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万字强文：深度剖析益生菌与肥胖（上）
这是《肠道产业》第 160 篇文章
编者按：
肥胖作为一种慢性代谢性疾病，从多方面影响着人们的健康，还可以导致多种其它代谢性疾病的发展。目前由于人们生活、饮食习惯的变化，在当代，肥胖患者越来越多。
发现益生菌或对人体健康有一些作用，那么它对于肥胖的预防或者治疗有没有什么帮助呢？
我们特别编译了发表在 Microorganisms 上关于益生菌与肥胖的综述，以详细解答这个问题，阐述益生菌-肠道-肥胖三者之间的关系。
本文将分为上下 2 篇，今天为上半部分，以下是上半部分的编译：
摘要：
肥胖及由肥胖所引起的健康风险在现代社会中越来越受到重视。引起肥胖的主要因素有：过量的食物摄取、久坐的生活习惯、高糖和高脂的饮食习惯及遗传因素等。
本综述汇总了肠道微生物用于干预宿主代谢的最新进展，评估了肠道微生物影响宿主代谢的一些重要的分子机制，比如胆盐代谢、短链脂肪酸代谢和代谢性内毒素血症。
之前的一些研究发现了微生物与包括肥胖在内的几种疾病之间的联系。因此，本综述聚焦于肠道微生物和肥胖间的相互影响以及其影响肥胖的机制机理。
特别的，本综述重点在于介绍一些饮食代替的治疗方式，包括饮食变化和增加益生菌辅食。此外，有关粪菌移植、合生元和代谢组学等方法也在本文中有所涉及。（这在我们的下篇文章会有所详述）
关键词：肥胖；肠道微生物；益生菌；机制；饮食
正文：
简介：肥胖与微生物
肠道微生物的失调
肥胖代谢的机制研究
1. World Health Organization. Overweightand Obesity. Available online:http://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight(accessed on 25 September 2018).2. Van Baal, P.H.; Hoogenveen, R.T.; deWit, A.G.; Boshuizen, H.C. Estimating health-adjusted life expectancyconditional on risk factors: Results for smoking and obesity. Popul. HealthMetrics 2006, 4, 14. 3. Nascimento Ferreira, M.V.;Rendo-Urteaga, T.; De Moraes, A.C.; Moreno, L.A.; Carvalho, H.B. AbdominalObesity in Children: The Role of Physical Activity, Sedentary Behavior, andSleep Time. In Nutrition in the Prevention and Treatment of Abdominal Obesity;Academic Press: Cambridge, MA, USA, 2019; pp. 81–94. [Google Scholar]4. FAO; WHO. Guidelines for the Evaluationof Probiotics in Foods. Report of a Joint FAO/WHO Working Group on DraftingGuidelines for the Evaluation of Probiotics in Food; FAO: Rome, Italy; WHO:Geneva, Switzerland, 2002. [Google Scholar]5. Rajilić-Stojanović, M.; De Vos, W.M. Thefirst 1000 cultured species of the human gastrointestinal microbiota. FEMSMicrobiol. Rev. 2014, 38, 996–1047. 6. Blandino, G.; Inturri, R.; Lazzara, F.;Di Rosa, M.; Malaguarnera, L. Impact of gut microbiota on diabetes mellitus.Diabetes Metab. 2016, 42, 303–315. 7. Gill, H.; Prasad, J. Probiotics,immunomodulation, and health benefits. Adv. Exp. Med. Biol. 2008, 206, 423–454.[Google Scholar]8. Ashraf, R.; Shah, N.P. Immune SystemStimulation by Probiotic Microorganisms. Crit. Rev. Food Sci. Nutr. 2014, 54,938–956.9. Kang, J.-H.; Yun, S.-I.; Park, M.-H.;Park, J.-H.; Jeong, S.-Y.; Park, H.-O. Anti-Obesity Effect of Lactobacillusgasseri BNR17 in High-Sucrose Diet-Induced Obese Mice. PLoS ONE 2013, 8,e54617.10. Park, Y.H.; Kim, J.G.; Shin, Y.W.; Kim,H.S.; Kim, Y.-J.; Chun, T.; Kim, S.H.; Whang, K.Y. Effects of Lactobacillusacidophilus 43121 and a mixture of Lactobacillus casei and Bifidobacteriumlongum on the serum cholesterol level and fecal sterol excretion inhypercholesterolemia-induced pigs. Biosci. Biotechnol. Biochem. 2008, 72,595–600.11. Sharma, P.; Bhardwaj, P.; Singh, R.Administration of Lactobacillus casei and Bifidobacterium bifidum AmelioratedHyperglycemia, Dyslipidemia, and Oxidative Stress in Diabetic Rats. Int. J.Prev. Med. 2016, 7, 102. [Google Scholar]12. So, J.-S.; Kwon, H.-K.; Lee, C.-G.; Yi,H.-J.; Park, J.-A.; Lim, S.-Y.; Hwang, K.-C.; Jeon, Y.H.; Im, S.-H.Lactobacillus casei suppresses experimental arthritis by down-regulating Thelper 1 effector functions. Mol. Immunol. 2008, 45, 2690–2699.13. Larsen, N.; Vogensen, F.K.; Berg,F.W.J.V.D.; Nielsen, D.S.; Andreasen, A.S.; Pedersen, B.K.; Abu Al-Soud, W.;Sørensen, S.J.; Hansen, L.H.; Jakobsen, M. Gut Microbiota in Human Adults withType 2 Diabetes Differs from Non-Diabetic Adults. PLoS ONE 2010, 5, e9085.14. Kong, Y.; He, M.; McAlister, T.;Seviour, R.; Forster, R. Quantitative Fluorescence In Situ Hybridization ofMicrobial Communities in the Rumens of Cattle Fed Different Diets. Appl.Environ. Microbiol. 2010, 76, 6933–6938. 15. Barrett, E.; Ross, R.; O’Toole, P.;Fitzgerald, G.; Stanton, C. γ-Aminobutyric acid production by culturablebacteria from the human intestine. J. Appl. Microbiol. 2012, 113, 411–417. 16. Khalili, L.; Alipour, B.; Jafar-Abadi,M.A.; Faraji, I.; Hassanalilou, T.; Abbasi, M.M.; Vaghef-Mehrabany, E.; Sani,M.A. The Effects of Lactobacillus casei on Glycemic Response, Serum Sirtuin1and Fetuin-A Levels in Patients with Type 2 Diabetes Mellitus: A RandomizedControlled Trial. Iran. Biomed. J. 2019, 23, 68–77. 17. Sabico, S.; Al-Mashharawi, A.;Al-Daghri, N.M.; Wani, K.; Amer, O.E.; Hussain, D.S.; Ansari, M.G.; Masoud,M.S.; Alokail, M.S.; McTernan, P.G. Effects of a 6-month multi-strain probioticssupplementation in endotoxemic, inflammatory and cardiometabolic status of T2DMpatients: A randomized, double-blind, placebo-controlled trial. Clin. Nutr.2018, 38, 1563–1569.18. Hu, C.; Wong, F.S.; Wen, L. Type 1diabetes and gut microbiota: Friend or foe? Pharmacol. Res. 2015, 98, 9–15.19. Ljungberg, M.; Korpela, R.; Ilonen, J.;Ludvigsson, J.; Vaarala, O. Probiotics for the Prevention of Beta CellAutoimmunity in Children at Genetic Risk of Type 1 Diabetes—The PRODIA Study.Ann. N. Y. Acad. Sci. 2006, 1079, 360–364.20. Hartstra, A.V.; Bouter, K.E.; Bäckhed,F.; Nieuwdorp, M. Insights into the role of the microbiome in obesity and type2 diabetes. Diabetes Care 2015, 38, 159–165.21. Grover, S.; Rashmi, H.M.; Srivastava,A.K.; Batish, V.K. Probiotics for human health—New innovations and emergingtrends. Gut Pathog. 2012, 4, 15.22. Szulinska, M.; Łoniewski, I.; VanHemert, S.; Sobieska, M.; Bogdański, P. Dose-Dependent Effects of MultispeciesProbiotic Supplementation on the Lipopolysaccharide (LPS) Level andCardiometabolic Profile in Obese Postmenopausal Women: A 12-Week RandomizedClinical Trial. Nutrients 2018, 10, 773.23. Chan, P.A.; Robinette, A.; Montgomery,M.; Almonte, A.; Cu-Uvin, S.; Lonks, J.R.; Chapin, K.C.; Kojic, E.M.; Hardy,E.J. Extragenital Infections Caused by Chlamydia trachomatis and Neisseriagonorrhoeae: A Review of the Literature. Infect. Dis. Obstet. Gynecol. 2016,2016, 1–17.24. Le Barz, M.; Anhê, F.F.; Varin, T.V.;Desjardins, Y.; Levy, E.; Roy, D.; Urdaci, M.C.; Marette, A. Probiotics asComplementary Treatment for Metabolic Disorders. Diabetes Metab. J. 2015, 39,291–303. 25. International Diabetes Federation. IDFDiabetes Atlas; IDF: Watermael-Boitsfort, Belgium, 2017. Available online:http://www.diabetesatlas.org/resources/2017-atlas.html (accessed on 12 July2019).26. Kobyliak, N.; Conte, C.; Cammarota, G.;Haley, A.P.; Štyriak, I.; Gaspar, L.; Fusek, J.; Rodrigo, L.; Kruzliak, P.Probiotics in prevention and treatment of obesity: A critical view. Nutr. Metab.2016, 13, 14. 27. Barrett, H.L.; Callaway, L.K.; Nitert,M.D. Probiotics: A potential role in the prevention of gestational diabetes?Acta Diabetol. 2012, 49, 1–13. 28. Mishra, A.K.; Dubey, V.; Ghosh, A.R.;Information, P.E.K.F.C. Obesity: An overview of possible role(s) of guthormones, lipid sensing and gut microbiota. Metablism 2016, 65, 48–65. 29. Zhao, X.; Higashikawa, F.; Noda, M.;Kawamura, Y.; Matoba, Y.; Kumagai, T.; Sugiyama, M. The Obesity and Fatty LiverAre Reduced by Plant-Derived Pediococcus pentosaceus LP28 in High FatDiet-Induced Obese Mice. PLoS ONE 2012, 7, e30696.30. Park, S.-Y.; Cho, S.-A.; Lee, M.-K.;Lim, S.-D. Effect of Lactobacillus plantarum FH185 on the Reduction ofAdipocyte Size and Gut Microbial Changes in Mice with Diet-induced Obesity.Food Sci. Anim. Resour. 2015, 35, 171–178.31. Park, S.; Ji, Y.; Jung, H.Y.; Park, H.;Kang, J.; Choi, S.H.; Shin, H.; Hyun, C.K.; Kim, K.T.; Holzapfel, W.H.Lactobacillus plantarum HAC01 regulates gut microbiota and adipose tissueaccumulation in a diet-induced obesity murine model. Appl. Microbiol.Biotechnol. 2017, 101, 1605–1614.32. Wu, C.-C.; Weng, W.-L.; Lai, W.-L.;Tsai, H.-P.; Liu, W.-H.; Lee, M.-H.; Tsai, Y.-C. Effect of Lactobacillusplantarum Strain K21 on High-Fat Diet-Fed Obese Mice. Evid. Based Complement.Altern. Med. 2015, 2015, 1–9. [Google Scholar]33. Park, J.E.; Oh, S.H.; Cha, Y.S.Lactobacillus plantarum LG42 isolated from gajami sik-hae decreases body andfat pad weights in diet-induced obese mice. J. Appl. Microbiol. 2014, 116,145–156.34. Callaway, L.K.; McIntyre, H.D.;Barrett, H.L.; Foxcroft, K.; Tremellen, A.; Lingwood, B.E.; Tobin, J.M.;Wilkinson, S.; Kothari, A.; Morrison, M.; et al. Probiotics for the Preventionof Gestational Diabetes Mellitus in Overweight and Obese Women: Findings Fromthe SPRING Double-blind Randomized Controlled Trial. Diabetes Care 2019, 42,dc182248.35. Okesene-Gafa, K.A.M.; Li, M.; McKinlay,C.J.D.; Taylor, R.S.; Rush, E.C.; Wall, C.R.; Wilson, J.; Murphy, R.; Taylor,R.; Thompson, J.M.D.; et al. Effect of antenatal dietary interventions inmaternal obesity on pregnancy weight-gain and birthweight: Healthy Mums andBabies (HUMBA) randomized trial. Am. J. Obstet. Gynecol. 2019, 221, 1–13. 36. Krumbeck, J.A.; Rasmussen, H.E.;Hutkins, R.W.; Clarke, J.; Shawron, K.; Keshavarzian, A.; Walter, J. ProbioticBifidobacterium strains and galacto oligosaccharides improve intestinal barrierfunction in obese adults but show no synergism when used together assynbiotics. Microbiome 2018, 6, 121. 37. Kim, J.; Yun, J.M.; Kim, M.K.; Kwon,O.; Cho, B. Lactobacillus gasseri BNR17 Supplementation Reduces the VisceralFat Accumulation and Waist Circumference in Obese Adults: A Randomized,Double-Blind, Placebo-Controlled Trial. J. Med. Food 2018, 21, 454–461. 38. Minami, J.; Iwabuchi, N.; Tanaka, M.;Yamauchi, K.; Xiao, J.-Z.; Abe, F.; Sakane, N. Effects of Bifidobacterium breveB-3 on body fat reductions in pre-obese adults: A randomized, double-blind,placebo-controlled trial. Biosci. Microbiota Food Health 2018, 37, 67–75. 39. Ogawa, A.; Kadooka, Y.; Kato, K.;Shirouchi, B.; Sato, M. Lactobacillus gasseri SBT2055 reduces postprandial andfasting serum non-esterified fatty acid levels in Japanesehypertriacylglycerolemic subjects. Lipids Health Dis. 2014, 13, 36. 40. Dietrich, C.G.; Kottmann, T.; Alavi, M.Commercially available probiotic drinks containing Lactobacillus caseiDN-114001 reduce antibiotic-associated diarrhea. World J. Gastroenterol. 2014,20, 15837–15844. 41. Iqbal, M.Z.; Qadir, M.I.; Hussain, T.;Janbaz, K.H.; Khan, Y.H.; Ahmad, B. Review: Probiotics and their beneficialeffects against various diseases. Pak. J. Pharm. Sci. 2014, 27, 405–415.[Google Scholar]42. Slavin, J. Fiber and Prebiotics:Mechanisms and Health Benefits. Nutrients 2013, 5, 1417–1435.43. Bejar, W.; Hamden, K.; Ben Salah, R.;Chouayekh, H. Lactobacillus plantarum TN627 significantly reduces complicationsof alloxan-induced diabetes in rats. Anaerobe 2013, 24, 4–11.44. Sakai, T.; Taki, T.; Nakamoto, A.;Shuto, E.; Tsutsumi, R.; Toshimitsu, T.; Makino, S.; Ikegami, S. Lactobacillusplantarum OLL2712 regulates glucose metabolism in C57BL/6 mice fed a high-fatdiet. J. Nutr. Sci. Vitaminol. 2013, 59, 144–147.45. Yakovlieva, M.; Tacheva, T.; Mihaylova,S.; Tropcheva, R.; Trifonova, K.; Tolesmall ka, C.A.; Danova, S.; Vlaykova, T.Influence of Lactobacillus brevis 15 and Lactobacillus plantarum 13 on bloodglucose and body weight in rats after high-fructose diet. Benef. Microbes 2015,6, 505–512. 46. Huang, H.-Y.; Korivi, M.; Tsai, C.-H.;Yang, J.-H.; Tsai, Y.-C. Supplementation of Lactobacillus plantarum K68 andFruit-Vegetable Ferment along with High Fat-Fructose Diet Attenuates MetabolicSyndrome in Rats with Insulin Resistance. Evid. Based Complement. Altern. Med.2013, 2013, 1–12. [Google Scholar]47. Li, X.; Yin, B.; Fang, D.; Jiang, T.;Zhao, J.; Wang, N.; Fang, S.; Zhang, H.; Wang, G.; Chen, W. Effects ofLactobacillus plantarum CCFM0236 on hyperglycaemia and insulin resistance inhigh-fat and streptozotocin-induced type 2 diabetic mice. J. Appl. Microbiol.2016, 121, 1727–1736. 48. Zuo, T.; Ng, S.C. The Gut Microbiota inthe Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Front.Microbiol. 2018, 9, 2247. 49. Opazo, M.C.; Ortega-Rocha, E.M.;Coronado-Arrázola, I.; Bonifaz, L.C.; Boudin, H.; Neunlist, M.; Bueno, S.M.;Kalergis, A.M.; Riedel, C.A. Intestinal microbiota influences non-intestinalrelated autoimmune diseases. Front. Microbiol. 2018, 9, 432. 50. Jumpertz, R.; Le, D.S.; Turnbaugh,P.J.; Trinidad, C.; Bogardus, C.; Gordon, J.I.; Krakoff, J. Energy-balancestudies reveal associations between gut microbes, caloric load, and nutrientabsorption in humans. Am. J. Clin. Nutr. 2011, 94, 58–65. 51. Ignacio, A.; Fernandes, M.; Rodrigues,V.; Groppo, F.; Cardoso, A.; Avila-Campos, M.; Nakano, V.; Avila-Campos, M.Correlation between body mass index and faecal microbiota from children. Clin.Microbiol. Infect. 2016, 22, 1–8.52. Patil, D.P.; Dhotre, D.P.; Chavan,S.G.; Sultan, A.; Jain, D.S.; Lanjekar, V.B.; Gangawani, J.; Shah, P.S.;Todkar, J.S.; Shah, S.; et al. Molecular analysis of gut microbiota in obesityamong Indian individuals. J. Biosci. 2012, 37, 647–657.53. Zhang, H.; DiBaise, J.K.; Zuccolo, A.;Kudrna, D.; Braidotti, M.; Yu, Y.; Parameswaran, P.; Crowell, M.D.; Wing, R.;Rittmann, B.E.; et al. Human gut microbiota in obesity and after gastricbypass. Proc. Natl. Acad. Sci. USA 2009, 106, 2365–2370.54. Santacruz, A.; Collado, M.C.;García-Valdés, L.; Segura, M.T.; Martín-Lagos, J.A.; Anjos, T.; Martí-Romero,M.; Lopez, R.M.; Florido, J.; Campoy, C.; et al. Gut microbiota composition isassociated with body weight, weight gain and biochemical parameters in pregnantwomen. Br. J. Nutr. 2010, 104, 83–92.55. Allen, J.M.; Jaggers, R.M.; Solden,L.M.; Loman, B.R.; Davies, R.H.; Mackos, A.R.; Ladaika, C.A.; Berg, B.M.;Chichlowski, M.; Bailey, M.T. Dietary oligosaccharides attenuate stress-induceddisruptions in immune reactivity and microbial B-vitamin metabolism. FrontImmunol. 2019, 10, 1774.56. Fei, N.; Zhao, L. An opportunisticpathogen isolated from the gut of an obese human causes obesity in germfreemice. ISME J. 2013, 7, 880–884. 57. Bervoets, L.; Van Hoorenbeeck, K.;Kortleven, I.; Van Noten, C.; Hens, N.; Vael, C.; Goossens, H.; Desager, K.N.;Vankerckhoven, V. Differences in gut microbiota composition between obese andlean children: A cross-sectional study. Gut Pathog. 2013, 5, 10. 58. Duncan, S.H.; Belenguer, A.; Holtrop,G.; Johnstone, A.M.; Flint, H.J.; Lobley, G.E. Reduced dietary intake ofcarbohydrates by obese subjects results in decreased concentrations of butyrateand butyrate-producing bacteria in feces. Appl. Environ. Microbiol. 2007, 73,1073–1078. 59. Costa, F.R.; Françozo, M.C.; DeOliveira, G.G.; Ignacio, A.; Castoldi, A.; Zamboni, D.S.; Ramos, S.G.; Câmara,N.O.; De Zoete, M.R.; Palm, N.W.; et al. Gut microbiota translocation to thepancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset.J. Exp. Med. 2016, 213, 1223–1239.60. Murugesan, S.; Ulloa-Martínez, M.;Martinez-Rojano, H.; Galván-Rodríguez, F.M.; Miranda-Brito, C.; Romano, M.C.;Piña-Escobedo, A.; Pizano-Zárate, M.L.; Hoyo-Vadillo, C.; García-Mena, J. Studyof the diversity and short-chain fatty acids production by the bacterialcommunity in overweight and obese Mexican children. Eur. J. Clin. Microbiol.Infect. Dis. 2015, 34, 1337–1346.61. Verdam, F.J.; Fuentes, S.; De Jonge,C.; Zoetendal, E.G.; Erbil, R.; Greve, J.W.; Buurman, W.A.; De Vos, W.M.;Rensen, S.S. Human intestinal microbiota composition is associated with localand systemic inflammation in obesity. Obesity 2013, 21, E607–E615.62. Kasai, C.; Sugimoto, K.; Moritani, I.;Tanaka, J.; Oya, Y.; Inoue, H.; Tameda, M.; Shiraki, K.; Ito, M.; Takei, Y.; etal. Comparison of the gut microbiota composition between obese and non-obeseindividuals in a Japanese population, as analyzed by terminal restrictionfragment length polymorphism and next-generation sequencing. BMC Gastroenterol.2015, 15, 100.63. Payahoo, L.; Khajebishak, Y.;Ostadrahimi, A. Akkermansia muciniphila bacteria: A new perspective on themanagement of obesity: An updated review. Rev. Med. Microbiol. 2019, 30, 83–89.64. Million, M.; Angelakis, E.; Paul, M.;Armougom, F.; Leibovici, L.; Raoult, D. Comparative meta-analysis of the effectof Lactobacillus species on weight gain in humans and animals. Microb. Pathog.2012, 53, 100–108.65. Qiao, Y.; Sun, J.; Xia, S.; Li, L.; Li,Y.; Wang, P.; Shi, Y.; Le, G. Effects of different Lactobacillus reuteri oninflammatory and fat storage in high-fat diet-induced obesity mice model. J.Funct. Foods 2015, 14, 424–434.66. Ridlon, J.M.; Kang, D.J. Hylemon PB.Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 2006,47, 241–259. 67. Binder, H.J.; Filburn, B.; Floch, M.Bile acid inhibition of intestinal anaerobic organisms. Am. J. Clin. Nutr.1975, 28, 119–125. 68. Kurdi, P.; Kawanishi, K.; Mizutani, K.;Yokota, A. Mechanism of Growth Inhibition by Free Bile Acids in Lactobacilliand Bifidobacteria. J. Bacteriol. 2006, 188, 1979–1986.69. Fiorucci, S.; Mencarelli, A.;Palladino, G.; Cipriani, S. Bile-acid-activated receptors: Targeting TGR5 andfarnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol. Sci.2009, 30, 570–580.70. Thomas, C.; Gioiello, A.; Noriega, L.;Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C.;Pruzanski, M.; et al. TGR5-mediated bile acid sensing controls glucosehomeostasis. Cell Metab. 2009, 10, 167–177.71. McGavigan, A.K.; Garibay, D.; Henseler,Z.M.; Chen, J.; Bettaieb, A.; Haj, F.G.; Ley, R.E.; Chouinard, M.L.; Cummings,B.P. TGR5 contributes to glucoregulatory improvements after vertical sleevegastrectomy in mice. Gut 2017, 66, 226–234.72. Parséus, A.; Sommer, N.; Sommer, F.;Caesar, R.; Molinaro, A.; Ståhlman, M.; Greiner, T.U.; Perkins, R.; Bäckhed, F.Microbiota-induced obesity requires farnesoid X receptor. Gut 2017, 66,429–437.73. Flint, H.J.; Bayer, E.A.; Rincon, M.T.;Lamed, R.; White, B.A. Polysaccharide utilization by gut bacteria: Potentialfor new insights from genomic analysis. Nat. Rev. Genet. 2008, 6, 121–131.74. Riley, L.W.; Raphael, E.; Faerstein, E.Obesity in the United States—Dysbiosis from Exposure to Low-Dose Antibiotics?Front. Public Health 2013, 1, 69.75. Canfora, E.E.; Meex, R.C.; Venema, K.;Blaak, E.E. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev.Endocrinol. 2019, 1. 76. Brinkworth, G.D.; Noakes, M.; Clifton,P.M.; Bird, A.R. Comparative effects of very low-carbohydrate, high-fat andhigh-carbohydrate, low-fat weight-loss diets on bowel habit and faecalshort-chain fatty acids and bacterial populations. Br. J. Nutr. 2009, 101,1493. 77. Brown, A.J.; Goldsworthy, S.M.; Barnes,A.A.; Eilert, M.M.; Tcheang, L.; Daniels, D.; Muir, A.I.; Wigglesworth, M.J.;Kinghorn, I.; Fraser, N.J.; et al. The Orphan G protein-coupled receptors GPR41and GPR43 are activated by propionate and other short chain carboxylic acids.J. Biol. Chem. 2003, 278, 11312–11319. 78. Xu, H.; Barnes, G.T.; Yang, Q.; Tan,G.; Yang, D.; Chou, C.J.; Sole, J.; Nichols, A.; Ross, J.S.; Tartaglia, L.A.;et al. Chronic inflammation in fat plays a crucial role in the development ofobesity-related insulin resistance. J. Clin. Investig. 2003, 112, 1821–1830.79. Cani, P.D.; Amar, J.; Iglesias, M.A.;Poggi, M.; Knauf, C.; Bastelica, D.; Neyrinck, A.M.; Fava, F.; Tuohy, K.M.;Chabo, C.; et al. Metabolic Endotoxemia Initiates Obesity and InsulinResistance. Diabetes 2007, 56, 1761–1772.80. Dalby, M.J.; Aviello, G.; Ross, A.W.;Walker, A.W.; Barrett, P.; Morgan, P.J. Diet induced obesity is independent ofmetabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamicexpression of the acute phase protein, SerpinA3N. Sci. Rep. 2018, 8, 15648.81. Amar, J.; Burcelin, R.; Ruidavets,J.B.; Cani, P.D.; Fauvel, J.; Alessi, M.C.; Chamontin, B.; Ferriéres, J. Energyintake is associated with endotoxemia in apparently healthy men. Am. J. Clin.Nutr. 2008, 87, 1219–1223.82. Hotamisligil, G.S. Inflammation andmetabolic disorders. Nature 2006, 444, 860–867.83. Chawla, A. Nuclear Receptors and LipidPhysiology: Opening the X-Files. Science 2001, 294, 1866–1870.84. Glass, C.K.; Ogawa, S. Combinatorial rolesof nuclear receptors in inflammation and immunity. Nat. Rev. Immunol. 2006, 6,44–55.85. Wellen, K.E.; Hotamisligil, G.S.Inflammation, stress, and diabetes. J. Clin. Investig. 2005, 115,1111–1119. 86. Ge, H.; Li, X.; Weiszmann, J.; Wang,P.; Baribault, H.; Chen, J.-L.; Tian, H.; Li, Y. Activation of GProtein-Coupled Receptor 43 in Adipocytes Leads to Inhibition of Lipolysis andSuppression of Plasma Free Fatty Acids. Endocrinology 2008, 149,4519–4526. 87. Semenkovich, C.F. Insulin resistanceand atherosclerosis. J. Clin. Investig. 2006, 116, 1813–1822. 88. Bäckhed, F.; Ding, H.; Wang, T.;Hooper, L.V.; Koh, G.Y.; Nagy, A.; Semenkovich, C.F.; Gordon, J.I. The gutmicrobiota as an environmental factor that regulates fat storage. Proc. Natl.Acad. Sci. USA 2004, 101, 15718–15723. 89. Shapiro, H.; Suez, J.; Elinav, E.Personalized microbiome-based approaches to metabolic syndrome management andprevention. J. Diabetes 2017, 9, 226–236. 90. Wang, Z.; Klipfell, E.; Bennett, B.J.;Koeth, R.; Levison, B.S.; Dugar, B.; Feldstein, A.E.; Britt, E.B.; Fu, X.;Chung, Y.-M.; et al. Gut flora metabolism of phosphatidylcholine promotescardiovascular disease. Nature 2011, 472, 57–63. 91. Koeth, R.A.; Wang, Z.; Levison, B.S.;Buffa, J.A.; Org, E.; Sheehy, B.T.; Britt, E.B.; Fu, X.; Wu, Y.; Li, L.; et al.Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat,promotes atherosclerosis. Nat. Med. 2013, 19, 576–585.92. Chiang, J.Y.L. Bile acids: Regulationof synthesis. J. Lipid Res. 2009, 50, 1955–1966.93. Vrieze, A.; Out, C.; Fuentes, S.;Jonker, L.; Reuling, I.; Kootte, R.S.; Van Nood, E.; Holleman, F.; Knaapen, M.;Romijn, J.A.; et al. Impact of oral vancomycin on gut microbiota, bile acidmetabolism, and insulin sensitivity. J. Hepatol. 2014, 60, 824–831.94. Reijnders, D.; Goossens, G.H.; Hermes,G.D.; Neis, E.P.; Van Der Beek, C.M.; Most, J.; Holst, J.J.; Lenaerts, K.;Kootte, R.S.; Nieuwdorp, M.; et al. Effects of Gut Microbiota Manipulation byAntibiotics on Host Metabolism in Obese Humans: A Randomized Double-BlindPlacebo-Controlled Trial. Cell Metab. 2016, 24, 341.95. Delgado, T.C. Glutamate and GABA inAppetite Regulation. Front. Endocrinol. 2013, 4, 103. 96. Duca, F.A.; Swartz, T.D.; Sakar, Y.;Covasa, M. Increased Oral Detection, but Decreased Intestinal Signaling forFats in Mice Lacking Gut Microbiota. PLoS ONE 2012, 7, e39748. 97. Ley, R.E.; Bäckhed, F.; Turnbaugh, P.;Lozupone, C.A.; Knight, R.D.; Gordon, J.I. Obesity alters gut microbialecology. Proc. Natl. Acad. Sci. USA 2005, 102, 11070–11075. 98. Turnbaugh, P.J.; Gordon, J.I. The coregut microbiome, energy balance and obesity. J. Physiol. 2009, 587, 4153–4158.99. Ussar, S.; Griffin, N.W.; Bézy, O.;Fujisaka, S.; Vienberg, S.; Softic, S.; Deng, L.; Bry, L.; Gordon, J.I.; Kahn,C.R. Interactions between Gut Microbiota, Host Genetics and Diet Modulate thePredisposition to Obesity and Metabolic Syndrome. Cell Metab. 2015, 22,516–530.100. Goodrich, J.K.; Waters, J.L.; Poole,A.C.; Sutter, J.L.; Koren, O.; Blekhman, R.; Beaumont, M.; Van Treuren, W.;Knight, R.; Bell, J.T.; et al. Human Genetics Shape the Gut Microbiome. Cell2014, 159, 789–799.101. Liu, R.; Hong, J.; Xu, X.; Feng, Q.;Zhang, D.; Gu, Y.; Shi, J.; Zhao, S.; Liu, W.; Wang, X.; et al. Gut microbiomeand serum metabolome alterations in obesity and after weight-loss intervention.Nat. Med. 2017, 23, 859–868.102. Bodenlos, J.S.; Schneider, K.L.;Oleski, J.; Gordon, K.; Rothschild, A.J.; Pagoto, S.L. Vagus nerve stimulationand food intake: Effect of body mass index. J. Diabetes Sci. Technol. 2014, 8,590–595.103. Meng, F.; Han, Y.; Srisai, D.;Belakhov, V.; Farias, M.; Xu, Y.; Palmiter, R.D.; Baasov, T.; Wu, Q. Newinducible genetic method reveals critical roles of GABA in the control offeeding and metabolism. Proc. Natl. Acad. Sci. USA 2016, 113, 3645–3650.104. Schellekens, H.; Dinan, T.G.; Cryan,J.F. Lean mean fat reducing “ghrelin” machine: Hypothalamic ghrelin and ghrelinreceptors as therapeutic targets in obesity. Neuropharmacology 2010, 58, 2–16.105. Heisler, L.K.; Jobst, E.E.; Sutton,G.M.; Zhou, L.; Borok, E.; Thornton-Jones, Z.; Liu, H.Y.; Zigman, J.M.;Balthasar, N.; Kishi, T.; et al. Serotonin Reciprocally Regulates MelanocortinNeurons to Modulate Food Intake. Neuron 2006, 51, 239–249. 106. Xu, Y.; Jones, J.E.; Kohno, D.;Williams, K.W.; Lee, C.E.; Choi, M.J.; Anderson, J.G.; Heisler, L.K.; Zigman,J.M.; Lowell, B.B.; et al. 5-HT2CRs expressed by pro-opiomelanocortin neuronsregulate energy homeostasis. Neuron 2008, 60, 582–589. 107. Sandhu, K.V.; Sherwin, E.;Schellekens, H.; Stanton, C.; Dinan, T.G.; Cryan, J.F. Feeding themicrobiota-gut-brain axis: Diet, microbiome, and neuropsychiatry. Transl. Res.2016, 179, 223–244. 108. Everard, A.; Cani, P.D. Gut microbiotaand GLP-1. Rev. Endocr. Metab. Disord. 2014, 15, 189–196. 109. Niwa, T.; Takeda, N.; Tatematsu, A.;Maeda, K. Accumulation of indoxyl sulfate, an inhibitor of drug-binding, inuremic serum as demonstrated by internal-surface reversed-phase liquidchromatography. Clin. Chem. 1988, 34, 2264–2267.110. Frost, G.; Sleeth, M.L.; Sahuri-Arisoylu,M.; Lizarbe, B.; Cerdan, S.; Brody, L.; Anastasovska, J.; Ghourab, S.; Hankir,M.; Zhang, S.; et al. The short-chain fatty acid acetate reduces appetite via acentral homeostatic mechanism. Nat. Commun. 2014, 5, 3611. 111. Perry, R.J.; Peng, L.; Barry, N.A.Acetate mediates a microbiome-brain-beta-cell axis to promote metabolicsyndrome. Nature 2016, 534, 213–217.112. Swartz, T.D.; Duca, F.A.; de Wouters,T.; Sakar, Y.; Covasa, M. Up-regulation of intestinal type 1 taste receptor 3and sodium glucose luminal transporter-1 expression and increased sucroseintake in mice lacking gut microbiota. Br. J. Nutr. 2012, 107, 621–630.