Abstract
Lactic acid bacteria (LAB) are among the most widely used microorganisms in food fermentation. However, some LAB species can also be used as live vehicles for the in situ delivery of therapeutic molecules to the mucosa of the human gastrointestinal tract (GIT). Many LAB species have 'qualified presumption of safety' status, and survive passage through the GIT. Indeed, some are part of the usual GIT microbiota. These are appropriate candidates for the in situ production of recombinant prophylactic and therapeutic proteins. Live recombinant LAB that produce microbial antigens have been shown to elicit an immune response that confers protection against the corresponding pathogens; these LAB could therefore be used as oral vaccines. In addition, some LAB have been genetically engineered to produce therapeutic, neutralizing antibodies. The variable domain of heavy-chain-only antibodies from camelids - known as VHH antibodies or nanobodies - have peculiar properties (nanoscale size, robust structure, acid resistance, high affinity and specificity, easily produced in bacteria, etc.) that make them ideal choices as LAB-produced immunotherapeutic agents. The present review examines the advantages offered by LAB for the in situ production of therapeutic proteins in the human GIT, discusses the use of in situ-produced VHH antibody fragments, and assesses the usefulness of this strategy in the treatment of infectious and non-infectious gastrointestinal diseases.
Highlights
New therapeutic strategies are needed if we are to better face the challenges posed by cancer, resistance to antibiotics, and viral infections
lactic acid bacteria (LAB) have emerged as powerful oral delivery vectors for the in situ production of VHH at the gastrointestinal tract (GIT) mucosa where they may act as therapeutic agents or provide passive protection against different gastrointestinal diseases
This has been achieved using expression systems based on replicative plasmids, which require a selection pressure such as the presence of antibiotic resistance genes for their maintenance in bacteria (Pant et al, 2006, 2011; Vandenbroucke et al, 2010; Gunaydin et al, 2014; Andersen et al, 2015) or by using other genetic tools that allow the integration of VHH-encoding genes into the bacterial chromosome
Summary
New therapeutic strategies are needed if we are to better face the challenges posed by cancer, resistance to antibiotics, and viral infections. The earliest use of therapeutic molecule-producing recombinant LAB was in the treatment of GIT inflammatory diseases and bacterial and viral infections. Andersen et al (2015) proposed an oral antitoxin strategy for the prevention and treatment of C. difficile-associated diarrhea, based on the neutralization of TcdB using engineered L. paracasei BL23 that constitutively produced anti-TcdB VHH in the GIT (Figure 2).
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