Total Flavonoids of Glycyrrhiza uralensis Alleviates Irinotecan-Induced Colitis via Modification of Gut Microbiota and Fecal Metabolism

Abstract

Irinotecan (CPT-11)-induced gastrointestinal toxicity strongly limits its anticancer efficacy. Glycyrrhiza uralensis Fisch., especially flavonoids, has strong anti-inflammatory and immunomodulatory activities. Herein, we investigate the protective effect of the total flavonoids of G. uralensis (TFGU) on CPT-11–induced colitis mice from the perspective of gut microbiota and fecal metabolism. The body weight and colon length of mice were measured. Our results showed that oral administration of TFGU significantly attenuated the loss of body weight and the shortening of colon length induced by CPT-11. The elevated disease activity index and histological score of colon as well as the up-regulated mRNA and protein levels of TNF-α, IL-1β, and IL-6 in the colonic tissue of CPT-11–treated mice were significantly decreased by TFGU. Meanwhile, TFGU restored the perturbed gut microbial structure and function in CPT-11–treated mice to near normal level. TFGU also effectively reversed the CPT-11–induced fecal metabolic disorders in mice, mainly call backing the hypoxanthine and uric acid in purine metabolism. Spearman’s correlation analysis further revealed that Lactobacillus abundance negatively correlated with fecal uric acid concentration, suggesting the pivotal role of gut microbiota in CPT-11–induced colitis. Since uric acid is a ligand of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, TFGU was further validated to inhibit the activation of NLRP3 inflammasome by CPT-11. Our findings suggest TFGU can correct the overall gut microbial dysbiosis and fecal metabolic disorders in the CPT-11–induced colitis mice, underscoring the potential of using dietary G. uralensis as a chemotherapeutic adjuvant.

NLRP3 Inflammasome Pharmacological Inhibitors in Glycyrrhiza for NLRP3-Driven Diseases Treatment: Extinguishing the Fire of Inflammation

“…The major flavonoid components in Glycyrrhiza uralensis are liquiritin apioside, liquiritin, naringin, liquiritigenin, quercetin, Lico A and glabridin, as measured by high-performance liquid chromatography analysis. 107 The upregulated mRNA and protein levels of TNF-α, IL-1β, and IL-6, are significantly decreased by all of the flavonoids from Glycyrrhiza uralensis in the colonic tissue of irinotecan-induced colitis mice, and the flavonoids also inhibit the activation of NLRP3 inflammasome triggered by irinotecan. 107 Huangqi decoction (Astragali Radix and Glycyrrhizae Radix et Rhizoma), a classic Chinese herbal formula, ameliorates 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestatic liver injury, and alleviates the increased hepatic expression of pro-inflammatory factors and NLRP3 inflammasome activation.…”

“…High glucose-induced extracellular matrix accumulation↓, oxidative stress↓, IL-6 and IL-1β production↓, NF-κB and NLRP3 inflammasome pathways↓ [47] Echinatin Mouse BMDMs and human PBMCs Bind to heat-shock protein 90↑, ATPase activity↓, the association between the cochaperone SGT1 and HSP90-NLRP3↓ [50] LPS-induced septic shock mouse model IL-1β↓, TNF-α production↓, mouse survival↑ [50] Dextran sodium sulfate-induced colitis mouse model Colonic inflammation↓, mucosal barrier and inflammatory cell infiltration↓, caspase-1 activation↓, IL-1β production↓ [50] MCD diet-induced NASH mouse model Morphological changes↓, hepatic steatosis↓, ballooning↓, fibrosis↓, caspase-1 activation↓, mRNA expression of proinflammatory genes IL-1β and TNF-α↓ [50] (Continued) Carrageenan-induced pleurisy mouse model TNF-α↓, IL-1β↓, IL-6↓, the NLRP3/NF-κB pathway↓, iNOS↓, COX-2↓ [68] The mouse periodontal ligament fibroblasts Chronic periodontitis↓, caspase-1 activation↓, IL-1β↓, HMGB1↓, ROS/ TXNIP/Nlrp3 inflammasome pathway↓ [67] Collagenase IV-induced intracerebral hemorrhage rat model Neurological deficits↓, histological damages↓, blood-brain barrier disruption↓, brain edema↓, neuronal degeneration↓, the NF-κB and NLRP3 inflammasome pathways↓, Nrf2-mediated antioxidant system↑ [58] LPS-induced ALI mouse model Recruitment of inflammatory cells↓, COX-2↓, iNOS↓, TNF-α↓, IL-1β↓, IL-6↓, the AMPK/Nrf2 signaling and its downstream antioxidant enzymes↑, the NLRP3 inflammasome and NF-κB pathways↓ [62] In vitro model of ischemia in organotypic slice cultures Ischemic neuronal death↓, NLRP3 inflammasome activation↓ [55] Indomethacin-induced small intestinal damage mouse model Small intestinal damage↓, cleaved caspase-1↓, mature IL-1β protein levels↓ [63] Ex vivo culture of epididymal white A corneal injury mouse model The expression of IL-1β↓, extracellular HMGB1 functions↓, the NF-κB-p65/ NLRP3/IL-1β signaling pathway↓ [89] An acute glaucoma mouse model The severity of the disease↓, the activation of NLRP3 and caspase-8 inflammasomes↓ [92] Traumatic spinal cord injury rat model Expression of NLRP3 inflammasome components↓, ASC↓, NLRP3↓, cleaved caspase-1↓, IL-1β↓, IL-18↓ [95] GA Mouse BV-2 microglial cells Nitric oxide↓, IL-1β maturation↓ [102] LPS-induced ALI mouse model ALI↓, the activation of NLRP3 inflammasome↓, ROS-PI3K/AKT pathway↓ [96] (Continued) Carbenoxolone HFD-induced obese mouse model Insulin sensitivity↓, the IκB-α/NF-κB pathway and NLRP3 inflammasome↓, [106] Licorice extract Irinotecan-induced colitis mouse model The mRNA and protein levels of TNF-α↓, IL-1β↓, and IL-6↓ [107] Notes: ↓, inhibition; ↑, promotion.…”

Synergistic Effects of Licorice Root and Walnut Leaf Extracts on Gastrointestinal Candidiasis, Inflammation and Gut Microbiota Composition in Mice

“…Recent findings suggest that licorice ( Glycyrrhiza uralensis Fisch.) could correct overall gut microbial dysbiosis and fecal metabolic disorders associated with CPT-11-induced colitis in mice ( 26 ). Compounds known to be present in walnut leaves, e.g., hydroxycinnamic acids and flavonoids, have also been reported to modulate gut microbiota composition ( 23 , 24 , 27 ).…”

Phytochemical‑rich herbal formula ATG‑125 protects against sucrose‑induced gastrocnemius muscle atrophy by rescuing Akt signaling and improving mitochondrial dysfunction in young adult mice

“…( 29 ), Capsicum annuum L. ( 30 , 31 ), Lophatherum gracile Brongn. ( 32 ), Curcuma longa ( 33 , 34 ) and Glycyrrhiza uralensis ( 35 ). Traditionally, these plants have been used for centuries for their antioxidant, anti-inflammatory and healing properties.…”

“…Traditionally, these plants have been used for centuries for their antioxidant, anti-inflammatory and healing properties. Different classes of bioactive constituents are present in ATG-125, including several pseudoalkaloids, phenols and flavonoids, thus resulting in a pharmaceutical composition comprised of a mixture of chlorogenic acid ( 36 – 38 ), leonurine ( 29 , 39 ), schaftoside ( 40 ), rutin ( 36 ), isoschaftoside ( 41 ), isochlorogenic acid ( 38 ), quercetin ( 42 , 43 ), apigenin ( 43 , 44 ), glycyrrhizic acid ( 35 ), curcumin ( 33 , 34 ) and artemisetin ( 27 ), all of which contribute to its medicinal properties.…”