Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic

Abstract

Nonsteroidal anti-inflammatory drugs, besides exerting detrimental effects on the upper digestive tract, can also damage the small and large intestine. Although the underlying mechanisms remain unclear, there is evidence that enteric bacteria play a pivotal role. The present study examined the enteroprotective effects of a delayed-release formulation of rifaximin-EIR (R-EIR, 50mg/kg BID, i.g.), a poorly absorbed antibiotic with a broad spectrum of antibacterial activity, in a rat model of enteropathy induced by indomethacin (IND, 1.5mg/kg BID for 14 days) administration. R-EIR was administered starting 7 days before or in concomitance with IND administration. At the end of treatments, blood samples were collected to evaluate hemoglobin (Hb) concentration (as an index of digestive bleeding). Small intestine was processed for: (1) histological assessment of intestinal damage (percentage length of lesions over the total length examined); (2) assay of tissue myeloperoxidase (MPO) and TNF levels, as markers of inflammation; (3) assay of tissue malondialdehyde (MDA) and protein carbonyl concentrations, as an index of lipid and protein peroxidation, respectively; (4) evaluation of the major bacterial phyla. IND significantly decreased Hb levels, this effect being significantly blunted by R-EIR. IND also induced the occurrence of lesions in the jejunum and ileum. In both intestinal regions, R-EIR significantly reduced the percentage of lesions, as compared with rats receiving IND alone. Either the markers of inflammation and tissue peroxidation were significantly increased in jejunum and ileum from IND-treated rats. However, in rats treated with R-EIR, these parameters were not significantly different from those observed in controls. R-EIR was also able to counterbalance the increase in Proteobacteria and Firmicutes abundance induced by INDO. To summarize, R-EIR treatment significantly prevents IND-induced intestinal damage, this enteroprotective effect being associated with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population.

Pathophysiology of NSAID-Associated Intestinal Lesions in the Rat: Luminal Bacteria and Mucosal Inflammation as Targets for Prevention

“…Histology of the small bowel injury, tissue myeloperoxidase (MPO, as an index of intestinal wall infiltration of polymorphonuclear cells) and malondialdehyde (MDA, reflecting membrane lipid peroxidation) concentrations were measured according to previously adopted methods ( Fornai et al, 2016 ), detailed in Supplementary Material .…”

“…Since rifaximin displays all the characteristics of an ideal antibiotic for targeting enterobacteria ( DuPont and Ericsson, 1993 ), its ability to prevent NSAID-induced intestinal damage has been evaluated in both experimental ( Ciobanu et al, 2014 ; Fornai et al, 2016 ) and clinical ( Scarpignato et al, 2017 ) studies. In healthy volunteers indeed the number and severity of diclofenac-induced intestinal lesions (as evaluated by video capsule endoscopy) were reduced by co-administration of the drug ( Scarpignato et al, 2017 ).…”

Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract

“…66 A resent animal study showed that rifaximin treatment significantly prevents indomethacin-induced intestinal damage following with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population. 72 Colucci et al 73 examined the pathophysiology of NSAID-associated intestinal lesions in a rat model and found that rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities. Other antibiotics like metronidazole, tetracycline, kanamycin, neomycin plus bacitracin and streptomycin were also reported to reduce the risk of NSAID induced enteropathy.…”

Clinical importance of nonsteroidal anti-inflammatory drug enteropathy: the relevance of tumor necrosis factor as a promising target

“…Similar rise in the level of TNF was observed in the small intestine of mice given indomethacin [134,138,139]. While, targeting enteric bacteria with a poorly absorbed antibiotic (like rifaximin), covering gram-positive and gram-negative bacteria (both aerobic and anaerobic) has been reported to attenuate the myeloperoxidase (MPO) and TNF tissue levels [140]. However, if left untreated, this consistent rise in TNF also activates neutrophils, which once entered the bowel microcirculation, undergo a rapid activation leading to tissue invasion, with massive production of injurious substances such as proteolytic enzymes and detrimental ROS leading to exacerbation of small intestinal injury [137].…”