Broccoli-Derived Glucoraphanin Activates AMPK/PGC1α/NRF2 Pathway and Ameliorates Dextran-Sulphate-Sodium-Induced Colitis in Mice

Abstract

As the prevalence of inflammatory bowel diseases (IBD) rises, the etiology of IBD draws increasing attention. Glucoraphanin (GRP), enriched in cruciferous vegetables, is a precursor of sulforaphane, known to have anti-inflammatory and antioxidative effects. We hypothesized that dietary GRP supplementation can prevent mitochondrial dysfunction and oxidative stress in an acute colitis mouse model induced by dextran sulfate sodium (DSS). Eight-week-old mice were fed a regular rodent diet either supplemented with or without GRP. After 4 weeks of dietary treatments, half of the mice within each dietary group were subjected to 2.5% DSS treatment to induce colitis. Dietary GRP decreased DSS-induced body weight loss, disease activity index, and colon shortening. Glucoraphanin supplementation protected the colonic histological structure, suppressed inflammatory cytokines, interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α), and reduced macrophage infiltration in colonic tissues. Consistently, dietary GRP activated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, and nuclear factor erythroid 2-related factor 2 (NRF2) pathways in the colonic tissues of DSS-treated mice, which was associated with increased mitochondrial DNA and decreased content of the oxidative product 8-hydroxydeoxyguanosine (8-OHDG), a nucleotide oxidative product of DNA. In conclusion, dietary GRP attenuated mitochondrial dysfunction, inflammatory response, and oxidative stress induced by DSS, suggesting that dietary GRP provides a dietary strategy to alleviate IBD symptoms.

Current Knowledge on the Preparation and Benefits of Cruciferous Vegetables as Relates to In Vitro, In Vivo, and Clinical Models of Inflammatory Bowel Disease

“…Similar to the findings from in vitro studies, broccoli has been reported to have anti-inflammatory, antioxidant, and prebiotic effects against IBD in animal models ( Table 2 [ 48 , 99 , 102 , 105 , 107 , 111 , 112 , 116 , 118 , 122 , 125 , [127] , [128] , [129] , [130] , [131] , [132] , [133] , [134] , [135] , [136] , [137] , [138] , [139] , [140] , [141] ] and Figure 1 ). Both the UC and CD models use chemical triggers or genetic knockouts.…”

“… Cruciferous vegetables Image Bioactive compounds Preparation Dose Treatment period Pathways Benefits Model References purified SFN — SFN purified compound 10, 20, and 40 mg/kg 14 d IL10 activation of STATs Anti-inflammatory DSS mice [ 118 ] purified SFN — SFN purified compound 2.5, 5, 10 and 20 mg/kg 19 d IL6 and TNFɑ, STAT3 and Nrf2, Bifidobacterium and Lactobacillus spp. Prebiotic, Anti-inflammatory DSS mice [ 107 ] Broccoli SFN, GLR purified 600 ppm 4 wk IL1β and IL18, AMPK and PGC-1ɑ, Nrf2, HO-1, 8-OHdG Anti-inflammatory, Antioxidant DSS mice [ 127 ] SFN Raw and slightly cooked 10% (w/w) 2 wk IL6, CCR2, and VCAM-1 Anti-inflammatory DSS mice [ 128 ] GLR, ITCs Freeze-dried 4.1 mg/g 7 d NQO1 Antioxidant C57BL/6 mice [ 99 ] SFN Seed extract 370 mg/kg/d 2 wk Bifidobacterium spp., Nrf2 signaling Prebiotic, Anti-inflammatory DSS mice [ 129 ] Glucobrassicin Freeze-dried 15% (w/w) 24 d AHR, Cyp1a1, IL1β, IL10, IL6, Ptgs and CXCL5, increased Actinobacteria and Alistipes …”

“…A study reported the effect of a broccoli diet rich in SFN and GLR against oxidative stress and inflammation in DSS mice. The diet decreased pathological score and TNFɑ, IL1β, and IL18 [ 127 ]. Meanwhile, it increased AMPK and PGC-1ɑ pathways and promoted Nrf2, HO-1, and 8-hydroxydeoxyguanosine (8-OHDG) activities against oxidative stress and DNA damage within the colon [ 127 ].…”

“…The diet decreased pathological score and TNFɑ, IL1β, and IL18 [ 127 ]. Meanwhile, it increased AMPK and PGC-1ɑ pathways and promoted Nrf2, HO-1, and 8-hydroxydeoxyguanosine (8-OHDG) activities against oxidative stress and DNA damage within the colon [ 127 ]. A similar anti-inflammatory effect was observed in DSS mice fed raw and lightly cooked broccoli diets [ 128 ].…”

The Role of AMPK Signaling in Ulcerative Colitis

“…GRP exhibits its therapeutic effects by activating the AMPK/PGC1α/NRF2 pathway, thus ameliorating dextran-sulphate-sodium (DSS)-induced colitis in mice. 99 Resveratrol (RES), a natural polyphenol, is found in several plants and fruits such as grapes, blueberries, and peanuts. Its microbial metabolite, 4HPP, is involved in the potential mechanism of maintaining intestinal barrier function.…”