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 impacting 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.

Figure 1

A general schematic illustrating microbial factors that influence the epithelial barrier in the intestine. Each of these factors varies by bacterial colony counts, spatial distribution, and time of sampling. The mammalian GI epithelial layer is rendered in orange with villi at the bottom, and schematics of the cell surfaces of Gm+ and Gm− bacteria arising from a range of differently shaped forms of microbiota are presented below. The microbiota encode the microbiome, which generate proteins, peptides, metabolites, and altered xenobiotics that impact the types of communication indicated. Abbreviations: GI, gastrointestinal; Gm+, gram-positive bacteria; Gm−, gram-negative bacteria.

Figure 2

This schematic illustrates the basics of several types of secretion pathways in bacteria, and they are outlined to indicate the level of complexity involved in bacterial-human cell communication considering only the prokaryotic side of the equation. Abbreviations: ABC, ATP-binding cassette; ATP, adenosine triphosphate; Clp B, a chaperone ATPase; GI, gastrointestinal; IM, inner membrane; MFP, membrane fusion protein; MM, mycomembrane; OM, outer membrane; OMP, outer membrane protein; VirB, a DNA transfer protein first identified in Agrobacterium tumefaciens; Y-E-G, a complex of transfer proteins associated with type II systems.

Figure 3

The microbiota plays direct roles in the drug-induced gastrointestinal (GI) toxicities of the anticancer drug irinotecan (33) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (158) and indomethacin.

Figure 4

Colonization of the gastrointestinal tract with E. coli aggravates indomethacin-induced enteropathy in mice. Male C57BL/6 × 129/SvEv mice that tested negative for E. coli before the beginning of the study were inoculated by oral gavage with 10¹¹ cells of E. coli. Positive colonization was confirmed after 2 weeks. Indomethacin (85 mg/kg/day, sc, for 2 days) was administered 2 weeks after successful colonization in the test (E. coli colonized) group, and the small intestines of the test and control groups were analyzed for pathological lesions 24 h post indomethacin discontinuation or control. Data are mean ± SD (n = 5 mice per group). Asterisk indicates P < 0.05 (M. Bopst & U.A. Boelsterli, unpublished data).

Figure 5

Multiple relationships between bacteria and NSAIDs in drug-induced enteropathy. ➊ NSAIDs can lead to unregulated overgrowth of the small intestine with bacteria and also change the relative composition of commensal OTUs, thus inducing dysbiosis. ➋ Certain OTUs differentially express β-glucuronidase, which can catalyze the hydrolytic cleavage of NSAID glucuronides in the lumen, enabling uptake into enterocytes of the aglycones (parent NSAID and/or oxidative metabolites of NSAID). These compounds can be further metabolized in the epithelial cells to reactive intermediates, and/or they can induce ER or mitochondrial stress, which leads to cell injury and increased permeability of the epithelia. ➌ Gram-negative bacteria release LPS; if LPS escapes inactivation by intestinal enzymes including alkaline phosphatase, and if the intestinal permeability is increased by NSAIDs, LPS can reach deeper layers of the mucosa and bind to TLR4 (other bacteria can release other cell wall components that act as ligands for other TLRs). TLR signaling results in activation of proinflammatory cytokines and recruitment of PMNs. In addition to producing pro-oxidants and proteases, PMNs may also be involved in enzymatic activation of NSAID metabolites to reactive intermediates. Abbreviations: ER, endoplasmic reticulum; GI, gastrointestinal; LPS, lipopolysaccharide; MPO, myeloperoxidase; NSAID, nonsteroidal anti-inflammatory drug; PMN, polymorphonuclear neutrophil; TLR, Toll-like receptor; OTU, operational taxonomic unit.