae, P. merdae, and severity of obesity) in responders to synbiotic supplementation among obese patients with type 2 diabetes. Key words: diabetes mellitus, chronic inflammation, gut microbiota, synbiotic, obesity INTRODUCTION Type 2 diabetes mellitus (T2DM) is a complex metabolic disease. Multiple factors, including genetics, lifestyle, diet, and aging, contribute to either the onset or progression of this disease, if not both [1]. Among these factors, diet is an important environmental factor affecting the gut microbiota, and dietinduced changes in microbial composition are involved in human physiology and disease processes [2]. We previously demonstrated that obese patients with T2DM had chronic inflammatory states accompanied by gut dysbiosis and bacterial translocation [3]. Therefore, the gut microbiota is a new therapeutic target for treating chronic inflammation in T2DM. To date, probiotics, prebiotics, and synbiotics (the combination of one or more probiotics and prebiotics) have been reported to be useful for inhibiting bacterial translocation [4] and improving the *Corresponding author. Akio Kanazawa (E-mail: ) (Supplementary materials: refer to PMC https://www.ncbi.nlm.nih.gov/pmc/journals/2480/) ©2022 BMFH Press This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.org/licenses/by-nc-nd/4.0/) doi: 10.12938/bmfh.2021-081 104 Y. Sugawara, et al. intestinal environment in metabolic disease [5] and other diseases [6]. Therefore, we previously performed a 24-week randomized controlled study to investigate the effects of daily intake of a synbiotic comprising Lacticaseibacillus paracasei (previously known as Lactobacillus casei) strain Shirota YIT 9029, Bifidobacterium breve strain Yakult YIT 12272, and galactooligosaccharides on chronic inflammation and gut microbiota in 86 obese patients with T2DM [7]. This synbiotic did not reduce plasma interleukin-6 (IL-6) levels as the primary outcome, although numerous bacterial species that showed significant changes in response to synbiotic supplementation were identified by using 16S rRNA amplicon gene analysis [7]. The presence of responders and non-responders to diet and probiotics in relation to cholesterol metabolism and insulin sensitivity has already been reported in obese individuals [8] and T2DM [9]. However, little is known about the clinical characteristics of responders with improvement of chronic inflammation in response to synbiotic supplementation among obese patients with T2DM. Therefore, it is important to identify clinical or microbial biomarkers for predicting responders to synbiotic supplementation in order to pave the way for personalized nutrition. Recently, the associations between specific bacterial species and inflammation have been reported in some diseases, such as inflammatory bowel diseases [10] and autoimmune diseases [11]. However, bacterial species relating to inflammatory markers, such as IL-6, high-sensitivity C-reactive protein (HsCRP), and lipopolysaccharide binding protein (LBP), have yet to be investigated in obese patients with T2DM. Based on this background information, we performed a post hoc analysis of a randomized controlled study using synbiotics to investigate gut microbiota related to chronic inflammation. We also sought to identify clinical and microbial markers among responders to synbiotic supplementation in obese patients with T2DM. MATERIALS AND METHODS Study participants In this post hoc analysis, inclusion and exclusion criteria were applied as previously described [7]. Briefly, the main inclusion criteria were 1) age ≥30 but <80 years, 2) HbA1c (National Glycohemoglobin Standardization Program, NGSP) ≥6.0 but <9.0%, and 3) body mass index (BMI) ≥25.0 kg/m2. The exclusion criteria were 1) serious kidney disease (serum creatinine level ≥1.5 mg/dL and/or hemodialysis), 2) serious liver disease excluding fatty liver, and 3) inflammatory bowel disease. A total of 86 patients with T2DM who met the requirements of the above in (...truncated)