Potencial terapêutico do kefir de leite em modelos experimentais de mucosite intestinal e colite ulcerativa

Abstract

Intestinal inflammation can be triggered by various factors, including diseases and pharmacological treatments, compromising patients' quality of life. Among intestinal inflammatory conditions, intestinal mucositis, an adverse reaction induced by certain chemotherapeutic agents, and ulcerative colitis, a chronic inflammatory bowel disease, are particularly noteworthy. Both conditions affect the gastrointestinal tract and are associated with symptoms such as weight loss, diarrhea, and abdominal pain, negatively impacting patients' well-being. Their treatment is complex, costly, and may present adherence challenges, highlighting the need to explore complementary therapies with therapeutic potential, such as probiotics, which provide health benefits, particularly to the gastrointestinal tract. This dissertation comprises two studies aimed at investigating the effects of milk kefir on intestinal inflammation: (1) "Enteroprotective effect of milk kefir in an experimental model of intestinal mucositis induced by 5-fluorouracil" and (2) "Effect of milk kefir treatment on DSS-induced ulcerative colitis: exploring its mechanisms of action." In the first study, results demonstrated that traditional kefir (TK) reduced the disease activity index (DAI) on the ninth day, without sustained effect, while commercial kefir (CK) achieved this reduction on the eleventh day. Body weight recovery occurred on the twelfth day for TK and the eleventh day for CK. Both treatments improved fecal consistency but did not significantly alter motility (35.74%-52.43%) or intestinal permeability (0.55-1.0 ng/ml). Intestinal mucositis led to increased H₂O₂ production and apoptosis in the jejunum, which were mitigated by kefir, suggesting antioxidant and antiapoptotic effects. Kefir did not modulate IL-12, IL-6, or IL-10 levels, although CK reduced IL-6 expression compared to the 5-FU group. TNF-α levels increased with mucositis and were not reversed by treatments, with CK further elevating this marker. IFN-γ also increased, with no significant differences among treated groups. In the second study, which evaluated ulcerative colitis, kefir demonstrated beneficial effects from the third day of treatment, reducing clinical symptoms (DAI). Weight loss was significant in the DSS group, whereas DSS+KEFIR animals began recovering weight on the fifth treatment day. No significant differences were observed in colon length or spleen weight. Kefir did not modulate local inflammation. Cell regeneration analysis showed reduced LGR5 expression in DSS and DSS+KEFIR groups, without affecting BMI1 expression, suggesting that kefir did not directly influence cellular recovery. Additionally, occludin expression, motility, and intestinal permeability remained unchanged. However, kefir reduced H₂O₂ levels in the colon, alleviating oxidative stress induced by colitis. A similar effect was observed in epithelial cell apoptosis, which was significantly increased in the DSS group but reduced in DSS+KEFIR. In conclusion, the findings of this dissertation demonstrate that milk kefir exerts beneficial effects on intestinal inflammation, promoting antioxidant and anti-apoptotic actions, reinforcing its potential as a promising complementary therapy.