Broad-spectrum antibiotics alter the microbiome, increase intestinalfxr, and decrease hepatic steatosis in zebrafish short bowel syndrome

Abstract

Short bowel syndrome (SBS) is associated with changes in the intestinal microbiome and marked local and systemic inflammation. There is also a late complication of SBS, intestinal failure associated liver disease (IFALD) in which hepatic steatosis progresses to cirrhosis. Most patients with SBS arrive at massive intestinal resection after a contaminating intraabdominal catastrophe and have a history of exposure to broad spectrum antibiotics. We therefore investigated whether the administration of broad spectrum antibiotics in conjunction with SBS in zebrafish (ZF) would replicate these systemic effects observed in humans in order to identify potentially druggable targets to aid in the management of SBS and resulting IFALD. In zebrafish with SBS, broad spectrum antibiotics altered the microbiome, decreased inflammation, and reduced the development of hepatic steatosis. After two weeks of broad spectrum antibiotics, these fish exhibited decreased alpha diversity, with less variation in microbial community composition between SBS and sham fish. Additionally, administration of broad spectrum antibiotics was associated with decreased expression of intestinal toll-like receptor 4 (tlr4), increased expression of the intestinal gene encoding the Farnesoid X receptor (fxr), decreased expression of downstream hepatic cyp7a1, and decreased development of hepatic steatosis. SBS in zebrafish reproducibly results in increased epithelial surface area as occurs in human patients who demonstrate intestinal adaptation, but antibiotic administration in zebrafish with SBS reduced these gains with increased cell death in the intervillus pocket that contains stem/progenitor cells. These alternate states in SBS zebrafish might direct the development of future human therapies.

Zebrafish as a Screening Model to Study the Single and Joint Effects of Antibiotics

“…Interestingly, Maselli et al [ 119 ] revealed that the administration of ampicillin (100 μg/mL), kanamycin (100 μg/mL) and amphotericin B (250 ng/mL) over two weeks to zebrafish with short bowel syndrome resulted in less intestinal inflammation and reduced liver steatosis after alteration of the intestinal microbiome ( Table 4 ).…”

Effects of Microplastics on Immune Responses of the Yellow Catfish Pelteobagrus fulvidraco Under Hypoxia

“…According to previous studies, harmful substances in the environment, such as MPs, heavy metals, pesticides, and antibiotics, could cause the inflammatory response of organisms (Liu H. et al, 2020;Maselli et al, 2020;Pirsaheb et al, 2020;Wang Y. et al, 2021). However, inflammatory responses in fish were often closely related to cytokines such as TNF, IL, and IFN (Falcão et al, 2021).…”

Signatures of dysbiosis in fish microbiomes in the context of aquaculture

“…In addition to the aforementioned studies, another three published works examined the effects of the use of combined antibiotics in the gut microbiome of the European seabass 67 and zebrafish, 68 and in the gut and skin microbiomes of the yellowtail kingfish ( Seriola lalandi Valenciennes, 1833) 66 (Table 1).…”

“…Finally, the work of Maselli et al 68 studied the effects of a 2‐week antibiotic cocktail bath treatment in zebrafish from which a portion of intestine was surgically removed to simulate short bowel disease and non‐operated zebrafish. A decrease in alpha diversity was observed in both operated and non‐operated groups, as well as an increase in potential pathogens from Aeromonas spp.…”