Antibiotic treatment affects the expression levels of copper transporters and the isotopic composition of copper in the colon of mice

Abstract

Copper is a critical enzyme cofactor in the body but also a potent cellular toxin when intracellularly unbound. Thus, there is a delicate balance of intracellular copper, maintained by a series of complex interactions between the metal and specific copper transport and binding proteins. The gastrointestinal (GI) tract is the primary site of copper entry into the body and there has been considerable progress in understanding the intricacies of copper metabolism in this region. The GI tract is also host to diverse bacterial populations, and their role in copper metabolism is not well understood. In this study, we compared the isotopic fractionation of copper in the GI tract of mice with intestinal microbiota significantly depleted by antibiotic treatment to that in mice not receiving such treatment. We demonstrated variability in copper isotopic composition along the length of the gut. A significant difference, ∼1.0‰, in copper isotope abundances was measured in the proximal colon of antibiotic-treated mice. The changes in copper isotopic composition in the colon are accompanied by changes in copper transporters. Both CTR1, a copper importer, and ATP7A, a copper transporter across membranes, were significantly down-regulated in the colon of antibiotic-treated mice. This study demonstrated that isotope abundance measurements of metals can be used as an indicator of changes in metabolic processes in vivo. These measurements revealed a host–microbial interaction in the GI tract involved in the regulation of copper transport.

Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation

“…Copper, an essential redox-active trace element, which is essential for most aerobic organisms (Tapiero et al, 2003;Solomon et al, 2014). Simultaneously, copper functions as a co-factor of various proteins and enzymes, including cytochrome C, superoxide dismutase, tyrosinase, ascorbate oxidase, lysyl oxidase, and amine oxidase, exhibiting diverse fundamental cellular functions in normal physiology, including energy generation, iron acquisition, oxygen transportation, cellular metabolism, peptide hormone maturation, blood clotting, neurotransmitter biosynthesis, and intracellular signal transduction (Huffman and O'Halloran, 2001;Hamza and Gitlin, 2002;Kim et al, 2008;Turski et al, 2012;Grubman and White, 2014;Wang et al, 2018;Miller et al, 2019). Generally, copper is able to exist in two oxidation states in the body of mammalians: Cu + and Cu 2+ (Lin and Kosman, 1990;Pushie et al, 2007;Solomon et al, 2014).…”

“…A cartilage matrix glycoprotein, a membrane-associated protein synthesized by chondrocytes, has been demonstrated to bind copper and exert some oxidase activity similar with ceruloplasmin, which may function as an important copper transporter in chondrocytes and a potential chondrogenic marker (Fife et al, 1986(Fife et al, , 1993Harris, 2000;Ranganathan et al, 2011;La Mendola et al, 2012;Ishihara et al, 2014;Linder, 2016;Magri et al, 2018). The proposed cellular model of copper intracellular transportation has been presented in Figure 3 according to current literature (Okado-Matsumoto and Fridovich, 2001;Carr et al, 2005;Horng et al, 2005;Turski and Thiele, 2009;Ohrvik and Thiele, 2014;Urso and Maffia, 2015;Miller et al, 2019;Shi et al, 2019), illustrating the routes of copper trafficking and how it functions within chondrocytes and during ECM remodeling.…”

Inter-comparison of stable iron, copper and zinc isotopic compositions in six reference materials of biological origin

“…The Cu isotopes are fractionated during Cu uptake and translocation in plants [21,22]. In healthy animals, the Cu isotopes are processed slightly differently in the gut via the involvement of the microbiota [23] and Cu isotopic compositions are highly fractionated between organs [8,24]. Similarly to Fe, the blood Cu isotopic composition is different between human males and premenopausal females due to menstrual losses and the corresponding reaction of the body to these losses [12,13].…”

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

“…It is because copper has been shown to affect microbiota diversity in the gut of mice (69) and microbiota content (both qualitative and quantitative) is critical for proper aging of neutrophils and their removal as well as for casting NETs (70). Furthermore, antibiotic therapy was shown to affect ATP7A expression in the colon of mice (71). Therefore, depending on the status of microbiota, diverse numbers of aged neutrophils might be available in mice with subchronic copper deficiency and Atp7a mutants, while it is the aged neutrophil phenotype that exhibits enhanced NET formation under inflammatory conditions (70).…”