NUTRITIONAL SUPPLEMENTS TESTED AS POTENTIAL ALTERNATIVE THERAPY IN DSS-INDUCED COLITIS
Citrus fruits are a good source of fiber, vitamins and polyphenols and have many health benefits. Naringenin is a major polyphenol isolated from citrus fruits that protected the intestinal barrier during DSS-colitis in mice. Naringenin reverted DSS-induced reduced expression of occludin, junctional adhesion molecule-A (JAM-A) and claudin-3 and epithelial hyperpermeability. Naringin, another flavonoid of citrus fruits, showed protective effects on epithelial barrier functions during DSS colitis due to activation of peroxisome proliferator-activated receptor γ and subsequent inhibition of NF-ĸB leading to reduced proinflammatory cytokine levels. Interestingly, naringin significantly suppressed DSS-induced NLRP3 inflammasome activation by decreasing the expression of NLRP3, ASC, caspase-1 and IL-1β. Naringin also inhibited DSS-induced MAPK activation and epithelial barrier dysfunction through regulation of ZO-1 expression suggesting that naringin protects epithelial barrier integrity on multiple levels.
Red raspberry (RB) is another fruit that has numerous health benefits and contains high amounts of fiber and polyphenols with antioxidative and anti-inflammatory properties. RB supplementation in a DSS-induced colitis model prevented DSS-induced mucosal damage, reduction of mucin-2, ZO-1 and claudin-3 expression and decreased expression of the pore-forming TJ protein claudin-2. Of note, RB also reversed DSS-induced NF-ĸB activation and AMP-activated protein kinase (AMPK) inhibition. Thus, RB also protects the epithelial barrier against DSS-induced colitis via its anti-inflammatory effects on multiple levels.
Apples and strawberries contain phloretin. Phloretin is a flavonoid with antioxidative and anti-inflammatory properties. Phloretin treatment improved mucosal injury caused by DSS-treatment in the colon in a dose-dependent manner. Phloretin inhibited loss of goblet cells, oxidative stress, inflammation and epithelial barrier dysfunction. Mechanistically, phloretin protected against colitis through inhibition of the NF-ĸB pathway and the NLRP3 inflammasome. Of note, phloretin decreased the expression of toll-like receptor 4 and increased peroxisome proliferator-activated receptor γ expression, which are activating and inhibiting signaling proteins upstream of NF-ĸB, respectively. Thus, inhibition of NF-ĸB and the NLRP3 inflammasome seem to be common protective mechanisms shared by different flavonoids.
Formononetin is a natural isoflavone and one of the major biologically active compounds in a variety of Chinese medicinal herbs such as Astragalus membranaceus. Intraperitoneal injection of formononetin attenuated in a dose-dependent manner DSS-induced leukocyte infiltration, increase of proinflammatory cytokine expression and reduction of claudin-1, occludin and ZO-1 levels in the colon of DSS-treated mice due to inhibition of the NLRP3 inflammasome. Phellinus igniarius is a medicinal mushroom that has been widely used in traditional Chinese medicine to treat stomach ache, inflammation and tumors. The aqueous extract of Phellinus igniaurius possesses antitumor, antidiabetic and immunity-modulating effects[61,62]. In a model of chronic DSS-induced colitis in mice, the aqueous extract of Phellinus igniarius significantly improved DSS-induced loss of crypts and goblets cells, epithelial barrier dysfunction, and reduced plasma lipopolysaccharide levels. The Phellinus igniarius extract significantly inhibited NF-ĸB activation through inhibition of IkBα phosphorylation and the ASC3-caspase-1 pathway.
Soybeans and barley are a good source of isoflavonoids with anti-inflammatory effects. A mixture of soybeans and barley protected against DSS-colitis by reversing DSS-induced epithelial permeability, redistribution and loss of ZO-1, occludin, and claudin-1 and by preventing bacterial translocation into mesenteric lymph nodes. Evodiamine is a bioactive alkaloid obtained from Evodia rutaecarpa that is used in traditional Chinese medicine because of its anti-inflammatory properties. Evodiamine ameliorated DSS-induced epithelial barrier damage, increased proinflammatory cytokines levels, loss of ZO-1, occludin and mucin-2 and decreased NF-ĸB, p65 and IĸB phosphorylation and NLRP3 inflammasome activation suggesting that the protective effect of evodiamine is due to its anti-inflammatory properties.
Salvia miltiorrhiza Bunge (Danshen) also has anti-inflammatory properties and contains the active phenolic compound salvianolic acid A (SAA). SAA inhibited DSS-induced histological damage, leukocyte infiltration, ulceration and edema in the mouse colon and protected against loss of ZO-1 and occludin. The cecal bacterial composition that was altered after DSS-treatment was similar to controls when mice received SAA in parallel to DSS treatment. Thus, apart from its anti-inflammatory effects, SAA protected the intestinal epithelial barrier by modulating the gut microbiota during colitis.
Magnolol is the main and active ingredient of Magnolia officinalis, which is being used in traditional Chinese medicine for the treatment of gastrointestinal disorders. Magnolol improved DSS-induced colitis signs in mice. In particular, epithelial erosion, disruption of crypt glands, loss of ZO-1 and occludin and leukocyte infiltration were reduced when colitic mice were treated with magnolol. Again, the anti-inflammatory mechanism of magnolol was shown to relate to the regulation of NF-ĸB, p65 and IĸB phosphorylation and peroxisome proliferator-activated receptor γ expression.
Eupatilin (Eup) is a major flavonoid found in the leaves of Artemisia argyi and is also the principal bioactive compound of Artemisia asiatica Nakai ex Kitam. Eup is used in traditional medicine due to its antioxidative and anti-inflammatory activities. Eup treatment alleviated DSS-induced inflammation and oxidative stress in mice by decreasing nicotinamide adenine dinucleotide phosphate oxidase and increasing occludin and ZO-1 levels in the colon epithelium. Eup inhibited DSS-induced NF-ĸB and MAPK activation and significantly promoted AMPK activation, thus contributing to barrier stabilization.
The Chinese herb QingBai decoction (QBD) is a mixture of six medicinal herbs that has been used in the treatment of UC. QBD effectively relieved intestinal symptoms such as diarrhea and bleeding during active colitis. When administered as enema in a DSS-colitis mouse model, QBD was able to diminish epithelial damage, mucosal inflammation, crypt damage and loss of goblet cells and mucin-2 in colon tissue. Hyperpermeability and loss of TJ proteins were also ameliorated by QBD, and these effects were comparable to what was observed in mesalazine-treated mice. Of note, QBD was able to inhibit epithelial apoptosis and to increase proliferation during colitis. These data suggest that QBD can contribute to wound healing and tissue recovery.
Terpinen-4-ol (TER) is a main component of Zanthoxylum bungeanum Maxim with high antibacterial, antioxidative and anti-inflammatory properties. Treatment with TEL completely blocked DSS-induced epithelial damage, crypt distortion, increase of proinflammatory cytokines and depletion of goblet cells. TEL also prevented loss of ZO-1 and occludin and NF-ĸB and NLRP3 activation.
Alnus japonica Steud (Betulaceae) has been used in traditional Asian medicine to treat fever, hemorrhage and gastric disorders. Ethanol extracts from Alnus japonica bark has been reported to have antioxidative and anti-inflammatory effects due to the presence of diarylheptanoids, triterpenoids and flavonoids[72-75]. Histological analysis of colon tissues showed a protective effect on tissue damage, inflammation and leukocyte infiltration during DSS-colitis. mRNA levels of proinflammatory cytokines and cyclo-oxygenase-2 protein levels were lower in Alnus japonica bark-treated colitic mice. Of note, Alnus japonica bark treatment not only increased ZO-1, occludin and heme-oxygenase 1 protein levels but also protected against epithelial apoptosis.
Pogostemon cablin (blanco) Benth is a plant used in the treatment of gastrointestinal disorders in Asia. Patchouli alcohol (PA) is the extract containing the major active components of Pogostemon cablin with anti-inflammatory and immune-modulatory properties. PA given during DSS-colitis in mice reduced proinflammatory cytokine levels and infiltration of inflammatory cells into the mucosa in a dose-dependent manner. Expression of mucin-1, mucin-2, ZO-1, ZO-2, claudin-1 and occludin were higher after PA treatment compared to the DSS group. In addition, PA inhibited DSS-induced apoptosis and improved tryptophan metabolism. Of note, the effect of PA was similar to that observed with sulfasalazine treatment.
Rhizoma coptidis is commonly used in traditional Chinese medicine as treatment for various diseases including IBD. Berberine (BBR) is the most abundant and major active isoquinoline alkaloid of Rhizoma coptidis but is characterized by poor intestinal absorption. Berberrubine is a BBR metabolite with better intestinal absorption. Treatment with both berberrubine and BBR ameliorated signs of DSS-colitis although higher doses were required for BBR. Mucosal inflammation, leukocyte infiltration, increased cytokine levels and decreased mRNA levels of mucin-1 and mucin-2 were effectively counteracted by both compounds. ZO-1, ZO-2, claudin-1 and occludin levels were maintained with BBR and berberrubine treatment, and apoptosis was inhibited.
Moringa oleifera (moringa) is a tropical plant traditionally used for its nutritional value and as treatment for a number of acute and chronic conditions such as inflammation and diabetes. Moringa has anti-inflammatory, antibacterial and antioxidative properties attributed mainly to glucosinolates, which can be metabolized into the main bioactive metabolites, moringa isothiocyanates (MICs). MIC-1 [4-(α-L-rhamnosyloxy)benz-isothiocyanates] is the most abundant MIC in moringa seeds. Moringa seed extracts enriched in MIC-1 were given as treatment during acute and chronic DSS-colitis in mice and, surprisingly only protective effects were observed in the acute model. Beneficial effects of moringa seed extracts during acute colitis included reduced inflammation and proinflammatory cytokine levels and increased levels of claudin-1, ZO-1 and phase-II-detoxifying enzymes including GSTP1, NQO1 and HO1. Moreover, the anti-inflammatory and antioxidative activities of moringa seed extracts were associated with Nrf2-mediated signaling.
Wasabia japonica is a popular traditional spice in Asia. Allyl isothiocynate is a bioactive molecule present in Wasabia japonica with anti-inflammatory effects. Allyl isothiocynate treatment during DSS-colitis increased mucin-2 and ZO-1 protein expression and the number of goblet cells. These protective effects were related in vitro after treatment of epithelial cells with lipopolysaccharides to attenuation of phosphorylation of p65 and ERK1/2, reduced expression of IL-1β and TNF-α and increased mucin-2 expression.
KIOM-20I5E is an active anti-inflammatory ingredient of Acer palmatum thumb that is widely distributed in various regions of Asia and has been used in traditional medicine for its antioxidative and anti-inflammatory properties. KIOM-20I5E ameliorated DSS-induced reduction of goblet cells and ZO-1 and occludin levels. However, the underlying mechanism was not determined.
Dietary fibers consumption affects the intestinal microbiota and consequently intestinal epithelial barrier functions. Intestinal microorganisms metabolize dietary fibers to short-chain fatty acids that suppress the transcription of proinflammatory mediators, thus positively affecting intestinal barrier functions. Like other fibers, Guar gum (GG) cannot be digested in the small intestine of mammals; however, it is quickly metabolized by colonic bacteria. Short-chain fatty acids then promote epithelial cell proliferation in the colon, mucosal blood flow and colonic motility. Fermentable GG and partially hydrolyzed GG improved the expression levels of ZO-1, ZO-2, occludin, JAM-A, claudin-3, claudin-4 and claudin-7 in a murine model of DSS-colitis. Both partially hydrolyzed GG and GG inhibited lipopolysaccharide-binding protein levels in the plasma indicating that both compounds protected the colonic barrier and increased the production of fecal organic acids, which could be important mediators of the observed protective effects.
Moreover, pre-treatment of mice with psyllium fiber before colitis induction with DSS ameliorated loss of ZO-2, occludin, JAM-A, claudin-3 and claudin-7 and reduced lipopolysaccharide-binding protein plasma concentration. In addition, the psyllium fiber diet increased intestinal cytoprotective heat-shock protein 25 levels and expression of extracellular matrix-associated genes including collagens and fibronectin. In summary, many phytochemicals have benefits during experimental colitis mostly due to anti-inflammatory and antioxidative effects that help to maintain junction architecture and epithelial barrier integrity. Thus, people susceptible to colitis should take great care of their diets.