Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and can progress to chronic kidney disease and renal failure (Pattrapornpisut et al., 2021). In the early stage, it is characterized by asymptomatic hematuria with minimal proteinuria, which can be detected by screening programs. As the disease progresses, a proportion will develop hypertension, significant proteinuria, progressive glomerulonephritis, and even end-stage kidney disease (ESKD). Another phenotype presents recurrent macroscopic hematuria and is associated with a favorable prognosis in the short term, commonly in patients aged under 40 years. The incidence of IgAN varies from 0.54 to 10.5 per 100,000 population per year, with a high prevalence in young people aged between 20 and 40 years (Schena and Nistor, 2018). IgAN is considered an immune-mediated disease influenced by a combination of genetic and environmental factors. The typical pathological feature of IgAN is the deposition of polymeric and galactose-deficient IgA1 (Gd-IgA1) in the glomerular mesangium. Kiryluk et al. (2011) indicated that circulating levels of Gd-IgA1 were a heritable trait and were increased in patients with IgAN and their first-degree relatives. Genome-wide association study (GWAS) data sets also identified multiple susceptibility loci for IgAN and several risk alleles associated with intestinal epithelial barrier maintenance and mucosal immunity (Yu et al., 2011; Kiryluk et al., 2014; Li et al., 2020).

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic and idiopathic inflammatory disease of the gastrointestinal tract (Torres et al., 2017; Ungaro et al., 2017). Mucosal inflammation in UC mainly affects the rectum to the proximal segments of the colon, whereas in CD, all segments of the gastrointestinal tract can be affected, with the terminal ileum being the most common site. The common features of IBD are abdominal pain, chronic diarrhea, weight loss, and varying degrees of systemic symptoms (Flynn and Eisenstein, 2019). Some patients with IBD might exhibit extraintestinal manifestations, such as arthritis, spondyloarthropathy, episcleritis, uveitis, erythema nodosum, and primary sclerosing cholangitis. With societies in newly industrialized countries becoming more westernized, the incidence of IBD is increasing worldwide. It has been reported that the incidence of UC ranges from 0.15 to 57.9 per 100,000 person-years, while the incidence of CD ranges from 0.09 to 23.82 per 100,000 person-years (Ng et al., 2017). As a multifactorial disease, the pathogenic etiology of IBD is still incompletely understood. At present, it is generally believed that chronic intestinal inflammation is caused by an interaction of genetic susceptibility, excessive immune response, gut microbiota, and various environmental triggers. As shown by existing evidence, the first-degree relatives of patients with IBD have a five-fold increased risk of developing IBD (Flynn and Eisenstein, 2019). Hundreds of genetic loci have also been shown to be associated with IBD via GWAS (Liu et al., 2015). Moreover, a nationwide cohort study in Sweden has revealed an association between IgAN and IBD (Rehnberg et al., 2021).

Mendelian randomization (MR) can be used to explore the causal effect of exposure on outcomes by taking the differences in genotype as instrumental variables (IVs) (Emdin et al., 2017). Due to the natural random assortment of genetic variation during meiosis, Mendelian randomization has been proposed as a method analogous to classic randomized controlled trials (Emdin et al., 2017; Wu et al., 2020). Because genotypes appear before diseases and are largely independent of the postnatal lifestyle and environmental factors, MR is free from confounding factors and can avoid the biasing effect of reverse causality. As the large-scale GWAS reliably identifies genetic variants, MR has been successfully adopted for investigating causal links.

In this two-sample MR study, significant and independent single-nucleotide polymorphisms (SNPs) were chosen as IVs to clarify the causal association at the genetic level using the GWAS data. The aims of this study are to clarify if IBD, UC, and CD have the potential causal effect on IgAN and whether the reverse causal effect exists.

To the best of our knowledge, this study has been considered the first to illustrate the causal effect of IBD (which includes UC and CD) on IgAN using MR analysis and summary statistics from GWAS. As the data from this study revealed, IBD, UC, and CD causally increased the risk of IgAN in individuals of European descent. However, there was no sufficient evidence supporting the inverse causal relationship between these two diseases.

IgAN is the most common type of primary glomerulonephritis worldwide, with an increasing incidence. An analysis of cohorts from Europe and North America found that the 5- and 10-year risks of a 50% decrease in eGFR or ESKD in IgAN patients were 11.2% and 26.8%, respectively (Barbour et al., 2016). The pathological mechanism of IgAN is complex and is yet to be fully elucidated. The “multi hit hypothesis” has been widely accepted to explain IgAN pathogenesis. In this hypothesis, aberrant Gd-IgA1 increased and was targeted by anti-glycan IgG autoantibodies, causing the formation of immune complexes. These immune complexes cannot be adequately cleared from circulation and deposit in the mesangium, which might activate the complement system and trigger glomerular inflammation (Pattrapornpisut et al., 2021).

Previous case reports and clinicopathologic series have shown the relationship between IBD and IgAN and discussed the pathophysiologic links. In a case study from Korea, it was reported that a patient with rapidly progressive IgAN, concurrently presented with CD exacerbation, demonstrating a direct link between the aggravation of renal function and intestinal symptoms. Moreover, both renal and inflamed colonic tissues were positive for IL-17 and responded to immunosuppressive therapy. This might indicate a potential common pathogenesis of these two diseases (Choi et al., 2012). Ambruzs et al. (2014) concluded that the frequency of IgAN in IBD was significantly higher than that in other native kidney biopsy specimens during the same period [20 of 83 (24%) versus 2,734 of 33,630 (8%)]. A cross-sectional study from China evaluated 33 renal biopsy specimens from patients with IBD, showing that more than half (66%) of the pathological lesions were IgAN (Zhao et al., 2021). Elaziz and Fayed (2018) included 896 patients with IBD in a study and found that 218 (24.3%) of them had developed renal manifestations, of whom 35 patients were diagnosed with IgAN. Furthermore, Rehnberg et al. (2021) launched a nationwide cohort study and found that IgAN patients had an increased risk of IBD both before and after a confirmed IgAN diagnosis. It has been reported that patients with IBD show increased serum IgA levels and an increased incidence of abnormal hematuria, while patients with IgAN present significantly higher intestinal permeability, which is related to increased hematuria, proteinuria, and serum levels of IgA (Wang et al., 2004; Papista et al., 2011).

Although the exact mechanisms linking IBD and IgAN are not fully understood, the gut–kidney axis hypothesis might potentially support the pathophysiological relationship. It was assumed that dysregulation of the interplay among intestinal immunity, microbiota, and diet could lead to the production of Gd-IgA1, which plays an important role in IgAN (Joher et al., 2022). Together with mucus and antimicrobial peptides, IgA forms the first line of defense against environmental and microbial antigenic exposures occurring in the intestinal mucosa (He et al., 2020). A disruption of the epithelial barrier is more likely to lead to exposure to immunogenic alimentary antigens and increased IgA production. Kovács et al. (1996) found that significantly higher intestinal epithelial permeability was associated with increased serum levels of IgA against food antigens, such as soy protein. Chronic intestinal inflammation contributes to persistent and excessive activation of toll-like receptors, which might eventually result in the overproduction of IgA1/Gd-IgA1 (He et al., 2020). Then, in patients with IBD, the overstimulation of mucosal B cells significantly shifts immunoglobulin production from IgA2 to IgA1 (Brandtzaeg et al., 2006). Moreover, the number of N-acetylgalactosamines in the O-linked oligosaccharides of IgA significantly decreased in CD patients and strongly correlated with clinical activity (Inoue et al., 2012). Additionally, Wang et al. (2004) demonstrated that abnormally activated T cells initiated severe intestinal inflammation that could result in the dysregulation of serum IgA levels, indicating that T-cell-mediated intestinal mucosal immunity was critical in the pathogenesis of IgAN. Hence, a complex interplay of mucosal inflammation, chronic immune stimulation, microbiota, abnormal IgA glycosylation, and dysregulated IgA production and transport might potentially influence the pathogenesis of IBD and IgAN. Furthermore, genetic studies have found that GWAS of patients with IgAN identifies risk loci involved in intestinal mucosal integrity and the immune network (Li et al., 2020).

In addition, patients with IgAN comorbid with IBD have accelerated disease progression, while the remission of bowel disease could also improve renal function. Rehnberg et al. (2021) confirmed that patients with IgAN and IBD had an increased risk of progression to ESKD when compared with patients with IgAN without IBD. The identification of IBD might be useful for predicting the risk of ESKD in patients with IgAN. In 1984, a French physician first reported IgAN associated with IBD (one patient with UC and one patient with CD). With symptomatic treatment of the intestinal disease, not only did hematuria subside but also did mesangial hyperplasia and IgA deposition disappear (Hubert et al., 1984). Since then, a growing number of studies have suggested that intestinal disease therapy is associated with improvements in renal manifestations (Onime et al., 2006; Filiopoulos et al., 2010). Smerud et al. (2011) suggested that enteric budesonide targeted to the ileocecal region could represent a new treatment of IgAN for reducing urine albumin excretion.

There are several limitations in this present research. First, a bidirectional two-sample MR analysis to identify the causal relationships between IgAN and IBD was attempted, but sufficient numbers of SNPs were not available to determine the causal effect of IgAN on IBD, UC, and CD, which led to biased results. Second, this analysis was based on GWAS data sets, making it difficult to stratify the causal effect by race, age, sex, or other risk factors. Although the evaluation of other IgAN cohorts would be ideal to confirm our findings, no other IgAN cohorts could be found in the GWAS data sets. As a result, we performed direct experiments on the causal relationships between IgAN and IBD, UC, and CD in a follow-up study. Lastly, although the SNPs that might cause pleiotropy were identified and removed with the outlier test in the MR-PRESSO analysis, there was still no evidence for the causal effect of IBD, UC, and CD on IgAN from the MR-Egger analysis. Hence, more advanced MR methods have to be developed for the causal estimate after suppressing the interference of pleiotropy.

In conclusion, we found a positive causal relationship of IBD, UC, and CD with IgAN at the genetic level by using two-sample MR analysis. However, there was not sufficient evidence for the causal effect of IgAN on IBD, UC, and CD. The findings of this study should remind clinicians that regular monitoring of renal function in patients with IBD should not be ignored and that optimized treatment for IBD could improve prognosis in patients with IgAN. However, additional studies are required to investigate and elucidate the potential mechanistic links between IBD and IgAN.