Understanding and Modulating Mammalian-Microbial Communication for Improved Human Health

Abstract

The fact that the bacteria in the human gastrointestinal (GI) tract play a symbiotic role was noted as early as 1885, well before we began to manage microbial infections using antibiotics. However, even with the first antimicrobial compounds used in humans, the sulfa drugs, microbes were recognized to be critically involved in the biotransformation of these therapeutics. Thus, the roles played by the microbiota in physiology and in the management of human health have long been appreciated. Detailed examinations of GI symbiotic bacteria that started in the early 2000s and the first phases of the Human Microbiome Project that were completed in 2012 have ushered in an exciting period of granularity with respect to the ecology, genetics, and chemistry of the mammalian-microbial axes of communication. Here we review aspects of the biochemical pathways at play between commensal GI bacteria and several mammalian systems, including both local-epithelia and nonlocal responses including inflammation, immunology, metabolism, and neurobiology. Finally, we discuss how the microbial biotransformation of therapeutic compounds, such as anticancer or nonsteroidal anti-inflammatory drugs, can be modulated to reduce toxicity and potentially improve therapeutic efficacy.

Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b

“…In order to assess the fate of SG secreted by Abcc2 into bile, we next performed ex vivo incubation studies of mouse intestinal (cecal) content based on the consideration that once in the intestines, SG may serve as a substrate for bacterial β-glucuronidase enzymes that are produced by bacteria normally inhabiting the intestines (30). The removal of the glucuronide group in SG by β-glucuronidase generates a carbon source for the bacteria and, in the process SG is reactivated back to the pharmacologically active sorafenib.…”

Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity

“…Like SN-38, NSAIDs are inactivated by glucuronidation and reactivated in the GI tract back to the parent drugs, which can then cause significant enteropathy largely in the small intestine via mechanisms that are not completely understood (Boelsterli et al, 2012). In mouse models of GI toxicity caused by the NSAIDs diclofenac, ketoprofen, or indomethacin, we showed that oral dosing of bacterial β-glucuronidase inhibitors significantly reduced the numbers of small-intestinal ulcers observed (LoGuidice et al, 2012; Mani et al, 2014; Saitta et al, 2014). We also demonstrated that inhibition of bacterial β-glucuronidases did not alter serum levels of diclofenac in mice (LoGuidice et al, 2012).…”

“…Changes to the microbiota have been found to accompany several disease states, including diabetes, atherosclerosis, obesity, malnutrition, cancer, gastrointestinal (GI) inflammatory disorders, and neurological diseases (Cho et al, 2012; Hsiao et al, 2013; Methé et al, 2012; The Human Microbiome Project Consortium, 2012; Morgan et al, 2012; Nicholson et al, 2012; Plottel and Blaser, 2011; Smith et al, 2013; Turnbaugh et al, 2006; Wang et al, 2011). Ongoing chemical interactions between mammalian tissues and their colonizing microbiota appear to play important roles in the symbiosis that sustains both domains of life (Mani et al, 2014; Redinbo, 2014). A key player in this interplay is glucuronic acid.…”

The Microbiota, Chemical Symbiosis, and Human Disease

“…It is known that 40% of fatalities caused by NSAID toxicity are due to intestinal, not stomach, damage. In mouse models of toxicity caused by three NSAIDs, diclofenac 73 , indomethacin 74 , and ketoprofen 75 , oral delivery of bacterial glucuronidase inhibitors significantly reduced small intestinal ulcers.…”