Gut microbiota-derived metabolites in obesity: a systematic review.

Bioscience of Microbiota, Food and Health Vol. 39 (3), 65–76, 2020 Review Gut microbiota-derived metabolites in obesity: a systematic review Hanieh-Sadat EJTAHED1, 2, Pooneh ANGOORANI1, Ahmad-Reza SOROUSH1, Shirin HASANI-RANJBAR1*, Seyed-Davar SIADAT2,3* and Bagher LARIJANI2 1Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, 5th Floor, Shariati Hospital, North Kargar Ave, 1411413137, Tehran, Iran 2Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 3Department of Mycobacteriology and Pulmonary Research, Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran Received September 5, 2019; Accepted January 21, 2020; Published online in J-STAGE February 13, 2020 Recent evidence suggests that gut microbiota-derived metabolites affect many biological processes of the host, including appetite control and weight management. Dysbiosis of the gut microbiome in obesity influences the metabolism and excretion of gut microbiota byproducts and consequently affects the physiology of the host. Since identification of the gut microbiota-host co-metabolites is essential for clarifying the interactions between the intestinal flora and the host, we conducted this systematic review to summarize all human studies that characterized the gut microbiota-related metabolites in overweight and obese individuals. A comprehensive search of the PubMed, Web of Science, and Scopus databases yielded 2,137 articles documented up to July 2018. After screening abstracts and full texts, 12 articles that used different biosamples and methodologies of metabolic profiling and fecal microbiota analysis were included. Amino acids and byproducts of amino acids, lipids and lipid-like metabolites, bile acids derivatives, and other metabolites derived from degradation of carnitine, choline, polyphenols, and purines are among the gut microbiota-derived metabolites which showed alterations in obesity. These metabolites play an important role in metabolic complications of obesity, including insulin resistance, hyperglycemia, and dyslipidemia. The results of this study could be useful in development of therapeutic strategies with the aim of modulating gut microbiota and consequently the metabolic profile in obesity. Key words: obesity, gut microbiota, dysbiosis, metabolites, metabolic profile INTRODUCTION Obesity is a global epidemic disorder with a multifaceted etiology, including genetics and environmental factors [1]. The gut microbiota, the microbial community inhabiting the intestine, has been recently implicated as an important environmental factor in obesity and its related metabolic disorders [2–4]. The most abundant phyla of the human gut microbiota are Firmicutes and Bacteroidetes, the ratio of which is strongly associated with obesity [2]. It has been shown that the Bacteroidetes to Firmicutes ratio decreases in obesity but increases after weight loss following gastric bypass or calorie restriction [5]. However, some studies have reported inconsistent findings, and these differences should be investigated in lower taxonomic ranks [6, 7]. The gut microbiota is considered to be an endocrine organ because of its comprehensive metabolic ability and its extensive genes that influence the host [8]. Recent studies indicate that the obesity-related intestinal microbiota leads to alterations in some circulating metabolites and are associated with fasting levels of some metabolites, such as amino acids, fatty acids, lipids, and glucose [9, 10]. The gut microbiota releases metabolites which can be passed through the intestinal barrier and eventually biotransformed by the host [11]. Metabolomics, the systematic study of low-molecular-weight molecules produced in biochemical pathways, is a strong method for recognition of the crosstalk between the gut microbiota and host metabolism [12]. Gut microbial species are the origin of key features of the serum metabolite profile associated with metabolic disorders, including obesity, insulin resistance, and cardiovascular diseases [9, 13]. The process used in metabolomics surveys is classified into five major phases: sample collection, sample preparation, data acquisition, data analysis, and biological interpretation of the *Corresponding authors. Shirin Hasani-Ranjbar (E-mail: ); Seyed-Davar Siadat (E-mail: ) *Equally contributed as Corresponding authors. ©2020 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.2019-026 66 H.-S. Ejtahed, et al. findings [14]. There are many targeted and untargeted metabolites profiling techniques capable of quantifying polar metabolites and molecular lipids present in biological samples, such as blood, urine and feces [15]. The most prevalent analytical techniques applied for the determination of the metabolic profile of a biological sample are liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) [16]. Specific metabolites are strongly associated with gut microbial community structure, and some of these correlations are specific to the overweight or obesity state [17, 18]. Therefore, we performed this systematic review to summarize all human studies that characterized the gut microbiota-related metabolites in overweight and obese individuals or focused on correlations between metabolites and gut microbiota in obesity. METHODS Search strategy and study selection PubMed, Web of Science, and Scopus databases were searched for all human studies focused on the gut bacteriarelated metabolites in obesity. The search was restricted to English language studies with no restriction regarding publication date up to July 2018. The search terms included the following: Metabolom*, metabonom*, metabolite*, “metabolic profiling”, “metabolic profile” AND “gut microbiota”, “intestinal microbiota”, “faecal microbiota”, “gut microbiome”, “intestinal microbiome”, “faecal microbiome”, “gut microbial profile”, “faecal microbial profile”, “gut flora” AND obesity, overweight, obese, adiposity. Two researchers independently screened titles, abstracts, and then full-text articles to lessen selection bias. Disagreements between the two researchers were resolved by discussing until reaching consensus. Moreover, other relevant references in the selected articles were also reviewed. Targeted and untargeted metabolomics approaches were both included in the selection strategy. Low-molecular-weight (<1,000 Da) metabolites related to gut microbiota which were significantly up- or downregulated in overweight and obese individuals compared with lean, healthy control subjects were the primary outco (...truncated)