genetically engineered streptococci are used in medicine ? how?
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ABSTRACT
The aims of this study were to develop strains of lactic acid bacteria (LAB) having both immunomodulatory and antioxidant properties and to evaluate their anti-inflammatory effects both in vitro, in different cellular models, and in vivo, in a mouse model of colitis. Different Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus strains were cocultured with primary cultures of mononuclear cells. Analysis of the pro- and anti-inflammatory cytokines secreted by these cells after coincubation with candidate bacteria revealed that L. delbrueckii subsp. bulgaricus CRL 864 and S. thermophilus CRL 807 display the highest anti-inflammatory profiles in vitro. Moreover, these results were confirmed in vivo by the determination of the cytokine profiles in large intestine samples of mice fed with these strains. S. thermophilus CRL 807 was then transformed with two different plasmids harboring the genes encoding catalase (CAT) or superoxide dismutase (SOD) antioxidant enzymes, and the anti-inflammatory effects of recombinant streptococci were evaluated in a mouse model of colitis induced by trinitrobenzenesulfonic acid (TNBS). Our results showed a decrease in weight loss, lower liver microbial translocation, lower macroscopic and microscopic damage scores, and modulation of the cytokine production in the large intestines of mice treated with either CAT- or SOD-producing streptococci compared to those in mice treated with the wild-type strain or control mice without any treatment. Furthermore, the greatest anti-inflammatory activity was observed in mice receiving a mixture of both CAT- and SOD-producing streptococci. The addition of L. delbrueckii subsp. bulgaricus CRL 864 to this mixture did not improve their beneficial effects. These findings show that genetically engineering a candidate bacterium (e.g., S. thermophilus CRL 807) with intrinsic immunomodulatory properties by introducing a gene expressing an antioxidant enzyme enhances its anti-inflammatory activities.
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INTRODUCTION
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gut with a substantial socioeconomic impact worldwide (1). The two major forms of IBD are Crohn's disease (CD) and ulcerative colitis (UC), which are characterized by an uncontrolled inflammatory response to luminal content and which differ mostly by the region of the gut where inflammation progresses and the depth of inflammatory damage. Conventional IBD therapy with antibiotics and corticosteroids is often associated with negative side effects. The difficulty in developing new therapeutic options for the treatment of IBD is thus a major challenge, from a medical and patient care point of view and in regard to economic and social aspects as well.
Currently, numerous studies have suggested possible health benefits associated with the consumption of probiotics (“live microorganisms which when administered in adequate amounts confer a health benefit on the host” [2]). In particular, probiotics represent a potential alternative for IBD treatment due to their active role in enhancing the intestinal barrier function, by either modifying the intestinal microbiota or modulating the host immune response (3, 4). Notably, it has been previously shown that a yogurt prepared with a pool of candidate probiotic strains of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus from the Culture Collection of the Centro de Referencia para Lactobacilos (CERELA) (San Miguel de Tucumán, Argentina) diminished the severity of inflammation in a mouse model of chemically induced colitis by modulating the immune response of the host, mainly due to an increase in the number of interleukin-10 (IL-10)-producing cells at the intestinal level with a significant decrease of IL-17 and IL-12 production (5, 6). More recently, it has been described that genetically engineered lactic acid bacteria (LAB) producing antioxidant enzymes such as catalase (CAT) or superoxide dismutase (SOD) were able to reduce the inflammation in different murine models of chemically induced colitis through a different mechanism, which was a reduction of reactive oxygen species (ROS) levels in the gut (7,–10). From this perspective, we hypothesized that the expression of such antioxidant enzymes in LAB strains with proven intrinsic immunomodulatory properties could enhance their anti-inflammatory activities. Therefore, the aims of this study were to construct a novel anti-inflammatory LAB strain with immunomodulating as well as antioxidant properties and to evaluate its anti-inflammatory activ
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