A Phase I Trial With Transgenic Bacteria Expressing Interleukin-10 in Crohn’s Disease

Braat, Henri; Rottiers, Pieter; Hommes, Daniël W.; Huyghebaert, Nathalie; Remaut, Erik; Remon, Jean‐Paul; Deventer, S. J. H. Van; Neirynck, Sabine; Peppelenbosch, Maikel P.; Steidler, Lothar

doi:10.1016/j.cgh.2006.03.028

Cited by 653 publications

(438 citation statements)

References 19 publications

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“…More recently, it has been shown in animal models that probiotic strains displaying an in vitro potential to induce higher levels of the anti-inflammatory cytokine IL-10 and lower levels of the inflammatory cytokine IL-12, offer the best protection against in vivo colitis in the model [13] . A genetically engineered Lactococcus lactis thy12 producing IL-10 ameliorated colitis in two models of experimental colitis, providing proof of principal that topically delivers IL-10, can be therapeutically efficacious [14] and a recent proof-or-principle experiment using this transgenic bacterium expressing IL-10 in 10 patients with Crohn's disease showed efficacy [15] . In addition, there is an increasing amount of evidence to suggest that the potent neutrophil chemoattractant, IL-8, has an important role in the pathogenesis of inflammatory bowel disease (IBD) [16][17][18][19] .…”

Section: Introductionmentioning

confidence: 94%

Anti-inflammatory activity of probiotic Bifidobacterium: Enhancement of IL-10 production in peripheral blood mononuclear cells from ulcerative colitis patients and inhibition of IL-8 secretion in HT-29 cells

Imaoka¹,

Shima²,

Kato³

et al. 2008

WJG

152

100

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AIM:To determine the anti-inflammatory activity of probiotic Bifidobacteria in Bifidobacteria-fermented milk (BFM) which is effective against active ulcerative colitis (UC) and exacerbations of UC, and to explore the immunoregulatory mechanisms. METHODS:Peripheral blood mononuclear cells (PBMNC) from UC patients or HT-29 cells were co-cultured with heat-killed probiotic bacteria or culture supernatant of Bifidobacterium breve strain Yakult (BbrY) or Bifidobacterium bifidum strain Yakult (BbiY) to estimate the amount of IL-10 or IL-8 secreted.RESULTS: Both strains of probiotic Bifidobacteria contained in the BFM induced IL-10 production in PBMNC from UC patients, though BbrY was more effective than BbiY. Conditioned medium (CM) and DNA of both strains inhibited IL-8 secretion in HT-29 cells stimulated with TNF-α, whereas no such effect was observed with heatkilled bacteria. The inhibitory effect of CM derived from BbiY was greater than that of CM derived from BbrY. DNAs of the two strains had a comparable inhibitory activity against the secretion of IL-8. CM of BbiY induced a repression of IL-8 gene expression with a higher expression of IκB-ζ mRNA 4 h after culture of HT-29 cells compared to that in the absence of CM. CONCLUSION:Probiotic Bifidobacterium strains in BFM enhance IL-10 production in PBMNC and inhibit IL-8 secretion in intestinal epithelial cells, suggesting that BFM has anti-inflammatory effects against ulcerative colitis.

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Section: Introductionmentioning

confidence: 94%

Anti-inflammatory activity of probiotic Bifidobacterium: Enhancement of IL-10 production in peripheral blood mononuclear cells from ulcerative colitis patients and inhibition of IL-8 secretion in HT-29 cells

Imaoka¹,

Shima²,

Kato³

et al. 2008

WJG

152

100

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“…26 In addition, new recombinant strains of probiotics are used as novel therapeutic strategies to deliver vaccines 27 or biologically active compounds such as interleukin-10 in murine colitis. 28,29 Lactobacillus plantarum is a nonpathogenic, noninvasive, Gram-positive bacterium found in the normal mucosal flora of the human mouth and intestine and frequently associated with lactic acid fermented foods of plant origin. In this study, ammonia absorption was modulated in the gut by the administration of a wild-type strain of L. plantarum, NCIMB8826, and a genetically engineered ammonia hyperconsuming L. plantarum strain, able to efficiently convert ammonia to alanine in three rodent models of hyperammonemia.…”

mentioning

confidence: 99%

Control of acute, chronic, and constitutive hyperammonemia by wild-type and genetically engineered Lactobacillus plantarum in rodents

et al. 2008

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Hyperammonemia is a common complication of acute and chronic liver diseases. Often accompanied with side effects, therapeutic interventions such as antibiotics or lactulose are generally targeted to decrease the intestinal production and absorption of ammonia. In this study, we aimed to modulate hyperammonemia in three rodent models by administration of wild-type Lactobacillus plantarum, a genetically engineered ammonia hyperconsuming strain, and a strain deficient for the ammonia transporter. Wild-type and metabolically engineered L. plantarum strains were administered in ornithine transcarbamoylase-deficient Sparse-fur mice, a model of constitutive hyperammonemia, in a carbon tetrachloride rat model of chronic liver insufficiency and in a thioacetamide-induced acute liver failure mice model. Constitutive hyperammonemia in Sparse-fur mice and hyperammonemia in a rat model of chronic hepatic insufficiency were efficiently decreased by Lactobacillus administration. In a murine thioacetamide-induced model of acute liver failure, administration of probiotics significantly increased survival and decreased blood and fecal ammonia. The ammonia hyperconsuming strain exhibited a beneficial effect at a lower dose than its wild-type counterpart. Improved survival in the acute liver failure mice model was associated with lower blood ammonia levels but also with a decrease of astrocyte swelling in the brain cortex. Modulation of ammonia was abolished after administration of the strain deficient in the ammonium transporter. Intestinal pH was clearly lowered for all strains and no changes in gut flora were observed. Conclusion: Hyperammonemia in constitutive model or after acute or chronic induced liver failure can be controlled by the administration of L. plantarum with a significant effect on survival. The mechanism involved in this ammonia decrease implicates direct ammonia consumption in the gut. (HEPATOLOGY 2008;48:1184-1192 H yperammonemia (HA) is a well-known complication of acute and chronic liver diseases and plays a central role in the pathogenesis of hepatic encephalopathy (HE). [1][2][3][4][5] This neurological dysfunction results, at least in part, from an increase in plasma ammonia level and the severity of the symptoms correlates with blood ammonia level. 6-9 Animal models used in studying hyperammonemic disorders are multiple: fulminant hepatic failure, 10 chronic liver failure, 11 or urea cycle deficiency. 12 Ammonia is produced by many tissues but its major external source results from deaminase and urease activities of the gut flora. Although its absorption occurs through the intestinal epithelium, ammonia is carried by the portal vein into the liver where it is metabolized into urea. 13 Classical treatments of HE, except through liver transplantation and liver replacement therapies, consist in decreasing the ammonia production of urease-positive bacteria by antibiotics or decreasing the ammonia absorption into the gut by acidifying the colon content with nonabsorbable sugars such as lactulose. 4,[13][14][1...

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“…A Lactococcus lactis strain was engineered to locally deliver the anti‐inflammatory cytokine IL‐10 in the GIT (Steidler et al ., 2000). This strain went successfully through a phase 1 clinical study in patients (Braat et al ., 2006). The strain was shown to be safe and biologically contained, but was not effective in treating the disease in the subsequent phase 2a clinical study.…”

Section: Engineered Bacteria Against Immunological and Metabolic Disementioning

confidence: 99%

Sustainable therapies by engineered bacteria

Álvarez

Fernández

2017

Microbial Biotechnology

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SummaryThe controlled in situ delivery of biologics (e.g. enzymes, cytokines, antibodies) by engineered bacteria of our microbiome will allow the sustainable production of these complex and expensive drugs locally in the human body, overcoming many of the technical and economical barriers currently associated with the global use of these potent medicines. We provide examples showing how engineered bacteria can be effective treatments against multiple pathologies, including autoimmune and inflammatory diseases, metabolic disorders, diabetes, obesity, infectious diseases and cancer, hence contributing to achieve the Global Sustainable Goal 3: ensure healthy lives and promote well‐being for all at all ages.

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A Phase I Trial With Transgenic Bacteria Expressing Interleukin-10 in Crohn’s Disease

Cited by 653 publications

References 19 publications

Anti-inflammatory activity of probiotic Bifidobacterium: Enhancement of IL-10 production in peripheral blood mononuclear cells from ulcerative colitis patients and inhibition of IL-8 secretion in HT-29 cells

Anti-inflammatory activity of probiotic Bifidobacterium: Enhancement of IL-10 production in peripheral blood mononuclear cells from ulcerative colitis patients and inhibition of IL-8 secretion in HT-29 cells

Control of acute, chronic, and constitutive hyperammonemia by wild-type and genetically engineered Lactobacillus plantarum in rodents

Sustainable therapies by engineered bacteria

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