Skip to main content

Engineering the gut microbiota to treat chronic diseases

Applied Microbiology and Biotechnology volume 104, pages 7657–7671 (2020)Cite this article

Abstract

Gut microbes play vital roles in host health and disease. A number of commensal bacteria have been used as vectors for genetic engineering to create living therapeutics. This review highlights recent advances in engineering gut bacteria for the treatment of chronic diseases such as metabolic diseases, cancer, inflammatory bowel diseases, and autoimmune disorders.

Key points

• Bacterial homing to tumors has been exploited to deliver therapeutics in mice models.

• Engineered bacteria show promise in mouse models of metabolic diseases.

• Few engineered bacterial treatments have advanced to clinical studies.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  • Arrach N, Zhao M, Porwollik S, Hoffman R, McClelland M (2008) Salmonella promoters preferentially activated inside tumors. Cancer Res 68:1363

    Google Scholar 

  • Behnsen J, Deriu E, Sassone-corsi M, Raffatellu M (2013) Probiotics: properties, examples, and specific applications. Cold Spring Harb Perspect Med 3:a010074

    PubMed  PubMed Central  Google Scholar 

  • Bilotta AJ, Cong Y (2019) Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Precis Clin Med 2:110–119

    PubMed  PubMed Central  Google Scholar 

  • Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L (2006) A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol 4:754–759

    CAS  PubMed  Google Scholar 

  • Broadway KM, Denson EAP, Jensen RV, Scharf BE (2015) Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009. J Biotechnol 211:117–120. https://doi.org/10.1016/j.jbiotec.2015.07.010

    Article  CAS  PubMed  Google Scholar 

  • Broadway KM, Suh S, Behkam B, Scharf BE (2017) Optimizing the restored chemotactic behavior of anticancer agent Salmonella enterica serovar Typhimurium VNP20009. J Biotechnol 251:76–83. https://doi.org/10.1016/j.jbiotec.2017.04.006

    Article  CAS  PubMed  Google Scholar 

  • Buescher JM, Liebermeister W, Jules M, Uhr M, Muntel J, Botella E, Hessling B, Kleijn RJ, Le Chat L, Lecointe F, Mäder U, Nicolas P, Piersma S, Rügheimer F, Becher D, Bessieres P, Bidnenko E, Denham EL, Dervyn E, Devine KM, Doherty G, Drulhe S, Felicori L, Fogg MJ, Goelzer A, Hansen A, Harwood CR, Hecker M, Hubner S, Hultschig C, Jarmer H, Klipp E, Leduc A, Lewis P, Molina F, Noirot P, Peres S, Pigeonneau N, Pohl S, Rasmussen S, Rinn B, Schaffer M, Schnidder J, Schwikowski B, Van Dijl JM, Veiga P, Walsh S, Wilkinson AJ, Stelling J, Aymerich S, Sauer U (2012) Global network reorganization during dynamic adaptations of Bacillus subtilis metabolism. Science 335(80):1099–1103

    CAS  PubMed  Google Scholar 

  • Buffa V, Stieh D, Mamhood N, Hu Q, Fletcher P, Shattock RJ (2009) Cyanovirin-N potently inhibits human immunodeficiency virus type 1infection in cellular and cervical explant models. J Gen Virol 90:234–243

    CAS  PubMed  Google Scholar 

  • Caluwaerts S, Vandenbroucke K, Steidler L, Neirynck S, Vanhoenacker P, Corveleyn S, Watkins B, Sonis S, Coulie B, Rottiers P (2010) AG013 , a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1 , provides a safe and efficacious therapeutic tool for treating oral mucositis. Oral Oncol 46:564–570. https://doi.org/10.1016/j.oraloncology.2010.04.008

    Article  CAS  PubMed  Google Scholar 

  • Cano-Garrido O, Seras-Franzoso J, Garcia-Fruitós E (2015) Lactic acid bacteria: reviewing the potential of a promising delivery live vector for biomedical purposes. Microb Cell Factories 14:137

    Google Scholar 

  • Carroll IM, Andrus JM, Bruno-Barcena JM, Klaenhammer TR, Hassan HM, Threadgill DS (2007) Anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase using the interleukin 10-deficient mouse model of colitis. Am J Physiol Gastrointest Liver Physiol 293:G729–G738

    CAS  PubMed  Google Scholar 

  • Charbonneau MR, Isabella VM, Li N, Kurtz CB (2020) Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat Commun 11:11(1738). https://doi.org/10.1038/s41467-020-15508-1

    Article  CAS  Google Scholar 

  • Chen Z, Niswender KD, Davies SS, 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 (2014) Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Investig 124:3391–3406. https://doi.org/10.1172/JCI72517

  • Cheong I, Huang X, Bettegowda C, Diaz LA, Kinzler KW, Zhou S, Vogelstein B (2006) A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science (80). https://doi.org/10.1126/science.1130651

  • Cheong I, Huang X, Thornton K, Diaz LA, Zhou S (2007) Targeting cancer with bugs and liposomes: ready, aim, fire. Cancer Res 67:9605–9608

    CAS  PubMed  Google Scholar 

  • Choi HH, Cho YS (2016) Fecal microbiota transplantation: current applications, effectiveness, and future perspectives. Clin Endosc 49:257–265

    PubMed  PubMed Central  Google Scholar 

  • Colaco CA, Bailey CR, Walker KB, Keeble J (2013) Heat shock proteins : stimulators of innate and acquired immunity. Biomed Res Int 2013:461230

    PubMed  PubMed Central  Google Scholar 

  • Cook DP, Gysemans C, Mathieu C (2018) Lactococcus lactis as a versatile vehicle for tolerogenic immunotherapy. Front Immunol 8:1961

    PubMed  PubMed Central  Google Scholar 

  • Crull K, Bumann D, Weiss S (2011) Influence of infection route and virulence factors on colonization of solid tumors by Salmonella enterica serovar Typhimurium. FEMS Immunol Med Microbiol 62:75–83. https://doi.org/10.1111/j.1574-695X.2011.00790.x

    Article  CAS  PubMed  Google Scholar 

  • Cunningham C, Nemunaitis J (2001) A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Hum Gene Ther 12:1594–1596

  • Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B (2001) Combination bacteriolytic therapy for the treatment of experimental tumors. PNAS 98:15155–15160

    CAS  PubMed  PubMed Central  Google Scholar 

  • De Moreno De Leblanc A, Del Carmen S, Chatel JM, Miyoshi A, Azevedo V, Langella P, Bermúdez-Humarán LG, Leblanc JG (2015) Current review of genetically modified lactic acid bacteria for the prevention and treatment of colitis using murine models. Gastroenterol Res Pract 2015:146972. https://doi.org/10.1155/2015/146972

  • del Carmen S, De Moreno De Leblanc A, Perdigon G, Bastos Pereira V, Miyoshi A, Azevedo V, Leblanc JG (2012) Evaluation of the anti-inflammatory effect of milk fermented by a strain of IL-10-producing Lactococcus lactis using a murine model of Crohn’s disease. J Mol Microbiol Biotechnol 21:138–146. https://doi.org/10.1159/000333830

    Article  CAS  Google Scholar 

  • Del Carmen S, Zurita-Turk M, Alvarenga Lima F, Coelho Dos Santos JS, Leclercq SY, Chatel JM, Azevedo V, De Moreno De Leblanc A, Miyoshi A, LeBlanc JG (2013) A novel interleukin-10 DNA mucosal delivery system attenuates intestinal inflammation in a mouse model. Eur J Inflamm 11:641–654. https://doi.org/10.1177/1721727X1301100308

    Article  Google Scholar 

  • del Carmen S, de Moreno de LeBlanc A, Martin R, Chain F, Langella P, Bermúdez-Humarán LG, LeBlanc JG (2014a) Genetically engineered immunomodulatory Streptococcus thermophilus strains producing antioxidant enzymes exhibit enhanced anti-inflammatory activities. Appl Environ Microbiol 80:869–877. https://doi.org/10.1128/AEM.03296-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Del Carmen S, Rosique RM, Saraiva T, Zurita-Turk M, Miyoshi A, Azevedo V, De Moreno De LeBlanc A, Langella P, Bermúdez-Humarán LG, LeBlanc JG (2014b) Protective effects of lactococci strains delivering either IL-10 protein or cDNA in a TNBS-induced chronic colitis model. J Clin Gastroenterol 48(Suppl 1):S12–S17. https://doi.org/10.1097/MCG.0000000000000235

  • del Carmen S, Miyoshi A, Azevedo V, de Moreno de LeBlanc A, LeBlanc JG (2015) Evaluation of a Streptococcus thermophilus strain with innate anti-inflammatory properties as a vehicle for IL-10 cDNA delivery in an acute colitis model. Cytokine. 73:177–183. https://doi.org/10.1016/j.cyto.2015.02.020

    Article  CAS  PubMed  Google Scholar 

  • del Carmen S, de Moreno de LeBlanc A, Levit R, Azevedo V, Langella P, Bermúdez-Humarán LG, LeBlanc JG (2017) Anti-cancer effect of lactic acid bacteria expressing antioxidant enzymes or IL-10 in a colorectal cancer mouse model. Int Immunopharmacol 42:122–129. https://doi.org/10.1016/j.intimp.2016.11.017

    Article  CAS  PubMed  Google Scholar 

  • Deyneko IV, Kasnitz N, Leschner S, Weiss S (2016) Composing a tumor specific bacterial promoter. PLoS One 11:e0155338. https://doi.org/10.1371/journal.pone.0155338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dosoky NS, Guo L, Chen Z, Feigley AV, Davies SS (2018) Dietary fatty acids control the species of N-acyl-phosphatidylethanolamines synthesized by therapeutically modified bacteria in the intestinal tract. ACS Infect Dis 4:3–13. https://doi.org/10.1021/acsinfecdis.7b00127

    Article  CAS  PubMed  Google Scholar 

  • Dosoky NS, Chen Z, Guo Y, Mcmillan C, Flynn CR, Davies SS (2019) Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment. Appl Microbiol Biotechnol 103:6711–6723. https://doi.org/10.1007/s00253-019-09958-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan F, Curtis KL, March JC (2008) Secretion of insulinotropic proteins by commensal bacteria: rewiring the gut to treat diabetes. Appl Environ Microbiol 74:7437–7438. https://doi.org/10.1128/AEM.01019-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan FF, Liu JH, March JC (2015) Engineered commensal bacteria reprogram intestinal cells into cells for the treatment of diabetes. 64:1794–1803. https://doi.org/10.2337/db14-0635

  • Felgner S, Kocijancic D, Frahm M, Heise U, Rohde M, Zimmermann K, Falk C, Erhardt M, Weiss S (2018) Engineered Salmonella enterica serovar Typhimurium overcomes limitations of anti-bacterial immunity in bacteria-mediated tumor therapy. Oncoimmunology. 7. https://doi.org/10.1080/2162402X.2017.1382791

  • Feng W, Ao H, Peng C (2018) Gut microbiota, short-chain fatty acids, and herbal medicines. Front Pharmacol 9:1354

    CAS  PubMed  PubMed Central  Google Scholar 

  • Forbes NS (2010) Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10:785–794. https://doi.org/10.1038/nrc2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forbes NS, Munn LL, Fukumura D, Jain RK (2003) Sparse initial entrapment of systemically injected Salmonella typhimurium leads to heterogeneous accumulation within tumors. Cancer Res 63:5188–5193

    CAS  PubMed  Google Scholar 

  • Ganai S, Arenas RB, Forbes NS (2009) Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice. Br J Cancer 101:1683–1691. https://doi.org/10.1038/sj.bjc.6605403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganai S, Arenas RB, Sauer JP, Bentley B, Forbes NS (2011) In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis. Cancer Gene Ther 18:457–466

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gerritsen J, Smidt H, Rijkers GT, de Vos WM (2011) Intestinal microbiota in human health and disease: the impact of probiotics. Genes Nutr 6:209–240

    PubMed  PubMed Central  Google Scholar 

  • Gillum MP, Zhang D, Zhang XM, Erion DM, Jamison RA, Choi C, Dong J, Shanabrough M, Duenas HR, Frederick DW, Hsiao JJ, Horvath TL, Lo CM, Tso P, Cline GW, Shulman GI (2008) N-acylphosphatidylethanolamine, a gut- derived circulating factor induced by fat ingestion, inhibits food intake. Cell 135:813–824. https://doi.org/10.1016/j.cell.2008.10.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goh YJ, Goin C, O’Flaherty S, Altermann E, Hutkins R (2011) Specialized adaptation of a lactic acid bacterium to the milk environment: the comparative genomics of Streptococcus thermophilus LMD-9. Microb Cell Factories 10:S22. https://doi.org/10.1186/1475-2859-10-S1-S22

    Article  Google Scholar 

  • Guimarães V, Innocentin S, Chatel JM, Lefèvre F, Langella P, Azevedo V, Miyoshi A (2009) A new plasmid vector for DNA delivery using lactococci. Genet Vaccines Ther 7:4. https://doi.org/10.1186/1479-0556-7-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han W, Mercenier A, Ait-Belgnaoui A, Pavan S, Lamine F, van Swam I, Kleerebezem M, Salvador-Cartier C, Hisbergues M, Bueno L, Theodorou V, Fioramonti J (2006) Improvement of an experimental colitis in rats by lactic acid bacteria producing superoxide dismutase. Inflamm Bowel Dis 12:1044–1052

    PubMed  Google Scholar 

  • Harris ML, Schiller HJ, Reilly PM, Donowitz M, Grisham MB, Bulkley GB (1992) Free radicals and other reactive oxygen metabolites in inflammatory bowel disease: cause, consequence or epiphenomenon? Pharmacol Ther 53:375–408

    CAS  PubMed  Google Scholar 

  • Hidaka A, Hamaji Y, Sasaki T, Taniguchi S, Fujimori M (2007) Exogenous cytosine deaminase gene expression in Bifidobacterium breve I-53-8w for tumor-targeting enzyme/prodrug therapy. Biosci Biotechnol Biochem 71:2921–2926

    CAS  PubMed  Google Scholar 

  • Hong HA, Duc le H, Cutting SM (2005) The use of bacterial spore formers as probiotics. FEMS Microbiol Rev 29:813–835

    CAS  PubMed  Google Scholar 

  • Hosseini S, Curilovs A, Cutting SM (2018) Biological containment of genetically modified Bacillus subtilis. Appl Environ Microbiol 84:e02334–e02317

    PubMed  PubMed Central  Google Scholar 

  • Huang CJ, Lin H, Yang X (2012) Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements. J Ind Microbiol Biotechnol 39:383–399

    CAS  PubMed  Google Scholar 

  • Huibregtse IL, Snoeck V, De Creus A, Braat H, De Jong EC, van Deventer SJH, Rottiers P (2007) Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology 133:517–552. https://doi.org/10.1053/j.gastro.2007.04.073

    Article  CAS  PubMed  Google Scholar 

  • Huibregtse IL, Marietta EV, Rashtak S, Koning F, Rottiers P, David CS, Van SJH, Murray JA (2009) Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered Immunodominant DQ8-restricted Gliadin peptide in sensitized nonobese diabetic abo Dq8 transgenic mice. J Immunol 183:2390–2396. https://doi.org/10.4049/jimmunol.0802891

    Article  CAS  PubMed  Google Scholar 

  • Huibregtse IL, Zaat SA, Kapsenberg ML, Sartori MA, Peppelenbosch MP, Van Deventer SJH, Braat H (2012, 2012) Genetically modified Lactococcus lactis for delivery of human Interleukin-10 to dendritic cells. https://doi.org/10.1155/2012/639291

  • Isabella VM, Ha BN, Castillo MJ, Lubkowicz DJ, Rowe SE, Millet YA, Anderson CL, Li N, Fisher AB, West KA, Reeder PJ, Momin MM, Bergeron CG, Guilmain SE, Miller PF, Kurtz CB, Falb D (2018) Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat Biotechnol 36:857–864

    CAS  PubMed  Google Scholar 

  • Jeong J-H, Kim K, Lim D, Jeong K, Hong Y, Nguyen VH, Kim T-H, Ryu S, Lim J-A, Kim JI, Kim G-J, Kim SC, Min J-J, Choy HE (2014) Anti-tumoral effect of the mitochondrial target domain of Noxa delivered by an engineered Salmonella typhimurium. PLoS One 9:e80050. https://doi.org/10.1371/journal.pone.0080050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang S, Phan TX, Nam T, Nguyen VH, Kim H, Bom H, Choy HE, Hong Y, Min J (2010) Inhibition of tumor growth and metastasis by a combination of Escherichia coli – mediated cytolytic therapy and radiotherapy. Mol Ther 18:635–642. https://doi.org/10.1038/mt.2009.295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jing H, Yong L, Haiyan L, Yanjun M, Yun X, Yu Z, Taiming L, Rongyue C (2011) Oral administration of Lactococcus lactis delivered heat shock protein 65 attenuates atherosclerosis in low-density lipoprotein receptor-deficient mice. Vaccine 29:4102–4109. https://doi.org/10.1016/j.vaccine.2011.03.105

    Article  CAS  PubMed  Google Scholar 

  • Juhas M, Reuß DR, Zhu B, Commichau FM (2014) Bacillus subtilis and Escherichia coli essential genes and minimal cell factories after one decade of genome engineering. Microbiology 160:2341–2351

    CAS  PubMed  Google Scholar 

  • Kasinskas RW, Forbes NS (2006) Salmonella typhimurium specifically chemotax and proliferate in heterogeneous tumor tissue in vitro. Biotechnol Bioeng 94:710–721

    CAS  PubMed  Google Scholar 

  • Kennedy EA, King KY, Baldridge MT (2018) Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut Bacteria. Front Physiol 9:1534

    PubMed  PubMed Central  Google Scholar 

  • King I, Bermudes D, Lin S, Belcourt M, Pike J, Troy K, Le T, Ittensohn M, Mao J, Lang W, Runyan JD, Luo X, Li Z, Zheng LM (2002) Tumor-targeted Salmonella expressing cytosine deaminase as an anticancer agent. Hum Gene Ther 13:1225–1233. https://doi.org/10.1089/104303402320139005

    Article  CAS  PubMed  Google Scholar 

  • Klijn N, Weerkamp AH, de Vos WM (1995) Genetic marking of Lactococcus lactis shows its survival in the human gastrointestinal tract. Appl Environ Microbiol 61:2771–2774

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kocijancic D, Felgner S, Frahm M, Komoll RM, Iljazovic A, Pawar V, Rohde M, Heise U, Zimmermann K, Gunzer F, Hammer J, Crull K, Leschner S, Weiss S (2016) Therapy of solid tumors using probiotic Symbioflor-2-restraints and potential. Oncotarget. 7:22605–22622. https://doi.org/10.18632/oncotarget.8027

    Article  PubMed  PubMed Central  Google Scholar 

  • Koo BM, Kritikos G, Farelli JD, Todor H, Tong K, Kimsey H, Wapinski I, Galardini M, Cabal A, Peters JM, Hachmann AB, Rudner DZ, Allen KN, Typas A, Gross CA (2017) Construction and analysis of two genome-scale deletion libraries for Bacillus subtilis. Cell Syst 4:291–305

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kubiak AM, Minton NP (2015) The potential of clostridial spores as therapeutic delivery vehicles in tumour therapy. Res Microbiol 166(4):244–254. https://doi.org/10.1016/j.resmic.2014.12.006

    Article  CAS  PubMed  Google Scholar 

  • Lagenaur LA, Sanders-beer BE, Brichacek B, Pal R, Liu X, Liu Y, Yu R, Venzon D, Lee PP, Hamer DH (2011) Prevention of vaginal SHIV transmission in macaques by a live recombinant Lactobacillus. 4:648–657. https://doi.org/10.1038/mi.2011.30

  • LeBlanc JG, del Carmen S, Miyoshi A, Azevedo V, Sesma F, Langella P, Bermudez Humaran L, Watterlot L, Perdigon G, de Moreno de LeBlanc A (2011) Use of superoxide dismutase and catalase expressing lactic acid bacteria to attenuate TNBS induced Crohn’s disease in mice. J Biotechnol 151:287–293

    CAS  PubMed  Google Scholar 

  • Lee CH, Wu CL, Shiau AL (2005) Systemic administration of attenuated Salmonella choleraesuis carrying thrombospondin-1 gene leads to tumor-specific transgene expression, delayed tumor growth and prolonged survival in the murine melanoma model. Cancer Gene Ther 12:175–184

    CAS  PubMed  Google Scholar 

  • Lehouritis P, Springer C, Tangney M (2013) Bacterial-directed enzyme prodrug therapy. J Control Release 170:120–131

    CAS  PubMed  Google Scholar 

  • Lemmon MJ, van Zijl P, Fox ME, Mauchline ML, Giaccia AJ, Minton NP, Brown JM (1997) Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Ther 8:791–796

    Google Scholar 

  • Leschner S, Deyneko IV, Lienenklaus S, Wolf K, Bloecker H, Bumann D, Loessner H, Weiss S (2012) Identification of tumor-specific Salmonella Typhimurium promoters and their regulatory logic. Nucleic Acids Res 40:2984–2994. https://doi.org/10.1093/nar/gkr1041

    Article  CAS  PubMed  Google Scholar 

  • Li X, Fu GF, Fan YR, Liu WH, Liu XJ, Wang JJ, Xu GX (2003) Bifidobacterium adolescentis as a delivery system of endostatin for cancer gene therapy: selective inhibitor of angiogenesis and hypoxic tumor growth. Cancer Gene Ther 10:105–111

    CAS  PubMed  Google Scholar 

  • Li Z, Fallon J, Mandeli J, Wetmur J, Woo SLC (2008) A genetically enhanced anaerobic bacterium for oncopathic therapy of pancreatic cancer. J Natl Cancer Inst 100:1389–1400. https://doi.org/10.1093/jnci/djn308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Fallon J, Mandeli J, Wetmur J, Woo SLC (2010) Retraction: a genetically enhanced anaerobic bacterium for oncopathic therapy of pancreatic cancer. J Natl Cancer Inst 102:283. https://doi.org/10.1093/jnci/djq027

    Article  PubMed  PubMed Central  Google Scholar 

  • Limaye SA, Haddad RI, Cilli F, Sonis ST, Colevas AD, Brennan MT, Hu KS, Murphy BA (2013) Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 119:4268–4276. https://doi.org/10.1002/cncr.28365

    Article  CAS  PubMed  Google Scholar 

  • Liu SC, Minton NP, Giaccia AJ, Brown JM (2002) Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 9:291–296

    CAS  PubMed  Google Scholar 

  • Liu K, Liu X, Li G, Lu S, Jin L, Wu J (2016) Oral administration of Lactococcus lactis- expressing heat shock protein 65 and tandemly repeated IA2P2 prevents type 1 diabetes in NOD mice. Immunol Lett 174:28–36. https://doi.org/10.1016/j.imlet.2016.04.008

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Li S, Zhang Q, Xu Z, Wang J, Sun H (2018) Oral engineered Bifidobacterium longum expressing rhMnSOD to suppress experimental colitis. Int Immunopharmacol 57:25–32. https://doi.org/10.1016/j.intimp.2018.02.004

    Article  CAS  PubMed  Google Scholar 

  • Loessner H, Leschner S, Endmann A, Westphal K, Wolf K, Kochruebe K, Miloud T, Altenbuchner J, Weiss S (2009) Drug-inducible remote control of gene expression by probiotic Escherichia coli Nissle 1917 in intestine , tumor and gall bladder of mice. Microbes Infect 11:1097–1105. https://doi.org/10.1016/j.micinf.2009.08.002

    Article  CAS  PubMed  Google Scholar 

  • Malmgren RA, Flanigan CC (1955) Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer Res 15:473–478

    CAS  PubMed  Google Scholar 

  • Manabe K, Kageyama Y, Morimoto T, Ozawa T, Sawada K, Endo K, Tohata M, Ara K, Ozaki K, Ogasawara N (2011) Combined effect of improved cell yield and increased specific productivity enhances recombinant enzyme production in genome-reduced Bacillus subtilis strain MGB874. Appl Environ Microbiol 77:8370–8381

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martín R, Miquel S, Ulmer J, Kechaou N, Langella P, Bermúdez-humarán LG (2013) Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. Microb Cell Factories 12:71

    Google Scholar 

  • May-Zhang LS, Chen Z, Dosoky NS, Yancey PG, Boyd KL, Hasty AH, Linton MF, Davies SS (2019) Administration of N-acyl-phosphatidylethanolamine expressing bacteria to low density lipoprotein receptor(−/−) mice improves indices of cardiometabolic disease. Sci Rep 9:420. https://doi.org/10.1038/s41598-018-37373-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mei S, Theys J, Landuyt W, Anne J, Lambin P (2002) Optimization of tumor-targeted gene delivery by engineered attenuated Salmonella typhimurium. Anticancer Res 22:3261–3266

    CAS  PubMed  Google Scholar 

  • Mengesha A, Dubois L, Lambin P, Landuyt W, Chiu RK, Wouters BG, Theys J (2006) Development of a flexible and potent hypoxia-inducible promoter for tumor-targeted gene expression in attenuated Salmonella. Cancer Biol Ther 5:1120–1128. https://doi.org/10.4161/cbt.5.9.2951

    Article  CAS  PubMed  Google Scholar 

  • Mi Z, Feng Z-C, Li C, Yang X, Ma M-T, Rong P-F (2019) Salmonella-mediated cancer therapy: an innovative therapeutic strategy. J Cancer 10:4765–4776. https://doi.org/10.7150/jca.32650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morimoto T, Kadoya R, Endo K, Tohata M, Sawada K, Liu S, Ozawa T, Kodama T, Kakeshita H, Kageyama Y, Manabe K, Kanaya S, Ara K, Ozaki K, Ogasawara N (2008) Enhanced recombinant protein productivity by genome reduction in Bacillus subtilis. DNA Res 15:73–81

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mukherjee S, Joardar N, Sengupta S, Babu SPS (2018) Gut microbes as future therapeutics in treating inflammatory and infectious diseases: lessons from recent findings. J Nutr Biochem 61:111–128. https://doi.org/10.1016/j.jnutbio.2018.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muyldermans S (2013) Nanobodies: natural single-domain antibodies. Annu Rev Biochem 82:775–797. https://doi.org/10.1146/annurev-biochem-063011-092449

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Sasaki T, Fujimori M, Yazawa K, Kano Y, Amano J, Taniguchi S (2002) Cloned cytosine deaminase gene expression of Bifidobacterium longum and application to enzyme/pro-drug therapy of hypoxic solid tumors. Biosci Biotechnol Biochem 66:2362–2366

    CAS  PubMed  Google Scholar 

  • Nemunaitis J, Cunningham C, Senzer N, Kuhn J, Cramm J, Litz C, Cavagnolo R, Cahill A, Clairmont C, Sznol M (2003) Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. https://doi.org/10.1038/sj.cgt.7700634

  • Nguyen VA, Huynh HA, Hoang TV, Ninh NT, Pham AT, Nguyen HA, Phan TN, Cutting SM (2013) Killed Bacillus subtilis spores expressing streptavidin: a novel carrier of drugs to target cancer cells. J Drug Target 21:528–541

    CAS  PubMed  Google Scholar 

  • Nuyts S, Theys J, Landuyt W, van Mellaert L, Lambin P, Anne J (2001a) Increasing specificity of anti-tumor therapy: cytotoxic protein delivery by non-pathogenic clostridia under regulation of radio-induced promoters. Anticancer Res 21:857–861

    CAS  PubMed  Google Scholar 

  • Nuyts S, Van Mellaert L, Theys J, Landuyt W, Bosmans E, Anne J, Lambin P (2001b) Radio-responsive recA promoter significantly increases TNFalpha production in recombinant Clostridia after 2 Gy irradiation. Gene Ther 8:1197–1201. https://doi.org/10.1038/sj.gt.3301499

  • Parker RC, Plummer HC, Siebenmann CO, Chapman MG (1947) Effect of Histolyticus infection and toxin on transplantable mouse tumors. Proc Soc Exp Biol Med 66:461–467. https://doi.org/10.3181/00379727-66-16124

  • Pinero-Lambea C, Ruano-Gallego D, Fernandez LA (2015) Engineered bacteria as therapeutic agents. Curr Opin Biotechnol 35:94–102. https://doi.org/10.1016/j.copbio.2015.05.004

    Article  CAS  PubMed  Google Scholar 

  • Piomelli D (2013) A fatty gut feeling. Trends Endocrinol Metab 24:332–341

    CAS  PubMed  PubMed Central  Google Scholar 

  • Plevy S (2006) Clostridium perfringens as a novel therapeutic vehicle in inflammatory bowel disease. Proposal No. IBD-0110. Final report. (https://site.crohnscolitisfoundation.org/science-and-professionals/broad/funding/funded-grants/final-reports.html)

  • Rao S, Hu S, McHugh L, Lueders K, Henry K, Zhao Q, Fekete RA, Kar S, Adhya S, Hamer DH (2005) Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide. Proc Natl Acad Sci U S A 102:11993–11998. https://doi.org/10.1073/pnas.0504881102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reuß DR, Altenbuchner J, Mäder U, Rath H, Ischebeck T, Sappa PK, Thürmer A, Guérin C, Nicolas P, Steil L, Zhu B, Feussner I, Klumpp S, Daniel R, Commichau FM, Völker U, Stülke J (2017) Largescale reduction of the Bacillus subtilis genome: consequences for the transcriptional network, resource allocation, and metabolism. Genome Res 27:289–299

    PubMed  PubMed Central  Google Scholar 

  • Rezende RM, Oliveira RP, Medeiros SR, Gomes-santos AC, Alves AC, Loli FG, Guimarães MAF, Amaral SS, André P, Weiner HL, Azevedo V, Miyoshi A, Faria AMC (2013) Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4 þ LAP þ regulatory T cells. J Autoimmun 40:45–57. https://doi.org/10.1016/j.jaut.2012.07.012

    Article  CAS  PubMed  Google Scholar 

  • Robert S, Gysemans C, Takiishi T, Korf H, Spagnuolo I, Sebastiani G, Van Huynegem K, Steidler L, Caluwaerts S, Demetter P, Wasserfall CH, Atkinson MA, Dotta F, Rottiers P, Van Belle TL, Mathieu C (2014) Oral delivery of glutamic acid decarboxylase ( GAD ) -65 and IL10 by Lactococcus lactis reverses diabetes in recent- onset NOD mice. Diabetes 63:2876–2887. https://doi.org/10.2337/db13-1236

    Article  CAS  PubMed  Google Scholar 

  • Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16:341–352

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenberg SA, Spiess PJ, Kleiner DE (2002) Antitumor effects in mice of the intravenous injection of attenuated Salmonella typhimurium. J Immunother 25:218–225

    CAS  PubMed  PubMed Central  Google Scholar 

  • Royo JL, Becker PD, Camacho EM, Cebolla A, Link C, Santero E, Guzmán CA (2007) In vivo gene regulation in Salmonella spp. by a salicylate-dependent control circuit. Nat Methods 4:937–942. https://doi.org/10.1038/nmeth1107

    Article  CAS  PubMed  Google Scholar 

  • Sasaki T, Fujimori M, Hamaji Y, Hama Y, Ito K, Amano J, Taniguchi S (2006) Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats. Cancer Sci 97:649–657

    CAS  PubMed  Google Scholar 

  • Sekirov I, Russell SL, Antunes LCM, Finlay BB (2010) Gut microbiota in health and disease. Physiol Rev 90:859–904. https://doi.org/10.1152/physrev.00045.2009

    Article  CAS  PubMed  Google Scholar 

  • Smith K, McCoy KD, Macpherson AJ (2007) Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 19:59–69. https://doi.org/10.1016/j.smim.2006.10.002

    Article  CAS  PubMed  Google Scholar 

  • Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E (2000) Treatment of murine colitis by Lactococcus lactis secreting Interleukin-10. Science 289(80):1352–1355

    CAS  PubMed  Google Scholar 

  • Steidler L, Neirynck S, Huyghebaert N, Snoeck V, Vermeire A, Goddeeris B, Cox E, Remon JP, Remaut E (2003) Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 21:785–789

    CAS  PubMed  Google Scholar 

  • Stordeur P, Goldman M (1998) Interleukin-10 as a regulatory cytokine induced by cellular stress: molecular aspects. Int Rev Immunol 16(5-6):501–522

    CAS  PubMed  Google Scholar 

  • Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558:263–275

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki A, Nakauchi H, Taniguchi H (2003) Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells. PNAS 100:5034–5039

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swofford CA, Van Dessel N, Forbes NS (2015) Quorum-sensing Salmonella selectively trigger protein expression within tumors. Proc Natl Acad Sci U S A 112:3457–3462. https://doi.org/10.1073/pnas.1414558112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takiishi T, Gysemans C, Mathieu C, Takiishi T, Korf H, Van Belle TL, Robert S, Grieco FA, Caluwaerts S, Galleri L, Spagnuolo I, Steidler L, Van Huynegem K, Demetter P, Wasserfall C, Atkinson MA (2012) Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. 122:1717–1725. https://doi.org/10.1172/JCI60530.with

  • Theys J, Landuyt W, Nuyts S, Van Mellaert L, van Oosterom A, Lambin P, Anne J (2001) Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum. Cancer Gene Ther 8:294–297

    CAS  PubMed  Google Scholar 

  • Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ, Sherry RM, Topalian SL, Yang JC, Stock F, Freezer LJ, Morton KE, Seipp C, Haworth L, Mavroukakis S, White D, MacDonald S, Mao J, Sznol M, Rosenberg SA (2002) Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20:142–152. https://doi.org/10.1200/jco.2002.20.1.142

    Article  PubMed  Google Scholar 

  • Tsai C-C, Emau P, Jiang Y, Tian B, Morton WR, Gustafson KR, Boyd MR (2004) Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. AIDS Res Hum Retrovir 19:535–541

    Google Scholar 

  • Turrens JF, Crapo J, Freeman BA (1984) Protection against oxygen toxicity by intravenous injection of liposome-entrapped catalase and superoxide dismutase. J Clin Invest 73:87–95

    CAS  PubMed  PubMed Central  Google Scholar 

  • Van Dessel N, Swofford CA, Forbes NS (2015) Potent and tumor specific: arming bacteria with therapeutic proteins. Ther Deliv 6:385–399. https://doi.org/10.4155/tde.14.113

    Article  CAS  PubMed  Google Scholar 

  • van Dijl JM, Hecker M (2013) Bacillus subtilis: from soil bacterium to super-secreting cell factory. Microb Cell Factories 12:3

    Google Scholar 

  • Vandenbroucke K, De Haard H, Beirnaert E, Dreier T, Lauwereys M, Huyck L, Van Huysse J, Demetter P, Steidler L, Remaut E, Cuvelier C, Rottiers P (2010) Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol 3:49–56. https://doi.org/10.1038/mi.2009.116

    Article  CAS  PubMed  Google Scholar 

  • Wei P, Yang Y, Ding Q, Li X, Sun H, Liu Z, Huang J, Gong Y (2015a) Oral delivery of Bifidobacterium longum expressing alpha-melanocyte-stimulating hormone to combat ulcerative colitis. J Med Microbiol 65:160

    PubMed  Google Scholar 

  • Wei P, Yang Y, Li T, Ding Q, Sun H (2015b) A engineered Bifidobacterium longum secreting a bioactive penetratin-glucagon-like peptide 1 fusion protein enhances glucagon-like peptide 1 absorption in the intestine. J Microbiol Biotechnol 2015. https://doi.org/10.4014/jmb.1412.12030

  • Weibel S, Stritzker J, Eck M, Goebel W, Szalay AA (2008) Colonization of experimental murine breast tumours by Escherichia coli K-12 significantly alters the tumour microenvironment. Cell Microbiol 10:1235–1248

    CAS  PubMed  Google Scholar 

  • Wen M, Zheng JH, Choi JM, Pei J, Li C-H, Li S-Y, Kim I-Y, Lim S-H, Jung T-Y, Moon K-S, Min J-J, Jung S (2018) Genetically-engineered Salmonella typhimurium expressing TIMP-2 as a therapeutic intervention in an orthotopic glioma mouse model. Cancer Lett 433:140–146. https://doi.org/10.1016/j.canlet.2018.06.031

    Article  CAS  PubMed  Google Scholar 

  • Westers H, Dorenbos R, van Dijl JM, Kabel J, Flanagan T, Devine KM, Jude F, Seror SJ, Beekman AC, Darmon E, Eschevins C, de Jong A, Bron S, Kuipers OP, Albertini AM, Antelmann H, Hecker M, Zamboni N, Sauer U, Bruand C, Ehrlich DS, Alonso JC, Salas M, Quax WJ (2003) Genome engineering reveals large dispensable regions in Bacillus subtilis. Mol Biol Evol 20:2076–2090

    CAS  PubMed  Google Scholar 

  • Westers L, Westers H, Quax WJ (2004) Bacillus subtilis as cell factory for pharmaceutical proteins: a biotechnological approach to optimize the host organism. Biochim Biophys Acta (BBA)–Mol Cell Res 1694:299–310

    CAS  Google Scholar 

  • Westphal K, Leschner S, Jablonska J, Loessner H, Weiss S (2008) Containment of tumor-colonizing bacteria by host neutrophils. Cancer Res 68:2952–2961. https://doi.org/10.1158/0008-5472.CAN-07-2984

    Article  CAS  PubMed  Google Scholar 

  • Xiang S, Fruehauf J, Li CJ (2006) Short hairpin RNA – expressing bacteria elicit RNA interference in mammals. Nat Biotechnol 24:697–702. https://doi.org/10.1038/nbt1211

    Article  CAS  PubMed  Google Scholar 

  • Xu Q (2002) Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 22:1547–1559

    CAS  PubMed  Google Scholar 

  • Yi C, Huang Y, Guo ZY, Wang SR (2005) Antitumor effect of cytosine deaminase/ 5-fluorocytosine suicide gene therapy system mediated by Bifidobacterium infantis on melanoma. Acta Pharmacol Sin 26:629–634

    CAS  PubMed  Google Scholar 

  • Ÿztürk S, Ÿalık P, Ÿzdamar TH (2016) Fed-batch biomolecule production by Bacillus subtilis: a state of the art review. Trends Biotechnol 34:329–345

    PubMed  Google Scholar 

  • Zhang C, Huang J, Zhang J, Liu S, Cui M, An B, Wang X, Pu J, Zhao T, Fan C, Lu TK, Zhong C (2019) Engineered Bacillus subtilis biofilms as living glues. Mater Today 28:40–48

    Google Scholar 

Download references

Funding

This work was supported in part by funds from the National Institutes of Health grant AT007830.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Division of Clinical Pharmacology, Vanderbilt University, 556B Robinson Research Building, Nashville, TN, 37232-6602, USA

    Noura S. Dosoky, Linda S. May-Zhang & Sean S. Davies

Authors
  1. Noura S. Dosoky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda S. May-Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sean S. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NSD wrote the initial draft of the manuscript. LSM revised the manuscript and added additional sections. SSD created the initial outline, revised drafts of the manuscript, and added additional sections.

Corresponding author

Correspondence to Sean S. Davies.

Ethics declarations

Conflict of interest

SSD holds a patent for the use of engineered bacteria for the treatment of obesity. NSD and LSD have no conflicts of interests.

Animal and human studies

This review article does not include any new animal or human studies performed by any of the authors. Previously published animal studies by the authors followed applicable national and institution guidelines for the care and use of animals.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dosoky, N.S., May-Zhang, L.S. & Davies, S.S. Engineering the gut microbiota to treat chronic diseases. Appl Microbiol Biotechnol 104, 7657–7671 (2020). https://doi.org/10.1007/s00253-020-10771-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-020-10771-0

Keywords

  • Gut microbiota
  • Engineered bacteria
  • Cancer
  • Diabetes
  • Inflammatory bowel disease
  • Atherosclerosis
  • Obesity