Microbiome therapeutics — Advances and challenges

Abstract

The microbial community that lives on and in the human body exerts a major impact on human health, from metabolism to immunity. In order to leverage the close associations between microbes and their host, development of therapeutics targeting the microbiota has surged in recent years. Here, we discuss current additive and subtractive strategies to manipulate the microbiota, focusing on bacteria engineered to produce therapeutic payloads, consortia of natural organisms and selective antimicrobials. Further, we present challenges faced by the community in the development of microbiome therapeutics, including designing microbial therapies that are adapted for specific geographies in the body, stable colonization with microbial therapies, discovery of clinically relevant biosensors, robustness of engineered synthetic gene circuits and addressing safety and biocontainment concerns. Moving forward, collaboration between basic and applied researchers and clinicians to address these challenges will poise the field to herald an age of next-generation, cellular therapies that draw on novel findings in basic research to inform directed augmentation of the human microbiota.

Opportunistic Sampling of Roadkill as an Entry Point to Accessing Natural Products Assembled by Bacteria Associated with Non-anthropoidal Mammalian Microbiomes

“…The first tactic involves the introduction or elimination of selected microbial taxa from the host. 6−8 This approach was successfully tested in animal models of inflammatory bowel disease, 9−11 arthritis, 12 colon cancer, 13 cystic fibrosis, 14 and depression, 15 resulting in the restoration of disease-free phenotypes. This method was also effectively used in humans to restore resilience against Clostridium difficile colonization.…”

Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation

“…Recombinant probiotics that have been engineered to exploit these features show promise as therapeutics and diagnostics for inflammatory bowel disease (IBD), autoimmune diabetes, obesity and other conditions 1 . However, engineered, live, bacterial diagnostics and therapies have only been tested under non-colonizing conditions in the guts of model organisms and humans.…”

“…Similarly, engineered bacteria in other applications such as tumor-targeted strains of Salmonella typhimurium were cleared from the body within approximately one month in mouse and non-human primate models 2 . If recombinant probiotic bacterial strains could colonize the mammalian gut and function for extended periods the potential for translation of such technologies to humans could be vastly improved 1 . Unfortunately, the burden that synthetic genetic circuits place on their bacterial hosts 3 can result in compensatory genetic mutation 4 , loss of engineered function 5 , or lack of growth of the recombinant strain 3 in a host and environment-dependent manner 6, 7 .…”

Nanosized Drug Delivery Systems in Gastrointestinal Targeting: Interactions with Microbiota

“…The improvements in cultivability of important microbiota candidates may lead to the advancement of novel therapies that will interfere with the microbiome in order to prevent dysbiosis (dysbiostatic drugs) and promote health [18,20]. Additionally, our ability to deliver nanosized particles effectively in the gut microbiome without adversely affecting its composition may provide valuable tools for the administration of novel drugs that will prevent dysbiosis and help to successfully treat diseases [21].…”