Engineering the gut microbiota to treat chronic diseases
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MINI-REVIEW
Engineering the gut microbiota to treat chronic diseases Noura S. Dosoky 1 & Linda S. May-Zhang 1 & Sean S. Davies 1 Received: 24 February 2020 / Revised: 18 June 2020 / Accepted: 2 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Gut microbes play vital roles in host health and disease. A number of commensal bacteria have been used as vectors for genetic engineering to create living therapeutics. This review highlights recent advances in engineering gut bacteria for the treatment of chronic diseases such as metabolic diseases, cancer, inflammatory bowel diseases, and autoimmune disorders. Key points • Bacterial homing to tumors has been exploited to deliver therapeutics in mice models. • Engineered bacteria show promise in mouse models of metabolic diseases. • Few engineered bacterial treatments have advanced to clinical studies. Keywords Gut microbiota . Engineered bacteria . Cancer . Diabetes . Inflammatory bowel disease . Atherosclerosis . Obesity
Introduction Studies with germ-free and antibiotic-treated animals reveal a critical role for commensal organisms of the mammalian gastrointestinal tract (the gut microbiota) in the regulation of host immune responses, metabolism, and behavior (Sudo et al. 2004; Smith et al. 2007; Sekirov et al. 2010; Rooks and Garrett 2016; Kennedy et al. 2018). In some cases, specific metabolites released by the gut microbiota that directly affect the host have been identified (e.g., short chain fatty acids) (Feng et al. 2018; Bilotta and Cong 2019). Such studies suggest the therapeutic potential of manipulating gut microbial metabolites to improve host health and treat disease. Approaches to alter microbial metabolites include the manipulation of diet, use of medications, or administration of bacteria known to release beneficial metabolites (e.g., probiotics) (Gerritsen et al. 2011; Choi and Cho 2016; Mukherjee et al. 2018). This review focuses on a key variant of the latter approach, which is genetically engineering specific bacterial species to produce beneficial metabolites and incorporating these bacteria into the host microbiota. The choice of
* Sean S. Davies [email protected] 1
Department of Pharmacology and Division of Clinical Pharmacology, Vanderbilt University, 556B Robinson Research Building, Nashville, TN 37232-6602, USA
metabolites includes novel compounds, enzymes that degrade toxic compounds found in diet or produced endogenously, beneficial host small molecule metabolites, or even bacterial secondary metabolites (Table 1). In the latter case, engineered bacteria may offer greater therapeutic utility than native bacteria because they can be manipulated to produce higher yields of endogenous bacterial products and to have additional safety features such as passive containment systems. When longterm delivery of a therapeutic compound is required for maximal therapeutic effects, engineered bacteria with a high potential for colonization may be advantageous due to less need for frequent administration (Pinero-Lam
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