Research progress on gut microbiota and hyperuricemia population

Gout is a common metabolic disease characterized by a disorder of purine metabolism or reduced uric acid excretion in patients, leading to elevated uric acid levels in the blood. This results in the deposition of urate crystals in tissues, joints, and kidneys, which can cause joint destruction and impaired kidney function in severe cases. Additionally, gout patients often have comorbidities such as diabetes, hypertension, hyperlipidemia, and cardiovascular diseases, posing a serious threat to human health. In recent years, with the improvement of people's quality of life and increased intake of high-fat, high-purine, and high-protein foods, the incidence of gout has been rising globally, with a noticeable trend towards younger patients.

Uric acid is the final product of purine nucleic acid metabolism in the body. When uric acid levels exceed normal levels, hyperuricemia (HUA) occurs. Clinically, hyperuricemia is defined as uric acid levels greater than 7 or 7.5 mg/dl in males and greater than 6 or 6.5 mg/dl in females. Recent statistics indicate that approximately 120 million people in China suffer from hyperuricemia, accounting for about 1/10 of the total population, with a higher prevalence in males. Correcting uric acid levels in the blood and alleviating hyperuricemia is an important clinical issue that needs urgent attention.

The intestinal microbiota participates in the metabolism of intestinal purines and uric acid.

About 80% of the uric acid generated daily in the human body comes from endogenous cellular metabolism breaking down nucleic acids and other purine compounds, while 20% comes from the consumption of foods rich in nucleic acids and purines, which are digested and broken down by enzymes. Approximately 2/3 of the generated uric acid is excreted by the kidneys, and 1/3 is secreted into the intestines. Under normal circumstances, endogenous uric acid can also be directly secreted from the blood into the intestinal segments. The mechanisms of intestinal uric acid excretion include transport proteins and intestinal probiotics. In humans, some polymorphic variants of the transport protein BCRP (also known as ATP-binding cassette transporter, subfamily G, member 2, ABCG2) can secrete uric acid into the intestines. A study by Uchida et al. showed that the ABCG2 transporter is abundantly expressed in the ileum. After foods rich in nucleic acids and purines enter the intestines, Escherichia coli can secrete xanthine dehydrogenase to convert them into uric acid. Research indicates that blocking uric acid transport into the intestines leads to increased serum uric acid concentrations, which also proves that the intestinal mechanism is crucial for regulating uric acid levels. The intestinal microbiota is an important executor of intestinal purine and uric acid metabolism, especially Lactobacillus and Pseudomonas, which are involved in the synthesis of uric acid-degrading enzymes.

Characteristics of the intestinal microbiota in gout patients.

The intestinal microecological system is the most complex and important microecological system in the human body, composed of bacteria, fungi, viruses, etc., with bacteria accounting for over 99% of the total intestinal microbiota, holding an absolute dominant position. Intestinal bacteria are mainly anaerobic and facultative anaerobic, concentrated in six major phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Verrucomicrobia, and Fusobacteria, with Bacteroidetes and Firmicutes being the main dominant groups. Based on their different effects on the human body, intestinal microbiota can be divided into three categories: physiological microbiota, which are the dominant beneficial and harmless bacteria in the intestinal microecology, such as bifidobacteria and lactobacilli; opportunistic pathogens, which reside in the human intestines and are harmless under normal conditions but can cause disease when the intestinal microecological balance is disrupted, such as enterobacteria and enterococci; and transient bacteria, most of which are pathogenic, temporarily residing in the body, such as Pseudomonas and Staphylococcus aureus, which can proliferate in large numbers and cause disease when the intestinal microbiota is disrupted. The intestinal microbiota can change due to various conditions. In recent years, many new studies have found that the intestinal microbiota of gout patients differs in quantity and function compared to healthy individuals.

Wen Chengping et al. used 1H NMR and Illumina Miseq technology to study the metabolic profiles and microbial communities of fecal extracts from 26 male gout patients and 26 healthy males. The results showed that opportunistic pathogens were upregulated in gout patients, such as Lactobacillus, Porphyromonadaceae, Rhodococcus, and anaerobic bacteria. Zhang Heping et al. found that in the intestines of gout patients, Bacteroides and Bacteroides species were enriched, while Prevotella and Bifidobacterium longum were depleted. After comparing with the reference gene catalog of the human intestinal microbiome, it was found that the gut microbiota of gout patients exhibited disorders in purine degradation and butyrate biosynthesis. Based on the analysis results of the intestinal microbiota from 33 normal controls and 35 gout patients, a gout intestinal microbiome index (MIG) based on 17 types of intestinal microbiota was proposed, which had a specificity of 88.9% for diagnosing gout, even higher than the measurement of blood uric acid levels.

The impact of probiotics on patients with hyperuricemia.

Probiotics may be a breakthrough in the treatment of HUA. Dietary control is one of the basic treatment measures for gout both domestically and internationally, with yogurt and dairy products recommended for patients with gout and hyperuricemia. Studies have found that gout patients who regularly consume yogurt and dairy products can lower their blood uric acid levels. Further research has shown that the probiotics rich in these foods play an important regulatory role in blood uric acid levels. A randomized double-blind controlled trial was conducted to treat HUA or gout with yogurt containing Lactobacillus casei PA-3 after the withdrawal period of uric acid-lowering medication. 25 patients with hyperuricemia or gout completed the study. Patients were randomly and evenly divided into two groups: one receiving yogurt drinks containing PA-3 and the other without PA-3, for a duration of 8 weeks after a 4-week withdrawal from uric acid-lowering medication. At the end of the study, blood uric acid levels were assessed, and the results showed that after 8 weeks, the reduction in blood uric acid levels in the PA-3 treatment group was significantly higher than that in the control group.

2014In 2019, Dalian Medical University first isolated the strain DM9218 from sauerkraut, which has the highest degradation rates of two key intermediates in purine metabolism, inosine and guanosine. It exhibited the best probiotic potential but had poor bile resistance. The domesticated strain DM9218-A showed good tolerance to 0.3% bile salts. Oral administration of DM9218-A effectively reduced serum uric acid levels in hyperuricemic rats, and preventive treatment with DM9218-A significantly lowered blood uric acid concentrations in hyperuricemic rats. The results suggest that DM9218-A may be an ideal choice for adjuvant therapy during the onset of hyperuricemia in patients, and DM9218-A also has potential in preventing hyperuricemia in the general population. Wang et al. used the isolated Lactobacillus DM9218 to treat fructose-induced HUA mice (high fructose intake exacerbates purine degradation and intestinal dysbiosis, which is closely related to the occurrence of hyperuricemia). The inosine hydrolase of DM9218 was heterologously expressed in E. coli from HUA mice, and its inosine degradation activity was detected. DM9218 reduced serum uric acid levels and liver xanthine oxidase activity in fructose-fed mice, demonstrating a therapeutic effect. García-Arroyo et al. also proved that probiotics containing uricase have the ability to reduce blood uric acid in hyperuricemic animals, while also helping to control blood pressure and protect against kidney disease.

In summary, dysbiosis of the gut microbiota leads to obstruction of uric acid metabolism in the intestines, resulting in elevated blood uric acid levels. On the other hand, dysbiosis of the gut microbiota prevents the resolution of inflammatory responses caused by urate crystals. The elevated blood uric acid levels and the inflammation caused by urate accumulation can further affect the quantity and types of gut microbiota, but the specific mechanisms still need to be explored in depth.

References:

[1]Research progress on gut microbiota and uric acid-related diseases.

[2]The impact of gut microbiota on uric acid metabolism.