Epidemiological studies revealed that antibiotics exposure increases a risk of inflammatory bowel diseases (IBD) development. It remained largely unknown how antibiotic-induced dysbiosis confers the risk for enhanced inflammatory response. The aim of the present study was to test the hypothesis that SCFAs, their receptors and transporters mediate the antibiotic long-term effects on the functional state of colonic mucosa and susceptibility to the experimental colitis. Male Wistar rats were treated daily for 14 days with antibiotic ceftriaxone (300 mg/kg, i.m.) or vehicle; euthanized by CO 2 inhalation followed by cervical dislocation in 1, 14 or 56 days after antibiotic withdrawal. We found increased cecum weight and sustained changes in microbiota composition after ceftriaxone treatment with increased number of conditionally pathogenic enterobacteria, E . coli , Clostridium , Staphylococcus spp . and hemolytic bacteria even at 56 days after antibiotic withdrawal. The concentration of SCFAs was decreased after ceftriaxone withdrawal. We found decreased immunoreactivity of the FFA2, FFA3 receptors, SMCT1 and increased MCT1 & MCT4 transporters of SCFAs in colon mucosa. These changes evoked a significant shift in colonic mucosal homeostasis: the disturbance of oxidant-antioxidant balance; activation of redox-sensitive transcription factor HIF1α and ERK1/2 MAP kinase; increased colonic epithelial permeability and bacterial translocation to blood; morphological remodeling of the colonic tissue. Ceftriaxone pretreatment significantly reinforced inflammation during experimental colitis 56 days after ceftriaxone withdrawal, which was confirmed by increased histopathology of colitis, Goblet cell dysfunction, colonic dilatation and wall thickening, and increased serum levels of inflammatory cytokines (TNF-α and IL-10). Since the recognition of the importance of microbiota metabolic activity rather than their composition in the development of inflammatory disorders, e.g. IBD, the present study is the first report on the role of the SCFA system in the long lasting side effects of antibiotic treatment and its implication in IBD development.
The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures. However, most of the research in this area has been devoted to the replacement of the para-substituted phenyl ring. Here we have developed saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures and the ortho-substituted phenyl ring indeed have similar geometric properties. Replacement of the phenyl ring in marketed agrochemicals fluxapyroxad (BASF) and boscalid (BASF) with 2-oxabicyclo[2.1.1]hexanes dramatically improved their water solubility, reduced lipophilicity and most importantly retained bioactivity. This work suggests an opportunity for chemists to replace the ortho-substituted phenyl ring in bioactive compounds with saturated bioisosteres in medicinal chemistry and agrochemistry.
Short-chain fatty acids (SCFAs) T he interchange of low molecular weight metabolites between gut microorganisms and macroorganism have attracted a lot of attention during last years [1][2][3]. The gut microbiota affects predominantly host physiology by the production of short-chain fatty acids (SCFAs). SCFAs are saturated aliphatic organic acids that consist of one to six carbons of which acetate (C2), propionate (C3), and butyrate (C4) are most abundant (≥95%). Acetate, propionate, and butyrate are present in an approximate molar ratio of 60:20:20 in the colon and stool [4]. Depending on the diet, the total maximum concentration of SCFAs decreases from 70 to 140 mM in the proximal colon from 20 to 70 mM in the distal colon [5].These metabolites, especially butyrate, serve as an important source of energy for the intestinal epithelial cells, providing about 60-70% of their ener gy demand. Colonocytes from germ-free mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the tricarboxylic acid cycle. Consequently, there is a marked decrease in NADH/NAD + , oxidative phosphorylation, and ATP levels, that results in AMP-activated protein kinase activation, cyclin-dependent kinase inhibitor 1B phosphorylation and autophagy. When butyrate is added to germ-free colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy [6].
Water-soluble analogues of the ortho-substituted phenyl ring were developed. Replacement of the phenyl ring in bioactive compounds with 2 oxabicyclo[2.1.1]hexanes in many cases improved solubility, reduced lipophilicity, enhanced metabolic stability, and most importantly – retained bioactivity.
Antibiotic treatment increases susceptibility to development of inflammatory bowel diseases (IBD) both in children and adults. Oxidative stress plays a prominent role in IBD pathogenesis. The aim of present study was to test an interrelationship between the morphological changes in rat colonic mucosa, the levels of antioxidant enzymes and redox sensitive transcription factors Egr-1 and Sp-1 after treatment with cephalosporin antibiotic ceftriaxone (Cf) with broad spectrum of action. Study was performed on male Wistar rats (180-230 g). Cf (50 mg/kg, i.m.) were injected daily for 5 days. The colonic levels of catalase and superoxide dismutase activity were measured by the colorimetric assays and zymography; levels of Egr-1 and Sp-1 -by Western-blot analysis; histological chan ges -by morphometric analysis. Body weight and diarrhea were recorded. Systemic administration of the ceftriaxone induced morphological and functional changes in rat colonic mucosa associated with initial stages of the acute inflammation. These changes were accompanied by a decrease of activity of superoxide dismutase and catalase. Levels of redox-sensitive transcription factors Egr-1 and Sp1 were significantly increased, which shows a disturbance of homeostasis of the intestinal barrier.
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