Microbiota-modulating interventions are an emerging strategy to promote gastrointestinal homeostasis. Yet, their use in the detection, prevention, and treatment of acute infections remains underexplored. We report the basis of a probiotic-based strategy to promote colonization resistance and point-of-need diagnosis of cholera, an acute diarrheal disease caused by the pathogen Vibrio cholerae Oral administration of Lactococcus lactis, a common dietary fermentative bacterium, reduced intestinal V. cholerae burden and improved survival in infected infant mice through the production of lactic acid. Furthermore, we engineered an L. lactis strain that specifically detects quorum-sensing signals of V. cholerae in the gut and triggers expression of an enzymatic reporter that is readily detected in fecal samples. We postulate that preventive dietary interventions with fermented foods containing natural and engineered L. lactis strains may hinder cholera progression and improve disease surveillance in populations at risk of cholera outbreaks.

Probiotic strains detect and suppress cholera in mice

The emerging field of precision medicine is rapidly growing, fostered by the advances in genome mapping and molecular diagnosis. In general, the translation of these advances into precision treatments relies on the use of biological macromolecules, whose structure offers a high specificity and potency. Unfortunately, due to their complex structure and limited ability to overcome biological barriers, these macromolecules need to be administered via injection. The scientific community has devoted significant effort to making the oral administration of macromolecules plausible thanks to the implementation of drug delivery technologies. Here, an overview of the current situation and future prospects in the field of oral delivery of biologics is provided. Technologies in clinical trials, as well as recent and disruptive delivery systems proposed in the literature for local and systemic delivery of biologics including peptides, antibodies, and nucleic acids, are described. Strategies for the specific targeting of gastrointestinal regions-stomach, small bowel, and colon-cell populations, and internalization pathways, are analyzed. Finally, challenges associated with the clinical translation, future prospects, and identified opportunities for advancement in this field are also discussed.

Oral Delivery of Biologics for Precision Medicine.

Engineering probiotics for therapeutic applications: recent examples and translational outlook.

The gut microbiota that inhabit our gastrointestinal tract are well known to play an important role in maintaining human health in many aspects, including facilitating the digestion and absorption of nutrients, protecting against pathogens and regulating immune system. Gut microbiota dysbiosis is associated with a lot of diseases, such as inflammatory bowel disease, allergy, obesity, cardiovascular and neurodegenerative diseases and cancers. With the increasing knowledge of the microbiome, utilization of probiotic bacteria in modulating gut microbiota to prevent and treat a large number of disorders and diseases has gained much interest. In recent years, aided by the continuous development of tools and techniques, engineering probiotic microbes with desired characteristics and functionalities to benefit human health has made significant progress. In this paper, we summarize the recent advances in design and construction of probiotics as living diagnostics and therapeutics for probing and treating a series of diseases including metabolic disorders, inflammation and pathogenic bacteria infections. We also discuss the current challenges and future perspectives in expanding the application of probiotics for disease treatment and detection. We intend to provide insights and ideas for engineering of probiotics to better serve disease therapy and human health.

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Engineering probiotics as living diagnostics and therapeutics for improving human health

Vibrio cholerae is a noninvasive pathogen that colonizes the small intestine and produces cholera toxin, causing severe secretory diarrhea. Cholera results in long lasting immunity, and recent studies have improved our understanding of the antigenic repertoire of V. cholerae Interactions between the host, V. cholerae, and the intestinal microbiome are now recognized as factors which impact susceptibility to cholera and the ability to mount a successful immune response to vaccination. Here, we review recent data and corresponding models to describe immune responses to V. cholerae infection and explain how the host microbiome may impact the pathogenesis of V. cholerae In the ongoing battle against cholera, the intestinal microbiome represents a frontier for new approaches to intervention and prevention.

Vibrio cholerae at the Intersection of Immunity and the Microbiome.

Outbreaks of cholera, a rapidly fatal diarrheal disease, often spread explosively. The efficacy of reactive vaccination campaigns-deploying Vibrio cholerae vaccines during epidemics-is partially limited by the time required for vaccine recipients to develop adaptive immunity. We created HaitiV, a live attenuated cholera vaccine candidate, by deleting diarrheagenic factors from a recent clinical isolate of V. cholerae and incorporating safeguards against vaccine reversion. We demonstrate that administration of HaitiV 24 hours before lethal challenge with wild-type V. cholerae reduced intestinal colonization by the wild-type strain, slowed disease progression, and reduced mortality in an infant rabbit model of cholera. HaitiV-mediated protection required viable vaccine, and rapid protection kinetics are not consistent with development of adaptive immunity. These features suggest that HaitiV mediates probiotic-like protection from cholera, a mechanism that is not known to be elicited by traditional vaccines. Mathematical modeling indicates that an intervention that works at the speed of HaitiV-mediated protection could improve the public health impact of reactive vaccination.

A live vaccine rapidly protects against cholera in an infant rabbit model

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A live vaccine rapidly protects against cholera in an infant rabbit model