The path towards microbiome-based metabolite treatment


The increasing evidence pointing towards the involvement of the gut microbiome in multiple diseases, as well as its plasticity, renders it a desirable potential therapeutic target. Nevertheless, classical therapies based on the consumption of live probiotic bacteria, or their enrichment by prebiotics, exhibit limited efficacy. Recently, a novel therapeutic approach has been suggested based on metabolites secreted, modulated or degraded by the microbiome. As many of the host–microorganism interactions pertaining to human health are mediated by metabolites, this approach may be able to provide therapeutic efficacy while overcoming caveats of current microbiome-targeting therapies, such as colonization resistance and inter-individual variation in microbial composition. In this Perspective, we will discuss the evidence that supports pursuing the metabolite-based therapeutic approach as well as issues critical for its implementation. In a broader context, we will discuss how recent advances in microbiome research may improve and refine current treatment modalities, and the potential of combining them with metabolite-based interventions as a means of achieving a person-specific, integrated and efficient therapy.

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Figure 1: An integrated approach to microbiome-based therapeutics.


  1. 1

    Collins, F. S., Morgan, M. & Patrinos, A. The Human Genome Project: lessons from large-scale biology. Science 300, 286–290 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Korem, T. et al. Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science 349, 1101–1106 (2015).

    CAS  Article  Google Scholar 

  3. 3

    Fuller, R. A review. J. Appl. Bacteriol. 66, 365–378 (1989).

    CAS  Article  Google Scholar 

  4. 4

    von Schillde, M.-A. et al. Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. Cell Host Microbe 11, 387–396 (2012).

    CAS  Article  Google Scholar 

  5. 5

    Yan, F. et al. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor. J. Biol. Chem. 288, 30742–30751 (2013).

    CAS  Article  Google Scholar 

  6. 6

    Probiotics: In Depth (NCCIH, 2016);

  7. 7

    Zhu, A., Sunagawa, S., Mende, D. R. & Bork, P. Inter-individual differences in the gene content of human gut bacterial species. Genome Biol. 16, 82 (2015).

    Article  Google Scholar 

  8. 8

    Nayfach, S., Rodriguez-Mueller, B., Garud, N. & Pollard, K. S. An integrated metagenomics pipeline for strain profiling reveals novel patterns of bacterial transmission and biogeography. Genome Res. 26, 1612–1625 (2016).

    CAS  Article  Google Scholar 

  9. 9

    Maldonado-Gómez, M. X. et al. Stable engraftment of Bifidobacterium longum AH1206 in the human gut depends on individualized features of the resident microbiome. Cell Host Microbe 20, 515–526 (2016).

    Article  Google Scholar 

  10. 10

    Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015).

    CAS  Article  Google Scholar 

  11. 11

    Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

    Article  Google Scholar 

  13. 13

    Alang, N. & Kelly, C. R. Weight gain after fecal microbiota transplantation. Open Forum Infect. Dis. 2, ofv004 (2015).

    Article  Google Scholar 

  14. 14

    Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109 (2015).

    Article  Google Scholar 

  15. 15

    Petrof, E. O. et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 1, 3 (2013).

    Article  Google Scholar 

  16. 16

    Ott, S. J. et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile Infection. Gastroenterology (2016).

  17. 17

    Glenn, G. & Roberfroid, M. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J. Nutr. 125, 1401–1412 (1995).

    Article  Google Scholar 

  18. 18

    Bindels, L. B., Delzenne, N. M., Cani, P. D. & Walter, J. Towards a more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol. 12, 303–310 (2015).

    CAS  Article  Google Scholar 

  19. 19

    Beserra, B. T. et al. A systematic review and meta-analysis of the prebiotics and synbiotics effects on glycaemia, insulin concentrations and lipid parameters in adult patients with overweight or obesity. Clin. Nutr. 34, 845–858 (2015).

    CAS  Article  Google Scholar 

  20. 20

    Ford, A. C. et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1547–1561 (2014).

    Article  Google Scholar 

  21. 21

    Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 22, 971–982 (2015).

    CAS  Article  Google Scholar 

  23. 23

    Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017).

    CAS  Article  Google Scholar 

  24. 24

    van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).

    CAS  Article  Google Scholar 

  25. 25

    Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015).

    CAS  Article  Google Scholar 

  26. 26

    Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015).

    CAS  Article  Google Scholar 

  27. 27

    Patel, N. et al. Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study. Ailment. Pharmacol. Ther. 40, 498–507 (2014).

    CAS  Google Scholar 

  28. 28

    De Preter, V. et al. Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD. Gut 64, 447–458 (2014).

    Article  Google Scholar 

  29. 29

    Butzner, J., Parmar, R., Bell, C. & Dalal, V. Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. Gut 38, 568–573 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Scheppach, W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas a placebo-controlled trial. German-Austrian SCFA Study Group. Dig. Dis. Sci. 41, 2254–2259 (1996).

    CAS  Article  Google Scholar 

  31. 31

    McIntyre, A., Gibson, P. & Young, G. Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut 34, 386–391 (1993).

    CAS  Article  Google Scholar 

  32. 32

    Hinnebusch, B. F., Meng, S., Wu, J. T., Archer, S. Y. & Hodin, R. A. The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J. Nutr. 132, 1012–1017 (2002).

    CAS  Article  Google Scholar 

  33. 33

    De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

    CAS  Article  Google Scholar 

  34. 34

    Gao, Z. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58, 1509–1517 (2009).

    CAS  Article  Google Scholar 

  35. 35

    Lin, H. V. et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS ONE 7, e35240 (2012).

    CAS  Article  Google Scholar 

  36. 36

    Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).

    CAS  Article  Google Scholar 

  37. 37

    Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    CAS  Article  Google Scholar 

  38. 38

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  Article  Google Scholar 

  39. 39

    Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    CAS  Article  Google Scholar 

  40. 40

    Perry, R. J. et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).

    CAS  Article  Google Scholar 

  41. 41

    Cassidy, A. & Minihane, A.-M. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am. J. Clin. Nutr. 105, 10–22 (2017).

    CAS  Article  Google Scholar 

  42. 42

    Thaiss, C. A. et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540, 544–551 (2016).

    CAS  Article  Google Scholar 

  43. 43

    Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510 (2016).

    CAS  Article  Google Scholar 

  44. 44

    Donia, M. S. & Fischbach, M. A. Small molecules from the human microbiota. Science 349, 1254766 (2015).

    Article  Google Scholar 

  45. 45

    Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353 (2016).

    CAS  Article  Google Scholar 

  46. 46

    Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).

    CAS  Article  Google Scholar 

  47. 47

    Klemashevich, C. et al. Rational identification of diet-derived postbiotics for improving intestinal microbiota function. Curr. Opin. Biotechnol. 26, 85–90 (2014).

    CAS  Article  Google Scholar 

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We thank the members of the Elinav Lab for fruitful discussions. We apologize to authors whose relevant work was not included in this Perspective owing to space constraints. J.S. is the recipient of the Strauss Institute research fellowship. E.E. is supported by Y. Ungar and R. Ungar, Israel; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the estate of J. Gitlitz; the estate of L. Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; the Adelis Foundation; J.L. Schwartz and V. Schwartz, Pacific Palisades; A. Markovitz, Canada; C. Adelson, Canada; CNRS (Centre National de la Recherche Scientifique); the estate of S. Weber and A.J. Weber; Mr and Mrs D.L. Schwarz, Sherman Oaks; grants funded by the European Research Council; the Kenneth Rainin Foundation; the German-Israel Binational Foundation; the Israel Science Foundation; the Minerva Foundation; the Rising Tide Foundation; and the Alon Foundation Scholar Award. E.E. is the incumbent of the Rina Gudinski Career Development Chair and is a senior fellow, CIFAR (Canadian Institute for Advanced Research).

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J.S. and E.E. chose the topics for the various sections, reviewed the literature, designed the figure and wrote the manuscript. Both authors contributed equally to the writing.

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Correspondence to Eran Elinav.

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Suez, J., Elinav, E. The path towards microbiome-based metabolite treatment. Nat Microbiol 2, 17075 (2017).

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