Effect of a Traditional Chinese Medicine Formula (CoTOL) on Serum Uric Acid and Intestinal Flora in Obese Hyperuricemic Mice Inoculated with Intestinal Bacteria

Abstract

CoTOL is a traditional Chinese medicine (TCM) formula in clinics for treating gout and hyperuricemia, especially in obese patients with recurrent attacks. However, fewer studies have investigated how CoTOL impacts the intestinal flora in reducing uric acid. In the present, we analyze the bacteria targeted by ingredients of CoTOL and evaluate the effects of CoTOL on uric acid and intestinal flora in a mice model of obese hyperuricemia inoculated with xanthine dehydrogenase- (XOD-) producing bacteria, Streptococcus faecalis. Firstly, ingredients of herbs in CoTOL and gene target by these ingredients were retrieved from TCMID 2.0, and these genes were screened by DAVID Bioinformatics Resources 6.8, deciphered to retrieve the bacteria. Then, 3-4-week-old male C57bl/6j mice were randomly divided into 6 groups and fed with high fat diet for 8 weeks up to obesity standard. The mice were inoculated intragastrically with 5 × 109 CFU Streptococcus faecalis 3 times at the 5th, 6th, and 7th week and intragastrically administrated with uricase inhibitor, potassium-oxonate (PO, 250 mg/kg), to induce hyperuricemia at the 8th week, once a day for 7 consecutive days, respectively (IB model). IB model plus CoTOL (0.4 ml/20g) and allopurinol (40 mg/kg) were administrated by gavage at the 5th week, once a day for 4 weeks. The feces and blood in each group were sampled at the 4th and 8th week. With no bacteria inoculation, CoTOL, allopurinol, and blank group were treated with CoTOL and allopurinol or water, respectively. 44 species of bacteria (i.e., Enterococcus faecalis, Streptococcus, etc.) genes were targeted by 6 ingredients of 6 herbs in CoTOL. Inoculation with Streptococcus faecalis significantly caused the elevation of uric acid and the change of intestinal flora structure, whereas treatment with CoTOL significantly increased the abundance of Akkermansia and those of Bacteroides and Alloprevotella decreased. Furthermore, CoTOL exhibited a unique effect on reducing weight unobserved in allopurinol intervention. The present study, for the first time, demonstrated that CoTOL has beneficial effects on hyperuricemia and overweight, which may be attributed to regulating material metabolism and improving the structure or function of intestinal flora. Thus, CoTOL may be a promising therapy for hyperuricemia and overweight in chronic gout management and can be integrated with conventional treatments.

Gut microbiota remodeling: A promising therapeutic strategy to confront hyperuricemia and gout

“…An analysis of CoTOL targeted bacteria in a mouse model of obesity HUA inoculated with the XDH-producing bacterium Streptococcus faecalis. The results showed that the S. faecalis inoculation resulted in elevated UA and altered the gut microbiota structure, while the CoTOL treatment increased the abundance of Akkermansia and decreased the abundance of Bacteroides and Alloprevotella ( Gao et al., 2020 ). In gouty arthritis model mice, Simiao Decoction can effectively reduce the serum UA levels, reduce myeloperoxidase (MPO), XOD, and adenosine deaminase (ADA) activities, and relieve gout-related symptoms such as foot swelling and pain ( Lin et al., 2020 ).…”

Sacha Inchi Oil Press-Cake Protein Hydrolysates Exhibit Anti-Hyperuricemic Activity via Attenuating Renal Damage and Regulating Gut Microbiota

“…Of importance, SISH intervention substantially rescued the relative abundance of those intestinal florae in hyperuricemic rats ( Figure 3 f, Supplementary Figure S2 ). Specifically, SISH enhanced the relative abundance of probiotics such as Akkermansia and Alistipes and reduced the Streptococcus (XOD-producing bacteria) population [ 10 ]. Taken together, these results evidenced that SISH could modulate the gut microbial organization and enhance the microbial diversity in hyperuricemic rats.…”

“…Compared with the hyperuricemic group, the SISH group had a significantly increased abundance of Ruminococcaceae (unidentified_ Ruminococcaceae , Oscillibacter , Ruminiclostridium , Intestinimonas ) which are considered butyrate-producing prebiotics [ 51 ]. In addition, SISH also increased the abundance of probiotics ( Akkermansia , Alistipes ) and reduced the population of the XOD-producing bacteria ( Streptococcus ) [ 10 ]. Lactobacillus is known to sequentially degrade UA to urea by synthesizing uricase, allantoinase, and allantoicase, thereby improving UA excretion [ 9 ].…”

“…UA is one product in the purine metabolism pathway. Xanthine oxidase (XOD), a critical enzyme in the purine catabolic pathway, catalyzes the oxidation and conversion of hypoxanthine and xanthine to UA [ 10 ]. In in vivo settings, kidneys are responsible for most UA excretion, while approximately 25% of UA is excreted into the intestines and further metabolized by gut microbiota [ 9 ].…”

Advances in Experimental and Clinical Research of the Gouty Arthritis Treatment with Traditional Chinese Medicine

“…Lin et al found that the traditional Chinese medicine (TCM) formula, Si-miao-tang, could reduce intestinal apoptosis by inhibiting the expression of NLRP3 inflammatory vesicles, regulating the expression of TNF- α , caspase 8, and AIFM1 proteins, and regulating the expression of APOB, LPL, and PPAR α proteins to affect lipid metabolism and restore intestinal flora [ 116 ]. Gao et al found that the TCM formula, CoTOL, could reduce body weight and uric acid in mice with hyperuricemia models by regulating intestinal flora [ 117 ]. The herbal chicory extract can reduce the activity of key enzymes of uric acid metabolism in hyperuricemic quail, which may be related to regulating intestinal flora and intestinal tight junction protein occludin, increasing the number of beneficial intestinal flora and reducing the number of pathogenic bacteria [ 118 ].…”