Microbial therapeutics for acute colitis based on genetically modified Lactococcus lactis hypersecreting IL-1Ra in mice

다국어 초록 (Multilingual Abstract)

The increased incidence of inflammatory bowel disease (IBD) in Western and rapidly Westernizing developing countries poses a global pandemic threat. The development of affordable drugs for treating IBD worldwide is thus a priority. Genetically modified lactic acid bacteria (gmLAB) as microbial therapeutics are inexpensive protein producers suitable for use as carriers of protein to the intestinal mucosa. Here, we successfully constructed gmLAB hypersecreting interleukin 1 receptor antagonist (IL-1Ra). Oral administration of these gmLAB suppressed body weight reduction and exacerbation of the disease activity index score in mice with acute colitis and decreased the number of CD4+ IL-17A+ cells in the mesenteric lymph nodes. These data suggest that the gmLAB deliver IL-1Ra to the colon, where it inhibits IL-1 signaling. We thus developed a novel IBD therapeutic that blocks IL-1 signaling using a gmLAB protein delivery system. This system could be an inexpensive oral microbial therapeutic.

참고문헌 (Reference)

1 Ng, S. C., "Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century : a systematic review of population-based studies" 390 : 2769-2778, 2017

2 Kimoto, H., "Survival of lactococci during passage through mouse digestive tract" 49 : 707-711, 2003

3 Cabral, V. P., "Severe infection in patients with rheumatoid arthritis taking anakinra, rituximab, or abatacept : a systematic review of observational studies" 56 : 543-550, 2016

4 Bermudez-Humaran, L. G., "Serine protease inhibitors protect better than IL-10 and TGF-beta anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci" 14 : 26-, 2015

5 Avall-Jaaskelainen, S., "Secretion of biologically active porcine interleukin-2 by Lactococcus lactis" 115 : 278-283, 2006

6 Loera-Arias, M. J., "Secretion of biologically active human interleukin 22(IL-22)by Lactococcus lactis" 36 : 2489-2494, 2014

7 Bolyen, E., "Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2" 37 : 852-857, 2019

8 Wang, J., "Preventative delivery of IL-35 by Lactococcus lactis ameliorates DSS-induced colitis in mice" 103 : 7931-7941, 2019

9 Shigemori, S., "Oral delivery of Lactococcus lactis that secretes bioactive heme oxygenase-1 alleviates development of acute colitis in mice" 14 : 189-, 2015

10 Hanson, M. L, "Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice" 146 : 210-221, 2014

11 Ogita, T., "Oral administration of Flavonifractor plautii strongly suppresses Th2 immune responses in mice" 11 : 379-, 2020

12 Fernandez, A., "Nisincontrolled extracellular production of interleukin-2 in Lactococcus lactis strains, without the requirement for a signal peptide sequence" 73 : 7781-7784, 2007

13 O’Toole, P. W., "Next-generation probiotics: the spectrum from probiotics to live biotherapeutics" 2 : 17057-, 2017

14 Casini-Raggi, V., "Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation" 154 : 2434-2440, 1995

15 Jimenez, M., "Microbial therapeutics : new opportunities for drug delivery" 216 : 1005-1009, 2019

16 Bermudez-Humaran, L. G., "Intranasal immunization with recombinant Lactococcus lactis secreting murine interleukin-12 enhances antigen-specific Th1 cytokine production" 71 : 1887-1896, 2003

17 Dosh, R. H., "Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model" 10 : 3559-3575, 2019

18 Wang, Y., "Inhibitory/suppressive oligodeoxynucleotide nanocapsules as simple oral delivery devices for preventing atopic dermatitis in mice" 23 : 297-309, 2015

19 Huibregtse, I. L., "Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin" 133 : 517-528, 2007

20 Ludwiczek, O., "Imbalance between interleukin-1 agonists and antagonists : relationship to severity of inflammatory bowel disease" 138 : 323-329, 2004

21 Mailer, R. K., "IL-1beta promotes Th17 differentiation by inducing alternative splicing of FOXP3" 5 : 14674-, 2015

22 Coccia, M., "IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+)Th17 cells" 209 : 1595-1609, 2012

23 Siegmund, B., "IL-1 beta-converting enzyme(caspase-1)in intestinal inflammation" 98 : 13249-13254, 2001

24 Ni, J., "Gut microbiota and IBD : causation or correlation? Nat" 14 : 573-584, 2017

25 Shigemori, S., "Generation of dipeptidyl peptidase-IV-inhibiting peptides from β-lactoglobulin secreted by Lactococcus lactis" 2014 : 393598-, 2014

26 Feizollahzadeh, S, "Expression of biologically active murine interleukin-18in Lactococcus lactis" 363 : 2016

27 Ikeda, S., "Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-beta-induced Foxp3 expression" 192 : 1449-1458, 2014

28 Fernandez, A., "Enhanced secretion of biologically active murine interleukin-12 by Lactococcus lactis" 75 : 869-871, 2009

29 Mahida, Y. R., "Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn’s disease" 30 : 835-838, 1989

30 Chassaing, B., "Dextran sulfate sodium (DSS)-induced colitis in mice" 104 : 25-, 2014

31 Callahan, B. J., "DADA2 : high-resolution sample inference from Illumina amplicon data" 13 : 581-583, 2016

32 Yamamoto, Y., "Class A CpG oligonucleotide priming rescues mice from septic shock via activation of platelet-activating factor acetylhydrolase" 8 : 1049-, 2017

33 Arend, W. P., "Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist" 85 : 1694-1697, 1990

34 Shigemori, S., "Applications of genetically modified immunobiotics with high immunoregulatory capacity for treatment of inflammatory bowel diseases" 8 : 22-, 2017

35 Cao, J., "Alginate/chitosan microcapsules for in-situ delivery of the protein, interleukin-1 receptor antagonist(IL-1Ra), for the treatment of dextran sulfate sodium(DSS)-induced colitis in a mouse model" 137 : 112-121, 2019

36 Caluwaerts, S., "AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis" 46 : 564-570, 2010

37 Sha, Y., "A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases" 2 : 35-42, 2011

38 Gresnigt, M. S., "A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1receptor antagonist" 10 : e1003936-, 2014

39 Braat, H., "A phase I trial with transgenic bacteria expressing interleukin-10in Crohn’s disease" 4 : 754-759, 2006

40 Vermeire, S, "A phase 2a randomized placebo-controlled double-blind multi-center dose escalation study to evaluate the safety, tolerability, pharmacodynamics and efficacy of AG011 in patients with moderately active ulcerative colitis" 138 : 2010

41 Mierau, I., "10 years of the nisin-controlled gene expression system(NICE)in Lactococcus lactis" 68 : 705-717, 2005