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Microbiome-based therapeutics

Nature Reviews Microbiology volume 20, pages 365–380 (2022)Cite this article

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Abstract

Symbiotic microorganisms inhabiting the gastrointestinal tract promote health by decreasing susceptibility to infection and enhancing resistance to a range of diseases. In this Review, we discuss our increasing understanding of the impact of the microbiome on the mammalian host and recent efforts to culture and characterize intestinal symbiotic microorganisms that produce or modify metabolites that impact disease pathology. Manipulation of the intestinal microbiome has great potential to reduce the incidence and/or severity of a wide range of human conditions and diseases, and the biomedical research community now faces the challenge of translating our understanding of the microbiome into beneficial medical therapies. Our increasing understanding of symbiotic microbial species and the application of ecological principles and machine learning are providing exciting opportunities for microbiome-based therapeutics to progress from faecal microbiota transplantation to the administration of precisely defined and clinically validated symbiotic microbial consortia that optimize disease resistance.

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Fig. 1: Classes of microbiome-based therapeutics.
Fig. 2: Major factors in using faecal microbiota transplantation treatment to restore the microbiome.
Fig. 3: Registered clinical trials using faecal microbiota transplantation.
Fig. 4: Generation of symbiotic microbial consortia.

References

  1. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dethlefsen, L. & Relman, D. A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4554–4561 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Borbet, T. C., Zhang, X., Muller, A. & Blaser, M. J. The role of the changing human microbiome in the asthma pandemic. J. Allergy Clin. Immunol. 144, 1457–1466 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Becattini, S., Taur, Y. & Pamer, E. G. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol. Med. 22, 458–478 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gottfried, J. History Repeating? Avoiding a Return to the Pre-antibiotic Age. Harvard Library http://nrs.harvard.edu/urn-3:HUL.InstRepos:8889467 (2005).

  6. Peled, J. U. et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N. Engl. J. Med. 382, 822–834 (2020). This large, multi-institutional clinical study spanning three continents demonstrates the association of microbiota diversity with survival following haematopoietic cell transplantation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fischbach, M. A. Microbiome: focus on causation and mechanism. Cell 174, 785–790 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pamer, E. G. Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns. Mucosal Immunol. 7, 210–214 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. DeFilipp, Z. et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N. Engl. J. Med. 381, 2043–2050 (2019).

    Article  PubMed  Google Scholar 

  11. Goodman, A. L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fehlner-Peach, H. et al. Distinct polysaccharide utilization profiles of human intestinal Prevotella copri isolates. Cell Host Microbe 26, 680–690 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sorbara, M. T. et al. Functional and genomic variation between human-derived isolates of Lachnospiraceae reveals inter- and intra-species diversity. Cell Host Microbe 28, 134–146 (2020). This study demonstrates genomic differences between symbiotic bacterial strains, many of which may impact their potential as live biotherapeutic products.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guo, C. J. et al. Depletion of microbiome-derived molecules in the host using Clostridium genetics. Science https://doi.org/10.1126/science.aav1282 (2019). A pioneering study demonstrating the impact of multiple genes on the production of metabolites by C. sporogenes.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Funabashi, M. et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature 582, 566–570 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Danne, C., Rolhion, N. & Sokol, H. Recipient factors in faecal microbiota transplantation: one stool does not fit all. Nat. Rev. Gastroenterol. Hepatol. 18, 503–513 (2021).

    Article  PubMed  Google Scholar 

  17. Abt, M. C., McKenney, P. T. & Pamer, E. G. Clostridium difficile colitis: pathogenesis and host defence. Nat. Rev. Microbiol. 14, 609–620 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eiseman, B., Silen, W., Bascom, G. S. & Kauvar, A. J. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44, 854–859 (1958).

    CAS  PubMed  Google Scholar 

  19. Gough, E., Shaikh, H. & Manges, A. R. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin. Infect. Dis. 53, 994–1002 (2011).

    Article  PubMed  Google Scholar 

  20. Kassam, Z., Lee, C. H., Yuan, Y. & Hunt, R. H. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am. J. Gastroenterol. 108, 500–508 (2013).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Smillie, C. S. et al. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation. Cell Host Microbe 23, 229–240 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kakihana, K. et al. Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut. Blood 128, 2083–2088 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van Lier, Y. F. et al. Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaz8926 (2020).

    Article  PubMed  Google Scholar 

  25. Zhao, Y. et al. Safety and efficacy of fecal microbiota transplantation for grade IV steroid refractory GI-GvHD patients: interim results from FMT2017002 trial. Front. Immunol. 12, 678476 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kootte, R. S. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 26, 611–619 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. de Groot, P. et al. Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial. Gut 70, 92–105 (2021).

    Article  PubMed  CAS  Google Scholar 

  28. Yu, E. W. et al. Fecal microbiota transplantation for the improvement of metabolism in obesity: the FMT-TRIM double-blind placebo-controlled pilot trial. PLoS Med. 17, e1003051 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Duvallet, C., Gibbons, S. M., Gurry, T., Irizarry, R. A. & Alm, E. J. Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nat. Commun. 8, 1784 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rossen, N. G. et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149, 110–118 (2015).

    Article  PubMed  Google Scholar 

  32. 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  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  34. Costello, S. P. et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321, 156–164 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sokol, H. et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome 8, 12 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kong, L. et al. Linking strain engraftment in fecal microbiota transplantation with maintenance of remission in Crohn’s disease. Gastroenterology 159, 2193–2202 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Witjes, J. J. et al. Donor fecal microbiota transplantation alters gut microbiota and metabolites in obese individuals with steatohepatitis. Hepatol. Commun. 4, 1578–1590 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. DeFilipp, Z., Bloom, P. P., Hohmann, E. L. & Group, F. M. T. S. Drug-resistant bacteremia after fecal microbiota transplant. N. Engl. J. Med. 382, 1961–1962 (2020).

    PubMed  Google Scholar 

  39. Terveer, E. M. et al. Human transmission of blastocystis by fecal microbiota transplantation without development of gastrointestinal symptoms in recipients. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciz1122 (2019).

    Article  PubMed Central  Google Scholar 

  40. Gareau, M. G., Sherman, P. M. & Walker, W. A. Probiotics and the gut microbiota in intestinal health and disease. Nat. Rev. Gastroenterol. Hepatol. 7, 503–514 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kim, Y. G. et al. Neonatal acquisition of Clostridia species protects against colonization by bacterial pathogens. Science 356, 315–319 (2017). This is an important study demonstrating the important role of the order Clostridiales in providing colonization resistance against a range of enteric pathogens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim, S. G. et al. Microbiota-derived lantibiotic restores resistance against vancomycin-resistant Enterococcus. Nature 572, 665–669 (2019). This study demonstrates that lantibiotic production by an obligate anaerobic commensal bacterium can markedly reduce intestinal colonization by vancomycin-resistant E. faecium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Becattini, S. et al. Commensal microbes provide first line defense against Listeria monocytogenes infection. J. Exp. Med. 214, 1973–1989 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Byndloss, M. X. et al. Microbiota-activated PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rivera-Chavez, F. et al. Depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella. Cell Host Microbe 19, 443–454 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013). This landmark study introduces the rational development of a commensal consortium to drive a beneficial interaction with the host.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Feehley, T. et al. Healthy infants harbor intestinal bacteria that protect against food allergy. Nat. Med. 25, 448–453 (2019). This study demonstrates that butyrate-producing commensal bacteria, such as A. caccae, can provide protection against food allergies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Campbell, C. et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature 581, 475–479 (2020). This study shows that modification of secondary bile acids by resident commensal bacteria of the lower intestinal tract can impact differentiation of T cells by impacting dendritic cell function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Kamdar, K. et al. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease. Cell Host Microbe 19, 21–31 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hall, A. B. et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med. 9, 103 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Laverde Gomez, J. A. et al. Formate cross-feeding and cooperative metabolic interactions revealed by transcriptomics in co-cultures of acetogenic and amylolytic human colonic bacteria. Envron. Microbiol. 21, 259–271 (2019).

    Article  CAS  Google Scholar 

  58. Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4578–4585 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    Article  PubMed Central  CAS  Google Scholar 

  61. Wexler, A. G. & Goodman, A. L. An insider’s perspective: Bacteroides as a window into the microbiome. Nat. Microbiol. 2, 17026 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sato, Y. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature https://doi.org/10.1038/s41586-021-03832-5 (2021). This study demonstrates that a wider range of commensal bacteria can modify secondary bile acids, leading to the production of isoall lithocholic acid, which has high activity against intestinal pathogens, such as C. difficile.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Li, W. et al. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. Cell Host Microbe 29, 1366–1377 (2021). This study demonstrates a mechanism by which secondary bile acids can enhance the differentiation of Treg cells.

    Article  CAS  PubMed  Google Scholar 

  64. Porter, N. T. & Martens, E. C. The critical roles of polysaccharides in gut microbial ecology and physiology. Annu. Rev. Microbiol. 71, 349–369 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Lee, S. M. et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Russell, A. B. et al. A type VI secretion-related pathway in Bacteroidetes mediates interbacterial antagonism. Cell Host Microbe 16, 227–236 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ross, B. D. et al. Human gut bacteria contain acquired interbacterial defence systems. Nature 575, 224–228 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Coyne, M. J. et al. A family of anti-Bacteroidales peptide toxins wide-spread in the human gut microbiota. Nat. Commun. 10, 3460 (2019). This study demonstrates one mechanism by which members of the order Bacteoridales can compete with the complex microbiota of the lower intestinal tract.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Shumaker, A. M., Laclare McEneany, V., Coyne, M. J., Silver, P. A. & Comstock, L. E. Identification of a fifth antibacterial toxin produced by a single bacteroides fragilis strain. J. Bacteriol. https://doi.org/10.1128/JB.00577-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Garcia-Bayona, L. & Comstock, L. E. Bacterial antagonism in host-associated microbial communities. Science https://doi.org/10.1126/science.aat2456 (2018).

    Article  PubMed  Google Scholar 

  76. Chia, L. W. et al. Deciphering the trophic interaction between Akkermansia muciniphila and the butyrogenic gut commensal Anaerostipes caccae using a metatranscriptomic approach. Antonie Van. Leeuwenhoek 111, 859–873 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P. D. & Backhed, F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 22, 658–668 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ribo, S. et al. Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abb0322 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Depommier, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25, 1096–1103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Seregin, S. S. et al. NLRP6 protects Il10-/- mice from colitis by limiting colonization of Akkermansia muciniphila. Cell Rep. 19, 733–745 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cirstea, M., Radisavljevic, N. & Finlay, B. B. Good bug, bad bug: breaking through microbial stereotypes. Cell Host Microbe 23, 10–13 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Katoh, T. et al. Enzymatic adaptation of Bifidobacterium bifidum to host glycans, viewed from glycoside hydrolyases and carbohydrate-binding modules. Microorganisms https://doi.org/10.3390/microorganisms8040481 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Sugahara, H. et al. Probiotic Bifidobacterium longum alters gut luminal metabolism through modification of the gut microbial community. Sci. Rep. 5, 13548 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sun, S. et al. Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade. Proc. Natl Acad. Sci. USA 117, 27509–27515 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Xiao, J. et al. Probiotic Bifidobacterium breve in improving cognitive functions of older adults with suspected mild cognitive impairment: a randomized, double-blind, placebo-controlled trial. J. Alzheimers Dis. 77, 139–147 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shin, N. R., Whon, T. W. & Bae, J. W. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 33, 496–503 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Zeng, M. Y., Inohara, N. & Nunez, G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 10, 18–26 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 204 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Sorbara, M. T. et al. Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification. J. Exp. Med. 216, 84–98 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jacobson, A. et al. A gut commensal-produced metabolite mediates colonization resistance to salmonella infection. Cell Host Microbe 24, 296–307 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Osbelt, L. et al. Variations in microbiota composition of laboratory mice influence Citrobacter rodentium infection via variable short-chain fatty acid production. PLoS Pathog. 16, e1008448 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Stoma, I. et al. Compositional flux within the intestinal microbiota and risk for bloodstream infection with gram-negative bacteria. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa068 (2020).

    Article  PubMed Central  Google Scholar 

  101. Taur, Y. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis. 55, 905–914 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wassenaar, T. M. Insights from 100 years of research with probiotic E. coli. Eur. J. Microbiol. Immunol. 6, 147–161 (2016).

    Article  Google Scholar 

  103. Gurry, T. et al. Predictability and persistence of prebiotic dietary supplementation in a healthy human cohort. Sci. Rep. 8, 12699 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Ang, Q. Y. et al. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell 181, 1263–1275 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. von Schwartzenberg, R. J. et al. Caloric restriction disrupts the microbiota and colonization resistance. Nature 595, 272–277 (2021). This study demonstrates that severe caloric restriction can markedly alter microbiota composition and may provide advantages to enteric pathogens.

    Article  CAS  Google Scholar 

  107. Korem, T. et al. Bread affects clinical parameters and induces gut microbiome-associated personal glycemic responses. Cell Metab. 25, 1243–1253 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Carmody, R. N. et al. Cooking shapes the structure and function of the gut microbiome. Nat. Microbiol. 4, 2052–2063 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Gehrig, J. L. et al. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Science https://doi.org/10.1126/science.aau4732 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Chen, R. Y. et al. A microbiota-directed food intervention for undernourished children. N. Engl. J. Med. 384, 1517–1528 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Delannoy-Bruno, O. et al. Evaluating microbiome-directed fibre snacks in gnotobiotic mice and humans. Nature 595, 91–95 (2021). This article drives home the impact of ingested fibre on microbiota composition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Galvez, E. J. C. et al. Distinct polysaccharide utilization determines interspecies competition between intestinal Prevotella spp. Cell Host Microbe 28, 838–852 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Patnode, M. L. et al. Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans. Cell 179, 59–73 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pamer, E. G. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 352, 535–538 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bohnhoff, M. & Miller, C. P. Enhanced susceptibility to Salmonella infection in streptomycin-treated mice. J. Infect. Dis. 111, 117–127 (1962).

    Article  CAS  PubMed  Google Scholar 

  117. Freter, R. In vivo and in vitro antagonism of intestinal bacteria against Shigella flexneri. II. The inhibitory mechanism. J. Infect. Dis. 110, 38–46 (1962).

    Article  CAS  PubMed  Google Scholar 

  118. Schaedler, R. W., Dubs, R. & Costello, R. Association of germfree mice with bacteria isolated from normal mice. J. Exp. Med. 122, 77–82 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wymore Brand, M. et al. The altered Schaedler flora: continued applications of a defined murine microbial community. ILAR J. 56, 169–178 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Kane, M. et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Stecher, B. et al. Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog. 6, e1000711 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. van der Waaij, D., Vossen, J. M., Altes, C. K. & Hartgrink, C. Reconventionalization following antibiotic decontamination in man and animals. Am. J. Clin. Nutr. 30, 1887–1895 (1977).

    Article  PubMed  Google Scholar 

  123. Tvede, M. & Rask-Madsen, J. Bacteriotherapy for Clostridium difficile diarrhoea. Lancet 335, 110 (1990).

    Article  CAS  PubMed  Google Scholar 

  124. Lawley, T. D. et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog. 8, e1002995 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Caballero, S. et al. Cooperating commensals restore colonization resistance to vancomycin-resistant Enterococcus faecium. Cell Host Microbe 21, 592–602 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Walker, M. C. et al. Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family. BMC Genomics 21, 387 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Brugiroux, S. et al. Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium. Nat. Microbiol. 2, 16215 (2016).

    Article  CAS  PubMed  Google Scholar 

  128. Eberl, C. et al. E. coli enhance colonization resistance against Salmonella Typhimurium by competing for galactitol, a context-dependent limiting carbon source. Cell Host Microbe 29, 1680–1692 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Sassone-Corsi, M. et al. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540, 280–283 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Nagao-Kitamoto, H. et al. Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota. Nat. Med. 26, 608–617 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Caballero-Flores, G., Pickard, J. M., Fukuda, S., Inohara, N. & Nunez, G. An enteric pathogen subverts colonization resistance by evading competition for amino acids in the gut. Cell Host Microbe 28, 526–533 (2020).

    Article  CAS  Google Scholar 

  132. Faith, J. J., Ahern, P. P., Ridaura, V. K., Cheng, J. & Gordon, J. I. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl. Med. 6, 220ra211 (2014).

    Article  CAS  Google Scholar 

  133. Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358, 359–365 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600–605 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Poyet, M. et al. A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research. Nat. Med. 25, 1442–1452 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Forster, S. C. et al. A human gut bacterial genome and culture collection for improved metagenomic analyses. Nat. Biotechnol. 37, 186–192 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zou, Y. et al. 1,520 reference genomes from cultivated human gut bacteria enable functional microbiome analyses. Nat. Biotechnol. 37, 179–185 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bisanz, J. E. et al. A genomic toolkit for the mechanistic dissection of intractable human gut bacteria. Cell Host Microbe 27, 1001–1013 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Venturelli, O. S. et al. Deciphering microbial interactions in synthetic human gut microbiome communities. Mol. Syst. Biol. 14, e8157 (2018). This study begins to dissect the interactions between members of an assembled consortium of commensal bacterial strains using computational platforms.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Stein, R. R. et al. Computer-guided design of optimal microbial consortia for immune system modulation. eLife https://doi.org/10.7554/eLife.30916 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Mimee, M., Tucker, A. C., Voigt, C. A. & Lu, T. K. Programming a human commensal bacterium, bacteroides thetaiotaomicron, to sense and respond to stimuli in the murine gut microbiota. Cell Syst. 1, 62–71 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lim, B., Zimmermann, M., Barry, N. A. & Goodman, A. L. Engineered regulatory systems modulate gene expression of human commensals in the gut. Cell 169, 547–558 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Garcia-Bayona, L. & Comstock, L. E. Streamlined genetic manipulation of diverse Bacteroides and Parabacteroides isolates from the human gut microbiota. mBio https://doi.org/10.1128/mBio.01762-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Bhattarai, Y. et al. Gut microbiota-produced tryptamine activates an epithelial G-protein-coupled receptor to increase colonic secretion. Cell Host Microbe 23, 775–785 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bhattarai, Y. et al. Bacterially derived tryptamine increases mucus release by activating a host receptor in a mouse model of inflammatory bowel disease. iScience 23, 101798 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Shepherd, E. S., DeLoache, W. C., Pruss, K. M., Whitaker, W. R. & Sonnenburg, J. L. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature 557, 434–438 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Quinn, R. A. et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 579, 123–129 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Guo, C. J. et al. Discovery of reactive microbiota-derived metabolites that inhibit host proteases. Cell 168, 517–526 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Heilbronner, S., Krismer, B., Brotz-Oesterhelt, H. & Peschel, A. The microbiome-shaping roles of bacteriocins. Nat. Rev. Microbiol. https://doi.org/10.1038/s41579-021-00569-w (2021).

    Article  PubMed  Google Scholar 

  150. Chen, H. et al. A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology. Cell 177, 1217–1231 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Backhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. Louis, P. & Flint, H. J. Formation of propionate and butyrate by the human colonic microbiota. Env. Microbiol. 19, 29–41 (2017).

    Article  CAS  Google Scholar 

  153. Reichardt, N. et al. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J. 8, 1323–1335 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  157. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Haak, B. W. et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood 131, 2978–2986 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Alavi, S. et al. Interpersonal gut microbiome variation drives susceptibility and resistance to cholera infection. Cell 181, 1533–1546 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Ridlon, J. M., Kang, D. J. & Hylemon, P. B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241–259 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Sorg, J. A. & Sonenshein, A. L. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190, 2505–2512 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Devlin, A. S. & Fischbach, M. A. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat. Chem. Biol. 11, 685–690 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Song, X. et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature 577, 410–415 (2020). This study demonstrates that secondary bile acid modifications can impact the differentiation of pro-inflammatory TH17 cells.

    Article  CAS  PubMed  Google Scholar 

  165. Sherkow, J. S. & Greely, H. T. The history of patenting genetic material. Annu. Rev. Genet. 49, 161–182 (2015).

    Article  CAS  PubMed  Google Scholar 

  166. FDA. Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information. FDA https://www.fda.gov/regulatory-information/search-fda-guidance-documents/early-clinical-trials-live-biotherapeutic-products-chemistry-manufacturing-and-control-information (2016).

  167. European Pharmacopoeia Commission. 3053E general monograph on live biotherapeutic products Vol. 9 (European Pharmacopoeia Commission, 2019).

  168. Paquet, J. C. et al. Entering first-in-human clinical study with a single-strain live biotherapeutic product: input and feedback gained from the EMA and the FDA. Front. Med. 8, 716266 (2021).

    Article  Google Scholar 

  169. Blount, K. F., Shannon, W. D., Deych, E. & Jones, C. Restoration of bacterial microbiome composition and diversity among treatment responders in a phase 2 trial of RBX2660: an investigational microbiome restoration therapeutic. Open Forum Infect. Dis. 6, ofz095 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Dubberke, E. R. et al. Results from a randomized, placebo-controlled clinical trial of a RBX2660-a microbiota-based drug for the prevention of recurrent Clostridium difficile infection. Clin. Infect. Dis. 67, 1198–1204 (2018).

    Article  CAS  PubMed  Google Scholar 

  171. Orenstein, R. et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin. Infect. Dis. 62, 596–602 (2016).

    Article  PubMed  Google Scholar 

  172. Dubberke, E. R. et al. Clearance of vancomycin-resistant Enterococcus concomitant with administration of a microbiota-based drug targeted at recurrent Clostridium difficile infection. Open. Forum Infect. Dis. https://doi.org/10.1093/ofid/ofw133 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Langdon, A. et al. Microbiota restoration reduces antibiotic-resistant bacteria gut colonization in patients with recurrent Clostridioides difficile infection from the open-label PUNCH CD study. Genome Med. 13, 28 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Khanna, S. et al. RBX7455, a room temperature-stable, orally-administered investigational live biotherapeutic, is safe, effective, and shifts patients’ microbiomes in a phase 1 study for recurrent Clostridioides difficile infections. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa1430 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Kao, D. et al. The effect of a microbial ecosystem therapeutic (MET-2) on recurrent Clostridioides difficile infection: a phase 1, open-label, single-group trial. Lancet Gastroenterol. Hepatol. 6, 282–291 (2021).

    Article  PubMed  Google Scholar 

  176. Bobilev, D. et al. 1953. VE303, a rationally designed bacterial consortium for prevention of recurrent Clostridioides difficile (C. difficile) infection (rCDI), stably restores the gut microbiota after vancomycin (vanco)-induced dysbiosis in adult healthy volunteers (HV). Open. Forum Infect. Dis. 6, S60 (2019).

    Article  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by US NIH grants R01 AI095706, P01 CA023766, U01 AI124275, and R01 AI042135 to E.G.P. and the Duchossois Family Institute of the University of Chicago. M.T.S. was supported by a postdoctoral fellowship from the Canadian Institute for Health Research (FRN#152527) and a postdoctoral fellowship from Emerald Foundation Inc.

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  1. Duchossois Family Institute, University of Chicago, Chicago, IL, USA

    Matthew T. Sorbara & Eric G. Pamer

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  1. Matthew T. Sorbara
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The authors contributed equally to all aspects of the article.

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Correspondence to Eric G. Pamer.

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Competing interests

E.G.P. serves on the advisory board of Diversigen, has received speaker honoraria from Bristol Myers Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis and Ferring Pharmaceuticals, is an inventor on patent applications WPO2015179437A1, entitled “Methods and compositions for reducing Clostridium difficile infection”, and WO2017091753A1, entitled “Methods and compositions for reducing vancomycin-resistant enterococci infection or colonization”, and holds patents that receive royalties from Seres Therapeutics Inc. M.T.S. declares no competing interests.

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Glossary

Microbiota restoration

Re-establishment of the diversity, density and beneficial functions of the microbiota following perturbation.

Colonization resistance

Inhibition of exogenous species, including pathogens, by the resident microbiota.

Colitis

Inflammation occurring in the large intestine.

Engraftment

Establishment of a replicating, self-sustaining population of an introduced species or strain in a community.

Alpha diversity

Measure of community diversity within a sample based on taxonomic richness (number of species) and evenness.

Hepatic steatosis

A condition of non-alcoholic fatty liver disease defined by the accumulation of intrahepatic fat to greater than 5% of liver weight.

Bacteroicins

Short ribosomally synthesized antimicrobial peptides produced by bacteria that often target closely related species but are, in general, not harmful to producing bacteria owing to immune mechanisms.

Mucins

A family of large, highly glycosylated proteins secreted at mucosal surfaces. In the intestine, secreted mucins form a protective and selective barrier between epithelial cells and luminal contents.

Checkpoint immunotherapy

Cancer therapy that functions by promoting an antitumour immune response by targeting proteins such as CTLA4 or PD1/PDL1 that normally function to limit immune responses.

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Sorbara, M.T., Pamer, E.G. Microbiome-based therapeutics. Nat Rev Microbiol 20, 365–380 (2022). https://doi.org/10.1038/s41579-021-00667-9

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