Gut microbiota-derived metabolites are novel targets for improving insulin resistance

TO THE EDITOR

We read with interest the recent publication by Jang and Lee[1] on the relationship of mechanisms linking the gut microbiota-derived metabolites to insulin resistance published in this journal.

如表1所示，從字符來看（見表1），特朗普政府的《報告》提及中國的次數最多，中國（China）在高頻詞排序中占位也最為靠前。與之前《報告》不同的是，中國在報告中被提及33次，并被定義為美國利益的“競爭對手”（competitor）和“修正主義者”（revisionist）。在所占總字符比方面，小布什政府《報告》的涉華比重最大，但是高頻詞排序占位卻位居第二，說明2002年的《報告》對外部實體表述較多，但是中國在外部實體中并沒有占首要地位。綜上所述，特朗普政府《報告》最重視中國在美國國家安全戰略中的地位及其所扮演的角色。

數據以統計學軟件SPSS18.0分析,以(±s)表示計量資料,經t檢驗;以率(%)表示計數資料,經檢驗,P<0.05為差異有統計學意義。

The gut microbiota plays a key role in metabolic diseases. Gut-microbiota-derived metabolites are found in different dietary sources, including: Carbohydrate (acetate, propionate, butyrate, and succinate); protein (hydrogen sulfide, indole, and phenylacetic acid); and lipids (resveratrol-, ferulic acid-, linoleic acid-, cathecin- and berry-derived metabolites). Insulin signaling pathways are directly targeted by these metabolites. Therefore, gut-microbiota-derived metabolites, in particular, the shortchain fatty acids (SCFAs), increase glucose uptake and lipid oxidation in skeletal muscle, whereas in the liver, SCFAs decrease lipogenesis and gluconeogenesis, increasing the lipid oxidation through activation of phosphatidylinositol 3-kinase - serine/threonine-protein kinase B (PI3K-AKT-PKB) and AMP-activated protein kinase. In adipose tissue, SCFAs stimulate adipogenesis and thermogenesis, inhibit lipolysis, and attenuate inflammation. Therefore, an increase in energy expenditure and fat oxidation occurs in the whole body. Collectively, these findings pave the way for the development of novel drugs or for investigation of the therapeutic potential of drugs currently used to treat insulin resistance, targeting the gut-microbiota-derived metabolites.

Notably, preclinical models and clinical studies substantiate the interaction between intestinal microbiota and the pathophysiology of insulin resistance in type 2 diabetes mellitus (DM)[2-4].

1984年，我把幾經省內外好幾家刊物退稿終于下決心重寫的《驚濤》交付《人民文學》，發表時他們加了整頁面篇幅的《編者按》，文字滾燙，激情洋溢。而溢于言表的，是扶持作者的拳拳之心、款款深情。我至今不知道這些文字出于誰人之手，我能感到的是那雙手的有力一握。即便是像《廬山瀑布云》這樣發在地方刊物的小短篇，已經退休的老主編崔道怡也趕緊推薦給了《新華文摘》。涂光群在將近三十年后還把我自己幾乎忘記的《唱歌吧樺樹林》收進他主編的小說集。

Therefore, this current article provides an overview of the important role of the specific microbiota-derived compounds in insulin-responsive tissues, acting as risk factors or protectors for the development of insulin resistance, and highlights the biologic implications of the muscle-liver-adipose tissue axis interaction.

20世紀六七十年代，文化大革命時期，全國大部分印刷企業處于停產歇業狀態，中科印刷卻依然在堅持生產。這一時期，中科院的主要科研成果——陳景潤的哥德巴赫猜想、人工合成胰島素等內容的排版印刷都在中科印刷完成。中科印刷在這一時期，發揮了舉足輕重的作用。

As we learn more about gut-microbiota-derived metabolites, we will better understand how to target these metabolites. Thus, acetate, which is involved in host energy, substrate metabolism, and appetite

secretion of the gut hormones [glucagon-like peptide (GLP) and peptide YY], may be increased by oral acetate administration (vinegar intake), colonic acetate infusions, acetogenic fibers and acetogenic probiotic administration[13]. These strategies may both decrease wholebody lipolysis and systemic proinflammatory cytokine levels, and increase energy expenditure, insulin sensitivity, and fat oxidation, which contributes to weight control and glucose homeostasis. Probiotics (live microorganisms) act as microbiome modulators and confer a health benefit, as demonstrated by the capacity of selected probiotic strains (lactobacilli and enterococci) to increase SCFA production; in particular, propionate and butyrate[14]. As reviewed elsewhere, probiotic administration (

,

, or the formula VSL#3) in preclinical models of obesity led to an increase in the intestinal barrier function, a reduction in the endotoxemia, acceleration in metabolism, and suppression of body weight gain and insulin resistance

modulation of the gut microbiota composition and SCFA production[15]. Probiotics may also ameliorate glucose homeostasis and lipid profile in diabetic mice[15].

Furthermore, hydrogen sulfide (H

S) and the role of sulfur-reducing bacteria from the intestinal microbiota have gained insights into the physiological implications of host glycemic control[9]. Thus, H

S metabolite may protect against oxidative stress by restoring reduced glutathione (GSH) and scavenging of mitochondrial reactive oxygen species, inducing pro-survival/angiogenesis signaling pathway (STAT3, signal transducer and activator of transcription 3), and promoting immunomodulation (inhibition/activation of nuclear factor-κB) and vasodilation (activation of K

ion channel)[10]. However, the balance between therapeutic and harmful effects of H

S should be considered when targeting that metabolite, as H

S either endogenous or exogenous, as well as that produced by the gut microbiota, promotes or inhibits a variety of characteristics in mucosal microbiota biofilms[11]. Depending on H

S concentration, in particular, when the gut microbiota produces an excessive amount, it may cause mucus disruption and inflammation in the colon and contribute to cancer. Conversely, low levels of H

S directly stabilize mucus layers, prevent fragmentation and adherence of the microbiota biofilm to the epithelium, inhibit the release of invasive opportunistic pathogens or pathobionts, and prevent inflammation and tissue injury[11]. Moreover, H

S overproduction is a causative factor in the pathogenesis of βcell death in DM due to increased levels of reactive oxygen and nitrogen species, whereas its deficiency, as a result of increased H

S consumption by hyperglycemic cells, may lead to endothelial dysfunction, and kidney and heart diseases[12].

Importantly, succinate is a metabolite of the tricarboxylic acid cycle and is produced equally by microbiota and the host[5]. Although this metabolite contributes to improving glucose homeostasis through the activation of intestinal gluconeogenesis[6], in obese individuals, high levels of this circulating metabolite are documented[5]. Furthermore, the imbalance of higher relative abundance of succinate-producing bacteria (Prevotellaceae and Veillonellaceae) and lower relative abundance of succinate-consuming bacteria Odoribacteraceae and Clostridaceae) may promote an increase in succinate levels and, ultimately, impaired glucose metabolism. These authors also pointed out succinate as having a potential role in metabolic-associated cardiovascular disorders and obesity. Additionally, succinate acts as an immunogenic molecule, identified as damage-associated molecular patterns. This molecule is recognized by immune cells and stabilizes hypoxia-inducible factor-1α through its Gprotein coupled receptor (succinate receptor 1/SUCNR1 or GPR19), which leads to the proinflammatory differentiation of T lymphocytes, and production of cytokines through interaction with Toll-like receptor ligands in dendritic cells[7,8]. Collectively, these findings may promote an enhancement of insulin resistance and DM burden.

Even though the authors documented the potential role of some bacterial metabolites as regulators of metabolic functions in the body, such as SCFAs derived from carbohydrates (propionate, butyrate and acetate), and the protein- and lipidderived metabolites, in modulating pathways of insulin signaling, the impact of these bacterial metabolites on host metabolism warrants further investigation.

Pharmacological interventions or xenobiotics may also have effects on gut microbiota. Metformin is the most frequently administered medication to treat patients with insulin resistance and type 2 DM. This drug may alter the gut microbiota composition through an increase in the Bacteroidetes and Verrucomicrobia phyla and the mucin-degrading

,

, and

genera, as well as in butyrate and propionate production, emphasizing maintenance of the integrity of the intestinal barrier, regulation of bile acid metabolism and improvement in glucose homeostasis[18,19]. Importantly, metformin may have these benefits in newly diagnosed DM[20].

From a clinical point of view, obese children treated with the probiotic

shirota for 6 mo presented with loss of weight, improved lipid metabolism, and an increase in the number of

spp. and acetate concentration in the feces[16]. Likewise, patients with type 2 DM treated with probiotics containing

La-5 and

subsp. lactis BB-12 for 6 wk had improved glucose and lipid profiles, which were associated with lower levels of systemic inflammation and increased concentration of acetate[17]. Additionally, modification of gut microbiota by dietary weight loss intervention decreased circulating succinate levels and improved the metabolic profile in a cohort of individuals with type 2 DM and obesity[6].

Sodium-glucose cotransporter 2 inhibitors represent the most recently approved class of oral medications for the treatment of type 2 DM. Dapagliflozin decreased the Firmicutes-to-Bacteriodetes ratio in diabetic mice, which was correlated with improvement in vascular function[21]. In a rodent model of type 1 DM, inhibition of SGLT2 reduced the intermediate metabolite succinate and increased butyrate levels, as well as decreased norepinephrine content in the kidney[22]. Hence, the impact of SGLT2 inhibitors on the gut microbiota is an area of active research.

Likewise, GLP-1 agonists reduced the abundance of the species of the Firmicutes phylum (Lachnospiraceae and Clostridiales) and increased the abundance of the species representing the Proteobacteria (

YL45) and Verrucomicrobia (

), as well as Firmicutes (Clostridiales and Oscillospiraceae) phyla in obese mice[23]. In particular, body weight loss was associated with increased abundance of

, a mucin-degrading SCFA-producing species, whose abundance is decreased in obesity and has a negative correlation with markers of gut permeability and inflammation. Notably, the GLP-1 agonist liraglutide can prevent weight gain by modulating gut microbiota composition in both obese and diabetic obese animals[24].

In the cardiometabolic disease setting, lipid-lowering drugs, such as statins, may also play an important role in modulating gut microbiota.

studies have documented increased levels of SCFA production, including propionate, butyrate and acetate[25]. These drugs may increase the abundance of the

,

and

genera

which is associated with a decrease in the inflammatory response, including lower levels of interleukin (IL)-1β and IL-6, and higher levels of transforming growth factor β-1 in the ileum, and improved hyperglycemia[26]. In humans, obesity is associated with a microbiota signature based on the abundance of the

genus profile, displaying the lowest abundances of

and

, as well as a decrease in the butyrate production potential[27]. Importantly, statin therapy resulted in a lower prevalence of a proinflammatory microbial community type in obese individuals.

In conclusion, the gut microbiota imbalances and maladaptive responses have been implicated in the pathology of insulin resistance, DM, and obesity[28]. Host-gut microbiota interaction is suggested to play a contributory role in the therapeutic effects of antidiabetics, statins, and weight-loss-promoting drugs. Therefore, additional studies combining untargeted metabolomics and proteomics are essential to identify further microbial metabolites or proteins and to determine how they interact with the host targets in improving host metabolism.

1 Jang HR, Lee HY. Mechanisms linking gut microbial metabolites to insulin resistance.

2021; 12: 730-744 [PMID: 34168724 DOI: 10.4239/wjd.v12.i6.730]

2 Wang H, Lu Y, Yan Y, Tian S, Zheng D, Leng D, Wang C, Jiao J, Wang Z, Bai Y. Promising Treatment for Type 2 Diabetes: Fecal Microbiota Transplantation Reverses Insulin Resistance and Impaired Islets.

2019; 9: 455 [PMID: 32010641 DOI: 10.3389/fcimb.2019.00455]

3 Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K. A metagenome-wide association study of gut microbiota in type 2 diabetes.

2012; 490: 55-60 [PMID: 23023125 DOI: 10.1038/nature11450]

4 Karlsson FH, Tremaroli V, Nookaew I, Bergstr?m G, Behre CJ, Fagerberg B, Nielsen J, B?ckhed F. Gut metagenome in European women with normal, impaired and diabetic glucose control.

2013; 498: 99-103 [PMID: 23719380 DOI: 10.1038/nature12198]

5 Serena C, Ceperuelo-Mallafré V, Keiran N, Queipo-Ortu?o MI, Bernal R, Gomez-Huelgas R, Urpi-Sarda M, Sabater M, Pérez-Brocal V, Andrés-Lacueva C, Moya A, Tinahones FJ, Fernández-Real JM, Vendrell J, Fernández-Veledo S. Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota.

2018; 12: 1642-1657 [PMID: 29434314 DOI: 10.1038/s41396-018-0068-2]

6 De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, B?ckhed F, Mithieux G. Microbiota-Produced Succinate Improves Glucose Homeostasis

Intestinal Gluconeogenesis.

2016; 24: 151-157 [PMID: 27411015 DOI: 10.1016/j.cmet.2016.06.013]

7 Garcia-Martinez I, Shaker ME, Mehal WZ. Therapeutic Opportunities in Damage-Associated Molecular Pattern-Driven Metabolic Diseases.

2015; 23: 1305-1315 [PMID: 26055926 DOI: 10.1089/ars.2015.6383]

8 Rodríguez-Nuevo A, Zorzano A. The sensing of mitochondrial DAMPs by non-immune cells.

2019; 3: 195-207 [PMID: 31225514 DOI: 10.15698/cst2019.06.190]

9 Pichette J, Fynn-Sackey N, Gagnon J. Hydrogen Sulfide and Sulfate Prebiotic Stimulates the Secretion of GLP-1 and Improves Glycemia in Male Mice.

2017; 158: 3416-3425 [PMID: 28977605 DOI: 10.1210/en.2017-00391]

10 Pal VK, Bandyopadhyay P, Singh A. Hydrogen sulfide in physiology and pathogenesis of bacteria and viruses.

2018; 70: 393-410 [PMID: 29601123 DOI: 10.1002/iub.1740]

11 Buret AG, Allain T, Motta JP, Wallace JL. Effects of Hydrogen Sulfide on the Microbiome: From Toxicity to Therapy.

2021 [PMID: 33691464 DOI: 10.1089/ars.2021.0004]

12 Szabo C. Roles of hydrogen sulfide in the pathogenesis of diabetes mellitus and its complications.

2012; 17: 68-80 [PMID: 22149162 DOI: 10.1089/ars.2011.4451]

13 Hernández MAG, Canfora EE, Jocken JWE, Blaak EE. The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity.

2019; 11 [PMID: 31426593 DOI: 10.3390/nu11081943]

14 Nagpal R, Wang S, Ahmadi S, Hayes J, Gagliano J, Subashchandrabose S, Kitzman DW, Becton T, Read R, Yadav H. Human-origin probiotic cocktail increases short-chain fatty acid production

modulation of mice and human gut microbiome.

2018; 8: 12649 [PMID: 30139941 DOI: 10.1038/s41598-018-30114-4]

15 Markowiak-Kope? P, ?li?ewska K. The Effect of Probiotics on the Production of Short-Chain Fatty Acids by Human Intestinal Microbiome.

2020; 12 [PMID: 32316181 DOI: 10.3390/nu12041107]

16 Nagata S, Chiba Y, Wang C, Yamashiro Y. The effects of the Lactobacillus casei strain on obesity in children: a pilot study.

2017; 8: 535-543 [PMID: 28618860 DOI: 10.3920/BM2016.0170]

17 Tonucci LB, Olbrich Dos Santos KM, Licursi de Oliveira L, Rocha Ribeiro SM, Duarte Martino HS. Clinical application of probiotics in type 2 diabetes mellitus: A randomized, double-blind, placebocontrolled study.

2017; 36: 85-92 [PMID: 26732026 DOI: 10.1016/j.clnu.2015.11.011]

18 Vallianou NG, Stratigou T, Tsagarakis S. Metformin and gut microbiota: their interactions and their impact on diabetes.

2019; 18: 141-144 [PMID: 30719628 DOI: 10.1007/s42000-019-00093-w]

19 Zhang Q, Hu N. Effects of Metformin on the Gut Microbiota in Obesity and Type 2 Diabetes Mellitus.

2020; 13: 5003-5014 [PMID: 33364804 DOI: 10.2147/DMSO.S286430]

20 Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Manner?s-Holm L, St?hlman M, Olsson LM, Serino M, Planas-Fèlix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernàndez-Real JM, B?ckhed F. Metformin alters the gut microbiome of individuals with treatmentnaive type 2 diabetes, contributing to the therapeutic effects of the drug.

2017; 23: 850-858 [PMID: 28530702 DOI: 10.1038/nm.4345]

21 Lee DM, Battson ML, Jarrell DK, Hou S, Ecton KE, Weir TL, Gentile CL. SGLT2 inhibition

dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice.

2018; 17: 62 [PMID: 29703207 DOI: 10.1186/s12933-018-0708-x]

22 Herat LY, Ward NC, Magno AL, Rakoczy EP, Kiuchi MG, Schlaich MP, Matthews VB. Sodium glucose co-transporter 2 inhibition reduces succinate levels in diabetic mice.

2020; 26: 3225-3235 [PMID: 32684737 DOI: 10.3748/wjg.v26.i23.3225]

23 Madsen MSA, Holm JB, Pallejà A, Wismann P, Fabricius K, Rigbolt K, Mikkelsen M, Sommer M, Jelsing J, Nielsen HB, Vrang N, Hansen HH. Metabolic and gut microbiome changes following GLP-1 or dual GLP-1/GLP-2 receptor agonist treatment in diet-induced obese mice.

2019; 9: 15582 [PMID: 31666597 DOI: 10.1038/s41598-019-52103-x]

24 Zhao L, Chen Y, Xia F, Abudukerimu B, Zhang W, Guo Y, Wang N, Lu Y. A Glucagon-Like Peptide-1 Receptor Agonist Lowers Weight by Modulating the Structure of Gut Microbiota.

2018; 9: 233 [PMID: 29867765 DOI: 10.3389/fendo.2018.00233]

25 Zhao C, Hu Y, Chen H, Li B, Cao L, Xia J, Yin Y. An

evaluation of the effects of different statins on the structure and function of human gut bacterial community.

2020; 15: e0230200 [PMID: 32214324 DOI: 10.1371/journal.pone.0230200]

26 Kim J, Lee H, An J, Song Y, Lee CK, Kim K, Kong H. Alterations in Gut Microbiota by Statin Therapy and Possible Intermediate Effects on Hyperglycemia and Hyperlipidemia.

2019; 10: 1947 [PMID: 31551944 DOI: 10.3389/fmicb.2019.01947]

27 Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, Forslund SK, Assmann K, Valles-Colomer M, Nguyen TTD, Proost S, Prifti E, Tremaroli V, Pons N, Le Chatelier E, Andreelli F, Bastard JP, Coelho LP, Galleron N, Hansen TH, Hulot JS, Lewinter C, Pedersen HK, Quinquis B, Rouault C, Roume H, Salem JE, S?ndertoft NB, Touch S; MetaCardis Consortium, Dumas ME, Ehrlich SD, Galan P, G?tze JP, Hansen T, Holst JJ, K?ber L, Letunic I, Nielsen J, Oppert JM, Stumvoll M, Vestergaard H, Zucker JD, Bork P, Pedersen O, B?ckhed F, Clément K, Raes J. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis.

2020; 581: 310-315 [PMID: 32433607 DOI: 10.1038/s41586-020-2269-x]

28 Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease.

2021; 19: 55-71 [PMID: 32887946 DOI: 10.1038/s41579-020-0433-9]