Gut microbiota participates and remodels host metabolism: From treating patients to treating their gut flora
Uric acid (UA) is the oxidative product of purine. The key enzyme catalyzing UA generation in homo sapiens is xanthine oxidase (XOD). Due to the inherited lack of functionally intact uricase, human beings tend to have higher levels of UA in circulation than other mammals. Genetic and diet factors resulting in abnormal UA accumulation in the blood will bring about hyperuricemia, and it is becoming a common metabolic disorder with increasing prevalence worldwide. It was estimated that the incidence of hyperuricemia was about 21% in the United States and about 13% in China. Hyperuricemia is not only the reason for gout but also brings about many health problems, e.g., cardiovascular diseases, diabetes, metabolic syndrome, and malignant tumors. The genetic difference between human beings and other mammals results in that animal models of hyperuricemia are different to construct. The most acknowledged strategy is the uricase inhibitor potassium oxonate (PO) administration alone or combined with other reagents as described in the current issue by Liu et al  . Imaginably, animal model-based studies facilitate our understanding of the mechanisms of UA-related diseases and the development of effective remedies. 

Currently, there are 3 groups of drugs prevailing in clinics for hyperuricemia management. Their mechanisms include suppressing UA production, prompting UA degradation and/or excretion. Whereas, the side effects of these drugs are also noteworthy, which include allergies and multi-organ damage. Many studies have demonstrated that peptides from food proteins, e.g. , tuna fish, shrimp, sea cumber, and kidney beans, could decrease serum UA levels. Most of the peptides with urate-lowering activity were enzymatically hydrolyzed products. The key issue to acquire satisfied bioactive peptides is the selection of proper enzymes. Different enzymes could produce different peptides with varied activities of XOD inhibition, renal UA transporter modulation, UA-related oxidative stress and inflammation alleviation, and gut microbiota remodeling. In the current issue, Liu et al  reported the protein extract of Poecilobdella manillensis leech total protein (LTP) could significantly inhibit the enzymatic activity of XOD. Histopathologically, LTP could reverse the over-expression of renal tissue reabsorption transporters URAT1 and GLUT9 and prompt the expression of the renal tissue secretory transporter ABCG2 in the hyperuricemia mouse models. These findings were in accordance with the previous reports about the UA-lowering effects of some food peptides. From the description of intragastric administration of LTP, we can speculate that the LTP must be digested into peptides by the host digestive system or the gut microbiota. We have no evidence to exclude the possibility of the activities of the prototype LTP. Whereas, the anti-hyperuricemia and gut microbiota reshaping effects must have something to do with the digestive peptide(s) of LTP. Unfortunately, the authors did not detect the peptide(s) in the digestive tract (fecal samples). It is highly warranted that the author’s future study will identify the concrete peptide(s) functionalized as UA-lowering agent(s) or the gut flora modulator(s). Although no new LTP-related anti-hyperuricemia manifestation was discovered compared with the previously reported peptides, the findings in Liu et al  study added a new weapon to our anti-hyperuricemia arsenal. 

Although bioactive peptides can exert anti-hyperuricemia function directly, some peptides affect the configuration of gut flora. A healthy gut flora mainly consists of Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes . Liu et al  demonstrated that LTP specifically regulated the microbiota members of Prevotella , Delftia , Dialister , Akkermansia , Lactococcus , Escherichia_Shigella , Enterococcus , and Bacteroides . About 1/3 of the endogenous UA is excreted into the intestine. Many gut microbes can catabolize UA. For example, lactobacillus could metabolize UA to urea and reduce intestinal purine absorption. Escherichia, Clostridium , and Pseudomonas were proven to metabolize UA. Hyperuricemia can result in the composition change of gut microbiota and vice versa. This notion can be reinforced by the findings of Liu et al  in that PO-induced hyperuricemia mouse models showed conspicuous gut microecological dysregulation. It was estimated that only 667 human proteins were identified as drug targets for diseases. According to the newly released 11 th revision of the International Classification of Diseases, 55000 injuries, diseases, and causes of death were coded. Although it was estimated that human druggable targets were 3000-10000, the number of the targets is not comparable with that of the kinds of diseases. Thus we are still in an era with limited choice for numerous human diseases. The gut microbiota contains over 100 trillion cells and unique genes about 500 times more than that of human beings. The different genera of species in gut microbiota can produce various bioactive metabolites that modulate host metabolism physiologically and pathologically. The gut flora was regarded as an organ cross talking with many other solid organs such as the brain, liver, and lung. The language linking the communication is the metabolites produced by the microbiota. Some metabolites are the products co-metabolized by both the host and the microbes. The well-recognized ones are the secondary bile acids. They can bind to different human targets such as the farnesoid X receptor and Takeda G-protein-coupled receptor 5 to modulate human metabolism. Many gut metabolites are unique to the microbiota and can be classified as xenobiotics. Sometimes, crosstalk is not only limited to the host and the microbiota but also the members of the microbiota. Nie et al  found that a lumen-restricted metabolite 3-succinylated cholic acid (3-sucCA) could alleviate metabolic dysfunction-associated steatohepatitis. 3-sucCA was synthesized by Bacteroides uniformis . This bacterium-specific metabolite was synthesized by a new beta-lactamase, and could promote the growth of Akkermansia muciniphila , a gut flora member with therapeutic potential for many chronic metabolic diseases. Studies carried out in rodent models and human beings have demonstrated that Akkermansia facilitated the recovery of obesity, type 2 diabetes, cardiovascular diseases, and metabolic fatty liver diseases. Of note, UA has long been considered to be an independent risk factor contributing to the above-mentioned disorders. LTP increased the abundance of Akkermansia and contributed to hyperuricemia recovery as described by Liu et al . Unfortunately, the study did not pay more attention to the relationship between Akkermansia and Bacteroides . Not limited to that, we still lack an understanding of most of the gut microbiota-related metabolites concerning their synthesis and mechanisms. The relevant exploring attempts were part of targetome study. Understanding the synthesis of microbiota-specific metabolites facilitates druggable target development. Utilizing the targets of the microbiota, instead of the host, has many advantages. The most valuable one is these targets can be developed with fewer or no side effects on the host. Penicillin was one of the typical examples. Eukaryotes have no cell wall. Penicillin only inhibits the cell wall synthesis in prokaryotes. To date, we still witness various antibiotics applied in clinics following the mechanisms of penicillin. Although the contribution of antibiotics is evident, abuse of antibiotics is also harmful. Inappropriate administration of antibiotics can bring about secondary infections and result in antimicrobial resistance. The gut microbiota is also prone to be affected by antibiotics when anti-infection treatment is executed. Recently, scientists engineered a strain of Lactococcus lactis carrying a β-lactamase-expression system. The system was composed of two separately controlled and expressed genes. This strategy could avoid horizontal resistance transfer and did not confer resistance to the engineered strain. Whereas, introducing the strain into the gut flora could selectively hydrolyze β-lactam antibiotics accumulating in the gut due to parenteral ampicillin administration. Furthermore, scientists could precisely remove certain unwanted species in the gut flora by bacteriophages. The so-called targeted bacterium-depleted strategy can be used not only to eliminate harmful species but also to construct specific animal models with unique gut flora features. Liu et al  performed metabolomics analysis for serum samples. They did not describe the perturbation by LTP on microbiota-related metabolites in the serum. One reason might be that the relevant changes were not significant. Another reason might be the adopted methodology was not compatible with the detection of the relevant metabolites. As for the lumen-specific metabolites, it is better to perform fecal metabolomics analysis. Metabolomics analysis usually focuses on metabolites with molecular weights (MWs) less than 1500 Da. MWs of many UA-lowering bioactive peptides fall into this range. In other words, a fecal metabolomics analysis might provide microbiota-related metabolite identification and LTP-related bioactive peptide detection simultaneously. Indeed, Liu et al  metabolomics analysis provided evidence of the reshaping of gut microbiota and its effect on sphingolipid metabolism in the serum. A study on Ginseng proved that the anti-hyperuricemia activity was accompanied by the perturbation of sphingolipid metabolism related to gut microbiota. Sphingolipid metabolism regulates many physiological and pathological processes. Many gut microbiota interfering strategies to treat disease trials showed plasma sphingolipid metabolism remodeling[ - ]. Thus, the sphingolipid metabolism perturbation is more likely a general response instead of an LTP-specific activity. 

We acknowledge that Liu et al  findings about LTP’s UA-lowering effect were closely related to reshaping gut microbiota. Although we have no confident proof to exclude the direct action of LTP, most possibly, the anti-hyperuricemia activity was from the digestive products (peptides) of LTP. That the peptides were generated by the host’s digestive system or by the gut microbiota is warranted to be clarified. Whether the composition change of the gut microbiota brought about some gut metabolite fluctuations also deserves to be explored. The relevant attempts might facilitate the development of new drug target(s) that have no or fewer side effects on the host. Extensively, new probiotics might be developed to treat gout or hyperuricemia-related diseases. It must be admitted that Liu’s study was not the first attempt to treat chronic disease with probiotics. Besides, bioactive compounds can be any chemicals. For example, polysaccharides extracted from Hericium erinaceus , a common fungus, have been demonstrated to alleviate inflammatory bowel diseases ex vivo . One mechanism was related to the downregulated cyclooxygenase-2 and tumor necrosis factor-α and the upregulation of interleukin-10 in the mucosal tissue. Another mechanism was ascribed to the reshaping of gut microbiota in that Hericium erinaceus tended to enlarge the population of short-chain fatty acid-producing strains. In summary, understanding the gut flora is a real challenge even though we have many techniques at hand to date. Although we have not explored human druggable targets comprehensively, seeking treatment targets from the gut microbiota should not be underestimated. 

