Diabetes Metab J.  2015 Aug;39(4):291-303. 10.4093/dmj.2015.39.4.291.

Probiotics as Complementary Treatment for Metabolic Disorders

• Le Barz M
• Anhe FF
• Varin TV
• Desjardins Y
• Levy E
• Roy D
• Urdaci MC
• Marette A

• KMID: 2174024
• DOI: http://doi.org/10.4093/dmj.2015.39.4.291

Abstract

Over the past decade, growing evidence has established the gut microbiota as one of the most important determinants of metabolic disorders such as obesity and type 2 diabetes. Indeed, obesogenic diet can drastically alter bacterial populations (i.e., dysbiosis) leading to activation of pro-inflammatory mechanisms and metabolic endotoxemia, therefore promoting insulin resistance and cardiometabolic disorders. To counteract these deleterious effects, probiotic strains have been developed with the aim of reshaping the microbiome to improve gut health. In this review, we focus on benefits of widely used probiotics describing their potential mechanisms of action, especially their ability to decrease metabolic endotoxemia by restoring the disrupted intestinal mucosal barrier. We also discuss the perspective of using new bacterial strains such as butyrate-producing bacteria and the mucolytic Akkermansia muciniphila, as well as the use of prebiotics to enhance the functionality of probiotics. Finally, this review introduces the notion of genetically engineered bacterial strains specifically developed to deliver anti-inflammatory molecules to the gut.

Keyword

Gut permeability; Insulin resistance; Metabolic disorders; Mucosal barrier; Obesity; Probiotics

MeSH Terms

Bacteria
Diet
Endotoxemia
Insulin Resistance
Microbiota
Obesity
Prebiotics
Probiotics*
Prebiotics

Figure

• 

  Fig. 1 Potential beneficial effects of probiotic supplementation against metabolic disorders. GPR, G protein-coupled receptor; SCFA, short-chain fatty acid; ChREBP, carbohydrate-responsive element-binding protein; SREBP, sterol regulatory element-binding protein; AMPK, AMP-activated protein kinase; ANGPTL4, angiopoietin-like protein 4; TJ, tight junction; AJ, adherens junction.

• 

  Fig. 2 Potential direct effects of probiotics to protect gut microbiota and intestinal barrier integrity. Obesogenic diet or "Western diet" alter gut microbiota population diversity and intestinal barrier integrity. Cross-talk between ingested probiotics, gut microbiota (commensal bacteria) and epithelial cells (1). Probiotics produce metabolites that could serve to increase both the diversity of commensal bacteria and the availability of nutrients used by intestinal epithelial cells (IEC). Commensal bacteria multiply and in turn, also produce metabolites that could be used by surrounding cells. In patients suffering from metabolic disorders, intestinal permeability is altered leading to an increase of low-grade inflammation and metabolic endotoxemia (2). Probiotics can increase production of tight- and adherens junction (TJ and AJ) proteins (3), improving gut permeability and inhibiting the passage of lipopolysaccharides (LPS) into systemic circulation that decreases metabolic endotoxemia. Moreover, probiotics express microorganism-associated molecular patterns (MAMPs) that could bind to host pattern recognition receptors (PRRs) located at cell surface of IEC (1) and dendritic cells (4), and induce the activation/inhibition of signaling pathways. For example (5), probiotics can stimulate dendritic cells leading to inhibition of pro-inflammatory CD4+ cell proliferation and activation of anti-inflammatory pathways (Treg and plasma cell proliferation, resulting in production of anti-inflammatory cytokines and IgA immunoglobulins (6), respectively). Mainly present in the mucus layer, IgA reinforce the protective role of mucosal barrier. Mucus production can also be increased by probiotics that stimulate goblet cells leading to activation of mucin gene expression and therefore production of mucin glycoproteins (7). Once assembled, these proteins are excreted and form the mucus layer, which acts as barrier against pathogen colonization. However, probiotics can also induce physical barrier against pathogens or produce bacteriocins that inhibits undesirable microorganism invasion (8). TLR, Toll-like receptor; NLR, NOD-like receptor; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; TGF-β, transforming growth factor β; IL-10, interleukin 10.

Reference

1. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444:1027–1031.

2. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004; 101:15718–15723.

3. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505:559–563.

4. Khan MT, Nieuwdorp M, Backhed F. Microbial modulation of insulin sensitivity. Cell Metab. 2014; 20:753–760.

5. Hur KY, Lee MS. Gut microbiota and metabolic disorders. Diabetes Metab J. 2015; 39:198–203.

6. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008; 57:1470–1481.

7. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014; 11:506–514.

8. Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol. 2010; 7:503–514.

9. de Moreno de LeBlanc A, LeBlanc JG. Effect of probiotic administration on the intestinal microbiota, current knowledge and potential applications. World J Gastroenterol. 2014; 20:16518–16528.

10. Champagne CP, Gardner NJ, Roy D. Challenges in the addition of probiotic cultures to foods. Crit Rev Food Sci Nutr. 2005; 45:61–84.

11. Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem. 2013; 288:25088–25097.

12. Yoo SR, Kim YJ, Park DY, Jung UJ, Jeon SM, Ahn YT, Huh CS, McGregor R, Choi MS. Probiotics L. plantarum and L. curvatus in combination alter hepatic lipid metabolism and suppress diet-induced obesity. Obesity (Silver Spring). 2013; 21:2571–2578.

13. Stenman LK, Waget A, Garret C, Klopp P, Burcelin R, Lahtinen S. Potential probiotic Bifidobacterium animalis ssp. lactis 420 prevents weight gain and glucose intolerance in diet-induced obese mice. Benef Microbes. 2014; 5:437–445.

14. Kang JH, Yun SI, Park MH, Park JH, Jeong SY, Park HO. Anti-obesity effect of Lactobacillus gasseri BNR17 in high-sucrose diet-induced obese mice. PLoS One. 2013; 8:e54617.

15. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013; 110:9066–9071.

16. Everard A, Matamoros S, Geurts L, Delzenne NM, Cani PD. Saccharomyces boulardii administration changes gut microbiota and reduces hepatic steatosis, low-grade inflammation, and fat mass in obese and type 2 diabetic db/db mice. MBio. 2014; 5:e01011–e01014.

17. Wang J, Tang H, Zhang C, Zhao Y, Derrien M, Rocher E, van-Hylckama Vlieg JE, Strissel K, Zhao L, Obin M, Shen J. Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. ISME J. 2015; 9:1–15.

18. Wu CC, Weng WL, Lai WL, Tsai HP, Liu WH, Lee MH, Tsai YC. Effect of Lactobacillus plantarum strain K21 on high-fat diet-fed obese mice. Evid Based Complement Alternat Med. 2015; 2015:391767.

19. Cousin FJ, Deutsch SM, Perez Chaia A, Foligne B, Jan G. Interactions between probiotic dairy propionibacteria and the intestinal epithelium. Curr Immunol Rev. 2012; 8:216–226.

20. Oksaharju A, Kooistra T, Kleemann R, van Duyvenvoorde W, Miettinen M, Lappalainen J, Lindstedt KA, Kovanen PT, Korpela R, Kekkonen RA. Effects of probiotic Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS supplementation on intestinal and systemic markers of inflammation in ApoE*3Leiden mice consuming a high-fat diet. Br J Nutr. 2013; 110:77–85.

21. Ritze Y, Bardos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, Bischoff SC. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS One. 2014; 9:e80169.

22. Park DY, Ahn YT, Park SH, Huh CS, Yoo SR, Yu R, Sung MK, McGregor RA, Choi MS. Supplementation of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 in diet-induced obese mice is associated with gut microbial changes and reduction in obesity. PLoS One. 2013; 8:e59470.

23. O'Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol. 2012; 152:189–205.

24. Thomas LV, Ockhuizen T, Suzuki K. Exploring the influence of the gut microbiota and probiotics on health: a symposium report. Br J Nutr. 2014; 112:Suppl 1. S1–S18.

25. Moya-Perez A, Romo-Vaquero M, Tomas-Barberan F, Sanz Y, Garcia-Conesa MT. Hepatic molecular responses to Bifidobacterium pseudocatenulatum CECT 7765 in a mouse model of diet-induced obesity. Nutr Metab Cardiovasc Dis. 2014; 24:57–64.

26. Hariri M, Salehi R, Feizi A, Mirlohi M, Kamali S, Ghiasvand R. The effect of probiotic soy milk and soy milk on anthropometric measures and blood pressure in patients with type II diabetes mellitus: a randomized double-blind clinical trial. ARYA Atheroscler. 2015; 11:1 Suppl. 74–80.

27. Minami J, Kondo S, Yanagisawa N, Odamaki T, Xiao JZ, Abe F, Nakajima S, Hamamoto Y, Saitoh S, Shimoda T. Oral administration of Bifidobacterium breve B-3 modifies metabolic functions in adults with obese tendencies in a randomised controlled trial. J Nutr Sci. 2015; 4:e17.

28. Nabavi S, Rafraf M, Somi MH, Homayouni-Rad A, Asghari-Jafarabadi M. Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. J Dairy Sci. 2014; 97:7386–7393.

29. Ahn HY, Kim M, Ahn YT, Sim JH, Choi ID, Lee SH, Lee JH. The triglyceride-lowering effect of supplementation with dual probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032: Reduction of fasting plasma lysophosphatidylcholines in nondiabetic and hypertriglyceridemic subjects. Nutr Metab Cardiovasc Dis. 2015; 25:724–733.

30. McNulty NP, Yatsunenko T, Hsiao A, Faith JJ, Muegge BD, Goodman AL, Henrissat B, Oozeer R, Cools-Portier S, Gobert G, Chervaux C, Knights D, Lozupone CA, Knight R, Duncan AE, Bain JR, Muehlbauer MJ, Newgard CB, Heath AC, Gordon JI. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med. 2011; 3:106ra106.

31. Veiga P, Pons N, Agrawal A, Oozeer R, Guyonnet D, Brazeilles R, Faurie JM, van Hylckama, Houghton LA, Whorwell PJ, Ehrlich SD, Kennedy SP. Changes of the human gut microbiome induced by a fermented milk product. Sci Rep. 2014; 4:6328.

32. Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS One. 2013; 8:e63388.

33. Luck H, Tsai S, Chung J, Clemente-Casares X, Ghazarian M, Revelo XS, Lei H, Luk CT, Shi SY, Surendra A, Copeland JK, Ahn J, Prescott D, Rasmussen BA, Chng MH, Engleman EG, Girardin SE, Lam TK, Croitoru K, Dunn S, Philpott DJ, Guttman DS, Woo M, Winer S, Winer DA. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 2015; 21:527–542.

34. Hulston CJ, Churnside AA, Venables MC. Probiotic supplementation prevents high-fat, overfeeding-induced insulin resistance in human subjects. Br J Nutr. 2015; 113:596–602.

35. Laukoetter MG, Bruewer M, Nusrat A. Regulation of the intestinal epithelial barrier by the apical junctional complex. Curr Opin Gastroenterol. 2006; 22:85–89.

36. Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007; 13:35–37.

37. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009; 9:799–809.

38. Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol. 2000; 78:80–88.

39. Verdam FJ, Greve JW, Roosta S, van Eijk H, Bouvy N, Buurman WA, Rensen SS. Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab. 2011; 96:E379–E383.

40. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011; 474:327–336.

41. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, Gibson GR, Delzenne NM. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007; 50:2374–2383.

42. Felice C, Lewis A, Armuzzi A, Lindsay JO, Silver A. Review article: selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015; 41:26–38.

43. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013; 145:396–406. 406.e1–406.e10.

44. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013; 341:569–573.

45. Eeckhaut V, Machiels K, Perrier C, Romero C, Maes S, Flahou B, Steppe M, Haesebrouck F, Sas B, Ducatelle R, Vermeire S, Van Immerseel F. Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut. 2013; 62:1745–1752.

46. den Besten G, Bleeker A, Gerding A, van Eunen K, Havinga R, van Dijk TH, Oosterveer MH, Jonker JW, Groen AK, Reijngoud DJ, Bakker BM. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARgamma-dependent switch from lipogenesis to fat oxidation. Diabetes. 2015; 64:2398–2408.

47. Quevrain E, Maubert MA, Michon C, Chain F, Marquant R, Tailhades J, Miquel S, Carlier L, Bermudez-Humaran LG, Pigneur B, Lequin O, Kharrat P, Thomas G, Rainteau D, Aubry C, Breyner N, Afonso C, Lavielle S, Grill JP, Chassaing G, Chatel JM, Trugnan G, Xavier R, Langella P, Sokol H, Seksik P. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut. 2015; 06. 04. [Epub]. DOI: 10.1136/gutjnl-2014-307649.

48. Falony G, Vlachou A, Verbrugghe K, De Vuyst L. Cross-feeding between Bifidobacterium longum BB536 and acetate-converting, butyrate-producing colon bacteria during growth on oligofructose. Appl Environ Microbiol. 2006; 72:7835–7841.

49. Bindels LB, Neyrinck AM, Salazar N, Taminiau B, Druart C, Muccioli GG, Francois E, Blecker C, Richel A, Daube G, Mahillon J, de Los Reyes-Gavilan CG, Cani PD, Delzenne NM. Non digestible oligosaccharides modulate the gut microbiota to control the development of leukemia and associated cachexia in mice. PLoS One. 2015; 10:e0131009.

50. Sanchez M, Darimont C, Drapeau V, Emady-Azar S, Lepage M, Rezzonico E, Ngom-Bru C, Berger B, Philippe L, Ammon-Zuffrey C, Leone P, Chevrier G, St-Amand E, Marette A, Dore J, Tremblay A. Effect of Lactobacillus rhamnosus CGMCC1.3724 supplementation on weight loss and maintenance in obese men and women. Br J Nutr. 2014; 111:1507–1519.

51. Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr. 2009; 89:1751–1759.

52. Dudonne S, Varin TV, Forato Anhe F, Dube P, Roy D, Pilon G, Marette A, Levy E, Jacquot C, Urdaci M, Desjardins Y. Modulatory effects of a cranberry extract co-supplementation with Bacillus subtilis CU1 probiotic on phenolic compounds bioavailability and gut microbiota composition in high-fat diet-fed mice. PharmaNutrition. 2015; 05. 01. [Epub]. DOI: 10.1016/j.phanu.2015.04.002.

53. Delzenne NM, Neyrinck AM, Cani PD. Gut microbiota and metabolic disorders: how prebiotic can work? Br J Nutr. 2013; 109:Suppl 2. S81–S85.

54. Neyrinck AM, Van Hee VF, Piront N, De Backer F, Toussaint O, Cani PD, Delzenne NM. Wheat-derived arabinoxylan oligosaccharides with prebiotic effect increase satietogenic gut peptides and reduce metabolic endotoxemia in diet-induced obese mice. Nutr Diabetes. 2012; 2:e28.

55. De Vuyst L, Leroy F. Cross-feeding between bifidobacteria and butyrate-producing colon bacteria explains bifdobacterial competitiveness, butyrate production, and gas production. Int J Food Microbiol. 2011; 149:73–80.

56. Neyrinck AM, Possemiers S, Druart C, Van de Wiele T, De Backer F, Cani PD, Larondelle Y, Delzenne NM. Prebiotic effects of wheat arabinoxylan related to the increase in bifidobacteria, Roseburia and Bacteroides/Prevotella in diet-induced obese mice. PLoS One. 2011; 6:e20944.

57. Van den Abbeele P, Gerard P, Rabot S, Bruneau A, El Aidy S, Derrien M, Kleerebezem M, Zoetendal EG, Smidt H, Verstraete W, Van de Wiele T, Possemiers S. Arabinoxylans and inulin differentially modulate the mucosal and luminal gut microbiota and mucin-degradation in humanized rats. Environ Microbiol. 2011; 13:2667–2680.

58. de Moreno de LeBlanc A, Del Carmen S, Chatel JM, Miyoshi A, Azevedo V, Langella P, Bermudez-Humaran LG, LeBlanc JG. Current review of genetically modified lactic acid bacteria for the prevention and treatment of colitis using murine models. Gastroenterol Res Pract. 2015; 2015:146972.

59. Duan FF, Liu JH, March JC. Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes. 2015; 64:1794–1803.

60. Chen Z, Guo L, Zhang Y, Walzem RL, Pendergast JS, Printz RL, Morris LC, Matafonova E, Stien X, Kang L, Coulon D, McGuinness OP, Niswender KD, Davies SS. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest. 2014; 124:3391–3406.