First verification of human small intestinal uric acid secretion and effect of ABCG2 polymorphisms

Main text

The small intestine is the main digestive, absorptive, and endocrine organ; however, it has also recently emerged as an essential excretory organ. Hyperuricemia, which causes gout, is primarily induced by decreased urate excretion. The current understanding of urate excretion is based on the premise that approximately two-thirds of total urate is eliminated via the kidneys into the urine, whereas the remaining one-third is excreted through the intestinal tract. This concept originates from tracer experiments using radioisotopes conducted on a small number of individuals more than half a century ago [1]. Recent reports have suggested that the intestinal excretion pathway via the urate transporter adenosine trisphosphate binding cassette subfamily G member 2 (ABCG2) plays a key role in the regulation of serum urate (SUA) levels as a complementary system of renal urate excretion [2,3,4]. Urate secretion from the intestine may make an essential contribution to SUA homeostasis; however, measurement of urate secretion using feces to demonstrate intestinal urate secretion is problematic because uric acid is catabolized by the gut microbiota [4]. The classification of hyperuricemia is solely based on the amount of urinary excretion in clinical practice, and the physiological role of intestinal urate secretion is underestimated. No studies have demonstrated urate secretion from the small intestine in addition to regulation of its secretion by ABCG2 in humans. To our knowledge, this is the first proof-of-concept study to directly measure urate secretion from the human intestine.

The study participants had Crohn’s disease (n = 30), simple ulcers (n = 2), and obscure gastrointestinal bleeding (n = 2) (Table 1). All participants were classified into three ABCG2 functional categories [100% (n = 11), 75% (n = 18), and 50% functional (n = 5)] based on the genotype combinations of p.Q126* and p.Q141K previously reported [3, 4]. Our repeated measurements detected uric acid levels in the intestinal fluid of all subjects at baseline and 5 min later (Fig. 1). At baseline, the uric acid concentration in the intestinal fluid was 99.5 [Interquartile range (IQR): 10.1–194.0] pg/µL. After 5 min, the uric acid concentrations increased; the change in uric acid concentration after 5 min (ΔC_UA) was + 119.9 pg/µL/5 min (IQR: 44.7–476.4, p < 0.001), demonstrating that urate is secreted into the intestinal lumen.

Table 1 Clinical data and ABCG2 functionality based on two variants [rs72552713 (p.Q126*) and rs2231142 (p.Q141K)].

Fig. 1

Procedure for small intestinal fluid sampling

ABCG2 dysfunctional single nucleotide polymorphisms (SNPs) tended to decrease urate secretion into the intestinal lumen. In the ABCG2 functional subgroup analysis, the uric acid concentrations at baseline in the 100%, 75%, and 50% functional ABCG2 groups were 105.3 pg/µL (IQR: 12.3–236.6), 113.0 pg/µL (IQR: 9.4–258.0), and 70.1 pg/µL (IQR: 25.5–110.9), respectively. The subgroup analysis showed that the ΔC_UA in the 100%, 75%, and 50% functional ABCG2 groups was + 175.6 pg/µL/5 min (IQR: 92.6–550.7), + 125.9 pg/µL/5 min (IQR: 7.7–476.4), and + 65.9 pg/µL/5 min (IQR: − 35.1–114.0), respectively (p for trend = 0.058) (Fig. 2). Our previous study demonstrated a negative correlation between SUA and ABCG2 function in patients with end-stage renal disease (ESRD), whose urate excretion pathway is exclusively intestinal [3]. The association between SUA and ABCG2 in patients with ESRD supports our direct observation that ABCG2 is highly involved in intestinal urate secretion. The major ABCG2 dysfunctional SNP, p.Q141K, is widespread in many ethnic groups and particularly common in Asian populations [29.1% in East Asians, 32.2% in other Asians, and 10.3% in European populations; browsed Allele Frequency Aggregator, https://www.ncbi.nlm.nih.gov/snp/rs2231142, ver.20230706150541)]. Given the high frequency of dysfunctional ABCG2 SNPs, our results present the possibility that decreased uric acid secretion in the intestine due to the SNPs contributes to SUA variability in the general population.

Fig. 2

Relationship between intestinal urate secretion and estimated ABCG2 function. (a) The uric acid concentration in the intestinal fluid at baseline and after 5-min intervals. (b) The change in uric acid concentration in the intestinal fluid during 5-min intervals. The means of change in uric acid concentration were indicated by ×: 600.5 pg/µL, 249.1 pg/µL, and 44.8 pg/µL in the 100%, 75%, and 50% functional ABCG2 groups, respectively

We acknowledge the limitations of our study regarding potential confounders and generalizability. First, our results were estimated using a small sample size, and background factors (e.g., age and sex) were not considered. Second, to avoid unnecessary invasion, our study included individuals who required endoscopy of the small intestine. Although intestinal fluid was collected from normal small intestinal segments without lesions, the effects of inflammation, lesions at other sites, and treatments in patients with Crohn’s disease were not considered in our analysis. Finally, the double balloon prevented fluid traffic on the anorectal side but not the oral side. Although the intestinal fluid was collected from an area where the intestinal flexure on the oral side was strong and fluid traffic was almost negligible, the possibility of intestinal fluid traffic on the oral side could not be completely ruled out.

In conclusion, we demonstrated, for the first time, that urate was secreted in the intestine of humans and regulated by ABCG2. ABCG2 causes the excretion of a variety of substances, including toxins (e.g., indoxyl sulfate) and urate, owing to its broad substrate specificity [5]. Therefore, the intestine is an excretory organ that may play an important role in the regulation of urate excretion and the dynamics of other substances.