Oral Supplementation of Butyrate Reduces Mucositis and Intestinal Permeability Associated with 5‐Fluorouracil Administration

Abstract

Mucositis affects about 40 % of patients undergoing chemotherapy. Short chain fatty acids (SCFA), mainly butyrate, are claimed to improve mucosal integrity, reduce intestinal permeability and act as anti-inflammatory agents for the colon mucosa. We evaluated the effects of oral administration of SCFA or butyrate in the 5FU-induced mucositis. Mice received water, SCFA or butyrate during all experiment (10 days) and a single dose of 5FU (200 mg/kg) 3 days before euthanasia. We evaluated inflammatory and histological score by morphometry, and by activity of enzymes specific to neutrophil, eosinophil and macrophage and TLR-4, TNF-alpha and IL6 expressions. Intestinal permeability and tight junction protein ZO-1 expression were evaluated. Mice from the 5FU (5-Fluorouracil) group presented weight loss, ulcerations and inflammatory infiltration of neutrophils and eosinophils, increased expression of IL6 and TNF-alpha and increased intestinal permeability. SCFA minimized intestinal damage, reduced ulcerations without affecting intestinal permeability. Butyrate alone was more efficient at improving those parameters than in SCFA solution and also reduced intestinal permeability. The expression of pro-inflammatory cytokines and ZO-1 tended to be higher in the SCFA supplemented but not in the butyrate supplemented group. We showed the beneficial effects of butyrate on intestinal mucositis and its promising function as an adjuvant in the treatment of diseases not only of the colon, but also of the small intestine.

L-Arginine Pretreatment Reduces Intestinal Mucositis as Induced by 5-FU in Mice

“…Neutrophil infiltration has been reported in several studies that assessed mucositis (24,32,33). We observed intermediate MPO activity in animals receiving L-arginine.…”

“…Water was supplemented with 2% L-arginine (23) or L-alanine (an isoproteic control) according to the experimental group during the entire experiment (10 days). Intestinal mucositis was induced on the 7th day with a single intraperitoneal dose (200 mg/kg body weight) of 5-FU (Fauldfluor!, Libbs Farmacêutica Ltda., São Paulo, Brazil) (24). The control group received the same intraperitoneal dose of phosphatebuffered saline (PBS).…”

Effects of dietary lysine levels on jejunal expression of amino acids transporters and hindgut microflora in weaned pigs

“…SCFA, particularly butyrate, are the major and preferred metabolic substrates for colonocytes providing at least 60-70% of their energy requirements necessary for their proliferation and differentiation (Suzuki et al, 2008). They can also maintain normal morphology of intestinal mucosal epithelial cells as well as the normal function of the intestinal mucosa barrier as well as inhibit intestinal inflammatory reaction (Ferreira et al, 2012). In the present study, the concentration of butyric acid increased quadratically with increasing SID Lys and maximize in 1.35% SID Lys group.…”

The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

“…Butyrate-producing bacteria play a vital role in regulating the functions and integrity of the intestinal epithelial barrier [132][133][134][135], and hence, dysbiosis involving a reduction in butyrate producers could disrupt the immune homeostasis in the gastric mucosa with profound systemic effects [136]. SCFAs stimulate the secretion of glucagon-like peptides 1 and 2 via ligation of glucagon-like peptide-43 [137][138][139] leading to decreased epithelial permeability and increased mucosal antibacterial defenses [140].…”