TYPE Original Research

PUBLISHED 03 April 2024

DOI 10.3389/fmicb.2024.1356478

Causal relationship between gut

OPEN ACCESS microbiota and chronic renal
failure: a two-sample Mendelian
EDITED BY
Liang Wang,
Guangdong Provincial People’s Hospital,
China

REVIEWED BY
randomization study
Yi Xiao Liu,
Peking University, China
George Grant,
Xingzheng Liu 1, Jinying Mo 1, Xuerui Yang 1, Ling Peng 1,
University of Aberdeen, United Kingdom Youjia Zeng 2, Yihou Zheng 2 and Gaofeng Song 2*
*CORRESPONDENCE 1
The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China,
Gaofeng Song 2
Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
[email protected]

RECEIVED 19December 2023

ACCEPTED 20 March 2024
PUBLISHED 03 April 2024
Background: Observational studies and some experimental investigations have
CITATION
indicated that gut microbiota are closely associated with the incidence and
Liu X, Mo J, Yang X, Peng L, Zeng Y,
Zheng Y and Song G (2024) Causal progression of chronic renal failure. However, the causal relationship between
relationship between gut microbiota and gut microbiota and chronic renal failure remains unclear. The present study
chronic renal failure: a two-sample Mendelian
employs a two-sample Mendelian randomization approach to infer the causal
randomization study.
Front. Microbiol. 15:1356478. relationship between gut microbiota and chronic renal failure at the genetic
doi: 10.3389/fmicb.2024.1356478 level. This research aims to determine whether there is a causal effect of gut
COPYRIGHT microbiota on the risk of chronic renal failure, aiming to provide new evidence
© 2024 Liu, Mo, Yang, Peng, Zeng, Zheng and to support targeted gut therapy for the treatment of chronic renal failure.
Song. This is an open-access article
distributed under the terms of the Creative Methods: Employing genome-wide association study (GWAS) data from
Commons Attribution License (CC BY). The the public MiBioGen and IEU OpenGWAS platform, a two-sample Mendelian
use, distribution or reproduction in other
forums is permitted, provided the original
randomization analysis was conducted. The causal relationship between gut
author(s) and the copyright owner(s) are microbiota and chronic renal failure was inferred using five different methods:
credited and that the original publication in Inverse Variance Weighted, MR-Egger, Weighted Median, Simple Mode, and
this journal is cited, in accordance with
accepted academic practice. No use,
Weighted Mode. The study incorporated sensitivity analyses that encompassed
distribution or reproduction is permitted evaluations for pleiotropy and heterogeneity. Subsequently, the results of the
which does not comply with these terms. Mendelian randomization analysis underwent a stringent correction for multiple
testing, employing the False Discovery Rate method to enhance the validity of
our findings.
Results: According to the results from the Inverse Variance Weighted method,
seven bacterial genera show a significant association with the outcome variable
chronic renal failure. Of these, Ruminococcus (gauvreauii group) (OR = 0.82, 95%
CI = 0.71–0.94, p = 0.004) may act as a protective factor against chronic renal
failure, while the genera Escherichia-Shigella (OR = 1.22, 95% CI = 1.08–1.38,
p = 0.001), Lactococcus (OR = 1.1, 95% CI = 1.02–1.19, p = 0.013), Odoribacter
(OR = 1.23, 95% CI = 1.03–1.49, p = 0.026), Enterorhabdus (OR = 1.14, 95%
CI = 1.00–1.29, p = 0.047), Eubacterium (eligens group) (OR = 1.18, 95%
CI = 1.02–1.37, p = 0.024), and Howardella (OR = 1.18, 95% CI = 1.09–1.28,
p < 0.001) may be risk factors for chronic renal failure. However, after correction
for multiple comparisons using False Discovery Rate, only the associations with
Escherichia-Shigella and Howardella remain significant, indicating that the other
genera have suggestive associations. Sensitivity analyses did not reveal any
pleiotropy or heterogeneity.
Conclusion: Our two-sample Mendelian randomization study suggests that
the genera Escherichia-Shigella and Howardella are risk factors for chronic
renal failure, and they may serve as potential targets for future therapeutic

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interventions. However, the exact mechanisms of action are not yet clear,
necessitating further research to elucidate their precise roles fully.

KEYWORDS

chronic renal failure, gut microbiota, gut-kidney axis, Mendelian randomization,

causal inference

1 Introduction With the proposal of the “gut-kidney axis” concept, targeting the gut
for treatment may become an emerging potential therapeutic strategy
Chronic renal failure (CRF) refers to a state in which the kidneys for CRF (Martínez-Hernández et al., 2023). While some observational
gradually lose function and can no longer maintain the normal studies and experiments suggest that the gut microbiota plays a
internal environment of the body. It is the consequence of the significant role in the development and progression of CRF (Tian
progression of various chronic kidney diseases (CKD), with some et al., 2022), the specific causal relationship between the gut microbiota
patients having to wait for renal replacement therapy. The pathogenesis and CRF remains unclear, and there is inconsistency in the findings
of CRF is relatively complex, as CKD can typically cause chronic of gut microbiota studies among dialysis patients, nondialysis patients,
inflammation of the renal tubules and interstitium. This inflammatory and those undergoing hemodialysis or peritoneal dialysis (Stadlbauer
response leads to kidney damage and promotes fibrosis, ultimately et al., 2017; Hu J. et al., 2020). Therefore, in this study, a two-sample
resulting in the deterioration of renal function (Peppa et al., 2004; Mendelian randomization approach was employed from a genetic
Fang et al., 2023). Patients with CRF are also affected by oxidative perspective to clarify the causal relationship between gut microbiota
stress; an excess generation of reactive oxygen species causes an and CRF, providing new evidence to support targeted gut therapy
imbalance between oxidation and antioxidation in the body, ultimately for CRF.
leading to pathologies such as lipid peroxidation of cell membranes, Mendelian randomization (MR) studies are commonly used to
renal mitochondrial homeostasis disturbance, and tissue damage (Ho assess the causal relationships between exposures or risk factors and
and Shirakawa, 2022; Piko et al., 2023). Additionally, the onset of CRF outcomes (Sekula et al., 2016). Observational studies are often subject
involves genetic susceptibility and epigenetics (Smyth et al., 2014). The to confounding by extraneous factors, whereas MR uses genetic
2023 ISN Global Kidney Health Atlas (ISN-GKHA) released by the variants as instrumental variables to infer causal effects of exposures
International Society of Nephrology (ISN) shows that the global or risk factors on outcomes. According to Mendel’s laws, alleles of
median prevalence of CKD is 9.5%, and the global median mortality genetic variants are randomly allocated and less likely to
rate is 2.4%. Due to the high cost of renal disease treatment and its be confounded by other factors; thus, MR serves as an analytical
significant impacts on health, the global burden of renal failure method that sits between randomized controlled trials and
remains substantial. However, there are currently no methods to fully observational studies (Ference et al., 2021). It can circumvent the
control the progression of CRF. For some renal failure patients, confounding inherent to observational studies and overcome issues
particularly those entering end-stage renal disease (ESRD), treatment such as the costly nature and practical challenges associated with
still relies mainly on dialysis. Given the expense and complexity of randomized trials. To date, research integrating gut microbiota with
CRF treatment, actively exploring new potential intervention MR has been widely applied, including in areas such as gut microbiota
measures to delay the progression of the disease is and cancer (Long et al., 2023), gut microbiota and autoimmune
particularly important. diseases (Xu et al., 2021), and gut microbiota and mental disorders (Ni
The gut microbiome is not only crucial for intestinal health but et al., 2021). This study employs MR to infer the causal relationship
also affects the function of numerous other organs in the body. An between the gut microbiota and CRF.
increasing body of evidence supports the association between the
human gut microbiome and extraintestinal organ function, including
a close correlation between the gut microbiome and CRF (Lozupone 2 Materials and methods
et al., 2012). Studies have indicated that patients with CKD exhibit
dysbiosis of the gut microbiota, with an increase in pathogenic 2.1 Study design
bacteria, impaired gut barrier function, increased intestinal
permeability, and generation of uremic toxins such as indoles (e.g., Mendelian randomization analysis must satisfy three critical
indoxyl sulfate), phenols (e.g., p-cresyl sulfate), and amines (e.g., assumptions: (1) Relevance assumption: the genetic variants chosen
trimethylamine-N-oxide) through the fermentation of undigested as instrumental variables should be associated with the exposure; (2)
products in the colon by the gut microbiota. These uremic toxins and Independence assumption: the instrumental variables used should not
the impairment of gut barrier function are closely related to be associated with any confounders; (3) Exclusion-restriction
inflammatory responses and oxidative stress, which further lead to the assumption: the instrumental variables must not have a direct effect
progression of the disease and the occurrence of related complications on the outcome but should only influence the outcome through the
(Mafra et al., 2014; Cigarran Guldris et al., 2017). The gut and kidney exposure. In this study, gut microbiota is considered the exposure, and
can be interconnected through a Metabolism-dependent pathway and chronic renal failure is the outcome. Significant single-nucleotide
an Immune pathway, forming the “gut-kidney axis” (Yang et al., 2018). polymorphisms (SNPs) are selected as instrumental variables (IVs).

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FIGURE 1
The flowchart for MR analysis between gut microbiota and CRF.

Two-sample Mendelian randomization methods are employed for the 24,185,976 SNPs, with the study population being of European
causal inference, supplemented by sensitivity analyses such as descent. These GWAS datasets are largely independent of each other,
horizontal pleiotropy and heterogeneity tests. The specific study and all original research data have been ethically approved and
flowchart can be seen in Figure 1. consented to by the participants.

2.2 Data sources 2.3 Instrumental variable

The gut microbiota GWAS data are obtained from the MiBioGen In this study, the gut microbiome GWAS data encompassed 211
consortium data (Kurilshikov et al., 2021).1 Researchers employed taxonomic groups, including 131 genera, 35 families, 20 orders, 16
high-throughput gene sequencing technologies to analyze the gut classes, and 9 phyla, with phyla representing the highest taxonomic
microbiota of a large cohort of individuals, classifying the microbiota level and genera being the lowest. The lower the taxonomic rank, the
into respective taxonomic groups based on their genetic information more common characteristics and similarities are shared among the
by targeting three different variable regions (V4, V3–V4, and V1–V2) microorganisms. Here, we conducted Mendelian randomization
of the 16S rRNA gene. This dataset on gut microbiome comprises 24 analyses using the genera level of gut microbiota, excluding 12 genera
cohorts, encompassing a total of 18,340 participants. Predominantly, with unknown bacterial names (Kurilshikov et al., 2021), resulting in
the study population consisted of Europeans, accounting for more the inclusion of the remaining 119 genera in the study. The selection
than 70% of the dataset (16 cohorts, N = 13,266). The GWAS data on of suitable SNPs was based on the following criteria: (1) To ensure a
CRF was sourced from the IEU OpenGWAS platform2 based on the sufficient number of instrumental variables, SNPs significantly
research data by Sakaue et al. (2021). This CRF dataset included associated at p < 1.0 × 10−5 were selected; (2) The chosen SNPs were
482,858 individuals, with 8,287 cases and 474,571 controls, featuring required not to be in linkage disequilibrium with each other, generally
measured by the parameters r2 and distance in kb. In this study, we set
r2 < 0.001 and distance at 10,000 kb, thus removing SNPs within a
10,000 kb range that had an r2 > 0.001 with the most significant SNP
1 https://mibiogen.gcc.rug.nl/ to reduce the impact of linkage disequilibrium and retaining more
2 https://gwas.mrcieu.ac.uk/ independent SNPs; (3) The F-Statistic was used to assess the statistical

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strength of the association between SNPs and the exposure factor, applied for multiple testing to minimize the likelihood of type
where an F > 10 suggested a strong relationship with the exposure, and I statistical errors, setting the threshold for the FDR-adjusted q_value
instrumental variables with an F < 10 were excluded. Finally, at 0.1. If p < 0.05 and q_value < 0.1, this suggests a significant
we harmonized SNPs with the same alleles in the GWAS data for gut association; if p < 0.05 but q_value > 0.1, it indicates an association of
microbiota and CRF, removing incompatible and palindromic SNPs suggestive significance (Storey and Tibshirani, 2003).
to align the effect sizes for the exposure and outcome.

3 Results
2.4 Statistical analysis
Based on the selection criteria for instrumental variables, a total
This study primarily utilized the “TwoSampleMR” package within of 1,480 SNPs were ultimately included as instrumental variables for
R language (version 4.3.1) for analysis. The causal relationship MR analysis; all SNPs had an F-value greater than 10, and details can
between gut microbiota and CRF was assessed using five MR methods: be found in Supplementary Table 1. MR analysis revealed that among
Inverse Variance Weighted (IVW), MR-Egger, Weighted Median, the gut microbiota of 119 bacterial genera, according to the results of
Simple Mode, and Weighted Mode. Each statistical method relies on the IVW method (p < 0.05), 7 genera were closely related to the
its specific model assumptions, and if these prerequisites are not met, outcome variable CRF. Among these, Ruminococcus (gauvreauii
the statistical power may be weakened or even rendered ineffective. group) (OR = 0.82, 95% CI = 0.71–0.94, p = 0.004) may be a protective
The IVW method weights the effects between SNPs and causal traits factor for CRF. In contrast, Escherichia-Shigella (OR = 1.22, 95%
by the inverse of their variance and combines them to estimate the CI = 1.08–1.38, p = 0.001), Lactococcus (OR = 1.1, 95% CI = 1.02–1.19,
overall effect. The results of IVW will be unbiased in the absence of p = 0.013), Odoribacter (OR = 1.23, 95% CI = 1.03–1.49, p = 0.026),
horizontal pleiotropy (Burgess et al., 2015). The MR Egger method, Enterorhabdus (OR = 1.14, 95% CI = 1.00–1.29, p = 0.047),
based on the Egger regression in MR analyses, tests for horizontal Eubacterium (eligens group) (OR = 1.18, 95% CI = 1.02–1.37,
pleiotropy through the MR-Egger regression. A significant intercept p = 0.024), and Howardella (OR = 1.18, 95% CI = 1.09–1.28, p < 0.001)
in the MR-Egger analysis, with p < 0.05, suggests the presence of may be risk factors for CRF. However, after FDR correction, only the
horizontal pleiotropy. If the intercept is close to zero, the MR-Egger genera Escherichia-Shigella and Howardella had significant positive
estimate will be close to the IVW estimate (Burgess and Thompson, associations, while the other genera showed suggestive correlations.
2017). The Weighted Median method can provide consistent estimates The detailed analysis results are available in Table 1. The complete MR
even if up to 50% of the SNP instruments are invalid, estimating the analysis results of gut microbiota from 119 genera related to CRF can
causal effect by weighting the effects of different SNPs (Bowden et al., be found in Supplementary Table 2. Sensitivity analysis was conducted
2016). The Simple Mode is a straightforward method of combining on the seven genera closely related to CRF, and based on the results of
MR results by directly taking the mode of effect size estimates from MR-Egger regression analysis and Cochran’s Q test, it was evident that
different studies for a combined result. The Weighted Mode is an there was no horizontal pleiotropy or heterogeneity among these
improved mode method that adds a step of weighting the effects of genera, with the MR-PRESSO analysis yielding a global test p > 0.05,
different studies on the basis of Simple Mode, calculating the indicating no significant outliers. Specific results of the sensitivity
combined result according to each study’s sample size or weight. analysis are presented in Table 2. The results of the pleiotropy and
Under certain conditions, the IVW method is more capable of heterogeneity tests can be found in Supplementary Tables 3, 4. A
effectively handling the synthesis of estimates, providing more precise leave-one-out analysis was performed for these seven genera
results and demonstrating higher efficacy compared to other statistical (Figure 2), which showed that the results did not change significantly
methods (Bowden et al., 2016). Therefore, we primarily employed the after sequentially removing individual SNPs, reflecting the robustness
IVW method for our analysis, with the remaining four methods of the study findings to some extent. Scatter plots, Funnel plots, and
serving as supplementary approaches. MR-PRESSO was utilized to Forest plots for these seven genera can be found in
detect significant outliers among the SNPs, and if the MR-PRESSO Supplementary Figures 1–3, respectively. Table 3 displays the relevant
global test statistic p < 0.05, it indicates the presence of significant information of SNPs for the genera Escherichia-Shigella and
outliers that should be removed before repeating the MR analysis. Howardella used in this study. We further annotated the SNPs of these
Cochran’s Q test was applied to assess if there was significant two genera using the VannoPortal database (Huang et al., 2022).
heterogeneity among the SNPs. A statistically significant Cochran’s Q
test (p < 0.05) indicates significant heterogeneity in the results,
necessitating a discussion of the possible sources of heterogeneity. 4 Discussion
Leave-one-out sensitivity analysis was conducted, systematically
excluding each SNP and calculating the combined effect of the Previous studies on the gut microbiome and CKD have primarily
remaining SNPs, to evaluate the impact of any single SNP on the utilized animal models (Vaziri et al., 2013), with observations often
relationship between exposure and outcome. Finally, the risk showing inconsistencies. While there have been reports on the causal
association between gut microbiota and CRF was expressed in terms relationship between the gut microbiome and CKD (Li et al., 2023;
of the odds ratio (OR) and its 95% confidence interval (CI), where Ren et al., 2023), significant variations in the richness and evenness
p < 0.05 provided evidence for a potential causal relationship. (α-diversity) of bacterial species across different CKD stages have been
Additionally, as the p-value threshold for SNP selection was set at observed (Wu et al., 2020). CRF represents a more severe stage of
p < 1.0 × 10−5, not meeting the conventional GWAS significance kidney pathology. This study focuses on the later stages of the disease,
threshold of p < 1.0 × 10−8, False Discovery Rate (FDR) correction was CRF, and evaluates the causal relationship between the gut microbiota

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TABLE 1 MR results of causal links between gut microbiota and CRF.

Exposure MR method No. of Beta OR 95% CI p-value q_value

(Bacterial taxa) snp
Escherichia-Shigella MR egger 15 −0.06 0.94 0.65–1.35 0.74

Escherichia-Shigella Weighted median 15 0.15 1.16 0.98–1.37 0.09

Escherichia-Shigella Inverse variance weighted 15 0.20 1.22 1.08–1.38 <0.01 0.086

Escherichia-Shigella Simple mode 15 0.34 1.41 1.03–1.92 0.05

Escherichia-Shigella Weighted mode 15 0.33 1.39 1.01–1.90 0.06

Lactococcus MR egger 11 0.06 1.06 0.73–1.54 0.77

Lactococcus Weighted median 11 0.09 1.09 0.98–1.21 0.11

Lactococcus Inverse variance weighted 11 0.10 1.10 1.02–1.19 0.01 0.377

Lactococcus Simple mode 11 0.10 1.10 0.93–1.31 0.28

Lactococcus Weighted mode 11 0.08 1.09 0.93–1.27 0.31

Odoribacter MR egger 8 0.36 1.44 0.76–2.72 0.31

Odoribacter Weighted median 8 0.25 1.28 1.01–1.64 0.04

Odoribacter Inverse variance weighted 8 0.21 1.23 1.03–1.49 0.03 0.509

Odoribacter Simple mode 8 0.25 1.29 0.88–1.87 0.23

Odoribacter Weighted mode 8 0.25 1.29 0.90–1.85 0.21

Enterorhabdus MR egger 7 −0.01 0.99 0.71–1.37 0.95

Enterorhabdus Weighted median 7 0.11 1.12 0.95–1.31 0.18

Enterorhabdus Inverse variance weighted 7 0.13 1.14 1.00–1.29 0.05 0.799

Enterorhabdus Simple mode 7 0.04 1.04 0.82–1.32 0.75

Enterorhabdus Weighted mode 7 0.11 1.11 0.90–1.37 0.35

Eubacterium (eligens
MR egger 10 0.07 1.07 0.72–1.61 0.74
group)

Eubacterium (eligens
Weighted median 10 0.14 1.15 0.95–1.39 0.16
group)

Eubacterium (eligens
Inverse variance weighted 10 0.17 1.18 1.02–1.37 0.02 0.573
group)

Eubacterium (eligens
Simple mode 10 0.09 1.10 0.82–1.47 0.55
group)

Eubacterium (eligens
Weighted mode 10 0.10 1.10 0.88–1.39 0.42
group)

Ruminococcus (gauvreauii
MR egger 13 −0.59 0.55 0.30–1.03 0.09
group)

Ruminococcus (gauvreauii
Weighted median 13 −0.14 0.87 0.72–1.06 0.16
group)

Ruminococcus (gauvreauii
Inverse variance weighted 13 −0.20 0.82 0.71–0.94 <0.01 0.145
group)

Ruminococcus (gauvreauii
Simple mode 13 −0.10 0.90 0.65–1.25 0.54
group)

Ruminococcus (gauvreauii
Weighted mode 13 −0.11 0.90 0.68–1.19 0.47
group)

Howardella MR egger 11 −0.04 0.97 0.69–1.36 0.84

Howardella Weighted median 11 0.18 1.20 1.08–1.33 <0.01

Howardella Inverse variance weighted 11 0.17 1.18 1.09–1.28 <0.01 0.005

Howardella Simple mode 11 0.22 1.25 1.03–1.51 0.04

Howardella Weighted mode 11 0.21 1.23 1.02–1.49 0.05

MR, Mendelian randomization; CRF, chronic renal failure; SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

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TABLE 2 Sensitivity analysis results.

Exposure Pleiotropy test Heterogeneity test

(bacterial taxa)
Egger intercept p-value MR-PRESSO Method Cochran’s Q Q_pval
Howardella 0.03 0.27 0.68 IVW 8.21 0.61

Escherichia-Shigella 0.02 0.16 0.85 IVW 8.73 0.85

Ruminococcus
0.03 0.23 0.63 IVW 10.31 0.59
(gauvreauii group)

Eubacterium (eligens
0.01 0.63 0.90 IVW 4.43 0.88
group)

Enterorhabdus 0.01 0.73 0.63 IVW 5.53 0.60

Odoribacter −0.01 0.64 0.49 IVW 6.79 0.45

Lactococcus 0.01 0.83 0.55 IVW 9.41 0.49

IVW, inverse variance weighted.

of 119 genera and CRF at a genetic level, utilizing large-scale GWAS between the genus Escherichia-Shigella and vascular calcification
data. After MR analysis and FDR correction of the results, in hemodialysis patients, identifying it as a risk factor for vascular
we ultimately discovered that Escherichia-Shigella and Howardella calcification in these patients.
may be risk factors for CRF, as they exhibited a significant association Howardella is a Gram-positive anaerobic bacterium that can
with CRF. produce ATP by decomposing urea (Cook et al., 2007). However,
Escherichia and Shigella both belong to the family while some gut microbes hydrolyze urea through urease, they can
Enterobacteriaceae, which is part of the phylum Proteobacteria, and generate large amounts of ammonia, which may affect the growth of
are Gram-negative rod-shaped bacteria. In many classification the intestinal microbiota (Ramezani and Raj, 2014). Moreover,
systems, Escherichia and Shigella are treated as separate genera; increased levels of ammonia are associated with tubulointerstitial
however, due to their high genomic similarity and the potential damage in the kidneys. The rise in renal ammonia levels can
inaccuracy of current metagenomic sequencing techniques in potentially activate the complement alternative pathway, resulting in
distinguishing members of the two genera, some bioinformatics the production of chemotactic and lytic complement components
analyses classify them as a single genus, especially in genomic that lead to tubulointerstitial inflammation (Nath et al., 1985).
studies of microbial communities, where these two genera are Additionally, the production of ammonia by the intestinal
commonly represented together as “Escherichia-Shigella.” Certain microbiota through urea hydrolysis can also lead to the disruption
strains of the Escherichia-Shigella genus are pathogenic, and thus of the structure and function of the intestinal epithelium.
this genus is often reported as a pathogen (Kamada et al., 2013). The Consequently, this promotes the translocation of uremic toxins,
genus Escherichia is most commonly represented by Escherichia coli endotoxins, antigens, and other microbial metabolites into the
(Tenaillon et al., 2010). It has been reported that Shiga toxin- circulation, which could be an important pathway for endogenous
producing E. coli can cause classic hemolytic uremic syndrome infections (Simões-Silva et al., 2018). Studies have reported an
(HUS), which is the most common cause of acute renal failure in increase in the abundance of the genus Howardella associated with
children. This condition is caused by endothelial cell damage and prediabetes (Yang et al., 2015), while a lower abundance of
leukocyte activation due to the production of Shiga-like toxins and Howardella has been observed in the gut of patients with depression
lipopolysaccharides, leading to the formation of glomerular (Barandouzi et al., 2020). Furthermore, Yang et al. (2023) found a
capillary thrombosis through the interaction of platelets with positive correlation between exposure to nitrogen dioxide and the
endothelial cells, ultimately affecting renal hemodynamics and abundance of the genus Howardella. However, there are limited
causing acute kidney injury (Palermo et al., 2014; Fakhouri et al., reports on the association between the genus Howardella and CRF,
2017). CRF is also one of the complications of HUS (Razzaq, 2006). warranting further in-depth research in the future.
Shigella typically causes bacterial dysentery, also known as Increasing research indicates the presence of gut microbiota
Shigellosis, and is genetically related to E. coli (Beld and Reubsaet, dysbiosis in patients with CRF. Vaziri et al. (2013) observed a
2011). Wu et al. (2020) discovered through 16S rRNA gene significant increase in the abundance of genera such as
sequencing that the genus Escherichia-Shigella is associated with Brachybacterium and Catenibacterium in CRF patients, while Jiang
various stages of CKD, particularly enriched in CRF, and that the et al. found a decrease in the abundance of butyrate-producing
abundance of Escherichia-Shigella is highly correlated with the bacteria, including Roseburia, Faecalibacterium, Clostridium,
levels of serum Indoxyl Sulfate. Research by Hu X. et al. (2020) Coprococcus, and Prevotella in CRF patients. They also discovered
indicates an increase in the quantities of the genus Escherichia- a negative correlation between bacteria such as Roseburia spp.,
Shigella and the phylum Proteobacteria in the gut of CRF patients, Faecalibacterium, Prevotella, and markers like C-reactive protein
especially prominent at stage 5 of the disease, with several genera and Cystatin C (Jiang et al., 2017). Furthermore, a systematic review
including Escherichia-Shigella showing high sensitivity and reported a decrease in microbial diversity in CKD patients
specificity in distinguishing CKD patients from healthy controls. compared to healthy individuals, with a consistent reduction in
Furthermore, Bao et al. (2023) also found a close association Roseburia abundance, especially in patients with end-stage kidney

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FIGURE 2
Leave-one-out plots for the causal effect of gut microbiota on CRF.

disease (Voroneanu et al., 2023). An increase in the abundance of with an increase in the Enterobacteriaceae family and the
the phylum Proteobacteria is a potential microbial diagnostic genus Escherichia. The inflammation-driven overgrowth of
marker of dysbiosis (Shin et al., 2015), which is mainly associated Enterobacteriaceae is closely linked to the development of various

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TABLE 3 Summary information on SNPs of Escherichia-Shigella and Howardella used for the Mendelian randomization analyses.

Bacterial SNP Effect Other EAF Chr Position* Gene p-value

taxa allele allele
Escherichia-
rs112767262 T C 0.196 16 3,750,623 TRAP1 8.21E-06
Shigella

Escherichia- MTND3P1/
rs113127095 A G 0.052 13 23,253,392 3.33E-06
Shigella FTH1P7

Escherichia- CCT4P1/RP4-
rs113513883 A G 0.058 7 140,678,199 5.28E-06
Shigella 813F11.3

Escherichia- B3GAT1/
rs1154904 A G 0.464 11 134,774,845 3.04E-06
Shigella AP003062.1

Escherichia-
rs11706043 T A 0.157 3 3,173,016 TRNT1 5.87E-06
Shigella

Escherichia-
rs117092367 A T 0.089 10 69,394,914 CTNNA3 9.65E-06
Shigella

Escherichia-
rs118526 C A 0.393 5 79,863,544 ANKRD34B 8.00E-06
Shigella

Escherichia-
rs2267739 G C 0.086 7 31,136,897 ADCYAP1R1 1.42E-06
Shigella

Escherichia- SPATA6/RP11-
rs2798105 A G 0.118 1 48,961,903 8.25E-06
Shigella 329A14.2

Escherichia- ADAMTS18/
rs35555519 C G 0.114 16 77,711,641 4.92E-06
Shigella NUDT7

Escherichia- IMPDH1/RP11-
rs4731451 G A 0.372 7 128,054,100 7.47E-06
Shigella 155G14.1

Escherichia-
rs57024273 T C 0.318 2 236,515,155 AGAP1 9.70E-06
Shigella

Escherichia-
rs592299 T C 0.468 9 136,179,347 LCN1P1/LCN1P2 4.77E-06
Shigella

Escherichia-
rs73208162 A G 0.059 21 39,324,484 DSCR4 2.19E-06
Shigella

Escherichia- HS3ST3B1/
rs7502686 G C 0.063 17 14,173,290 5.90E-06
Shigella CDRT15

Howardella rs10048062 C T 0.107 15 98,476,920 ARRDC4 8.59E-06

Howardella rs12452946 A G 0.501 17 17,253,288 NT5M/RPL13P12 3.80E-06

Howardella rs1484873 A G 0.069 18 43,206,985 SLC14A2 2.56E-06

Howardella rs17167098 G A 0.113 7 133,154,356 EXOC4 1.12E-06

Howardella rs2154047 C A 0.068 14 95,452,797 DICER1/RPL15P2 9.97E-06

Howardella rs36081916 T C 0.111 7 93,527,414 GNGT1 4.70E-06

Howardella rs3791893 A G 0.123 2 218,819,396 TNS1 9.50E-06

Howardella rs609430 T G 0.339 4 169,178,315 DDX60 3.34E-06

RPL31P12/
Howardella rs61771805 A T 0.187 1 72,972,799 4.03E-06
KRT8P21

Howardella rs672217 G A 0.141 18 60,125,134 ZCCHC2/ACTBP9 3.52E-06

Howardella rs901099 T G 0.312 11 77,901,287 USP35 6.53E-07

SNP, single nucleotide polymorphism; EAF, effect allele frequency; Chr, chromosome; *Position based on GRCh37.

host diseases (Lupp et al., 2007). The findings on the gut microbiota investigating the causal relationship between bacterial genera and
of CRF patients are varied, possibly limited by the nature of CRF at the genus level, addressing the current inadequacies in gut
observational studies, and these studies have not further explored microbiota research in CRF. However, the mechanisms of action
their causal relationships. This study addresses the gap by remain unclear. Based on the gut-kidney axis concept and current

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Liu et al. 10.3389/fmicb.2024.1356478

research, we hypothesize that the mechanisms of action of the gut of Indoxyl Sulfate and high-sensitivity C-reactive protein in patients
microbiota on CRF relate to the following aspects: (1) Microbiome: with CRF. This finding supports the effectiveness of Synbiotic targeted
The microbial communities within the gut can affect intestinal gut therapy in reducing uremic toxin levels and improving the micro-
health and the systemic inflammatory state, and they can influence inflammatory state in CRF patients, proving it to be a safe and effective
renal function through their metabolic products. (2) Metabolic treatment strategy (Mitrović et al., 2023). This indicates that correcting
Products: Urea and other nitrogenous wastes produced in the gut gut microbiota dysbiosis, improving gut barrier function, and
can affect kidney health through the circulatory system. (3) Mucosal reducing endotoxin load can all contribute to improving kidney health
Barrier Function and Intestinal Permeability: Impairment of the gut and delaying the progression of CRF.
barrier may allow bacteria and endotoxins access to the It is noteworthy that the gut microbiota encompasses bacteria,
bloodstream, from where they can reach the kidneys and potentially fungi, viruses, archaea, and other microorganisms, together
cause inflammatory responses. (4) Immune System: Immune cells constituting a complex ecosystem. Bacteria are the most abundant
in the gut may impact kidney function by promoting systemic microorganisms in the gut microbiota, and hence, current research on
inflammatory responses. Therefore, correcting gut microbial gut microbiota primarily focuses on the bacterial component.
dysbiosis, improving gut barrier function, and reducing endotoxin However, other microorganisms can also influence the health and
load, among other measures, may contribute to better kidney health disease states of the host under certain conditions.
and slow the progression of CRF. The gut mycobiome, a component of the gut microbiome, plays
In the gut of CRF patients, there is a significant increase in the an indispensable role in maintaining the balance of the intestinal
number of bacterial families capable of producing urease as well as environment and host health, despite fungi being less numerous than
enzymes that generate indoles and p-cresol, whereas the number of bacteria in the gut. Research by Qiu et al. has identified significant
bacterial families that can convert dietary fiber into short-chain fatty alterations in the composition of the gut fungi in individuals with both
acids (such as butyrate) significantly decreases (Wong et al., 2014). hypertension and CKD. Compared to healthy controls, this specific
Urease can break down urea into ammonia and carbon dioxide. In population exhibited increased richness and diversity of gut fungi,
CRF patients, this could lead to excessive production of ammonia, particularly elevated levels of the genera Apiotrichum and
thereby increasing the concentration of ammonia in the gut and Saccharomyces, while the abundance of Candida decreased. Further
blood, potentially exacerbating symptoms of uremia. Enzymes that analysis revealed a negative correlation between Candida and tumor
produce indoles and p-cresol are involved in the metabolism of necrosis factor alpha (TNF-α), and a positive correlation was found
tryptophan and phenolic compounds in the intestine, ultimately between the filtration rate of the glomeruli and the genera
generating toxic substances to the human body, such as Indoxyl Apiotrichum, Ophiocordyceps, Saccharomyces, Nakaseomyces, and
Sulfate (IS) and p-Cresyl Sulfate (pCS). IS and pCS are metabolites in Septoria (Qiu et al., 2023). These findings suggest that these specific
the blood associated with renal failure. They are commonly used as gut fungi may play an important role in protecting kidney function.
biomarkers to measure kidney function and damage extent. Studies Research by Ren et al. also found that patients with ESRD have a
have shown that high levels of IS and pCS play a crucial role in the higher diversity of gut fungi compared to healthy individuals,
progression of CKD, with their accumulation closely linked to characterized by a decrease in Saccharomyces cerevisiae and an
accelerated renal fibrosis, reduced kidney function, and CKD increase in various opportunistic pathogens (such as Aspergillus
progression (Meijers and Evenepoel, 2011; Mutsaers et al., 2015). fumigatus, Exophiala spinifera, Hortaea werneckii, etc.). Further
Indoxyl sulfate can trigger cellular oxidative stress response by metabolomic analysis revealed that the enriched opportunistic
generating reactive oxygen species, activate NF-κB promoting cellular pathogens correlated positively with levels of serum creatinine,
senescence, and activate p53 accelerating the aging process of homocysteine, and phenylacetylglycine, while the yeast community
proximal tubular cells, ultimately exacerbating CRF progression negatively correlated with the levels of toxic metabolites in feces (Ren
(Shimizu et al., 2011). In CRF patients, due to renal function decline, et al., 2024). Additionally, studies have shown a certain link between
the accumulation of these compounds in the serum further aggravates the risk of inflammatory bowel disease and CKD (Vajravelu et al.,
disease progression. The accumulation of these toxins causes damage 2020), while Saccharomyces cerevisiae has been found to inhibit and
not only to the kidneys but also to other tissues and organs of the reduce chemically induced colonic inflammation (Sivignon et al.,
body. Short-chain fatty acids (SCFAs), particularly butyrate, are 2015). Hu et al. (2022) also discovered a correlation between yeast and
extremely important for intestinal health, providing energy for serum levels of gamma light chains. These findings indicate that the
intestinal cells, regulating local and systemic immune responses, and gut mycobiome is closely associated with the inflammatory state,
promoting the integrity of the gut barrier. In CRF patients, the immune response, and toxin levels in patients with CRF.
reduction in this probiotic conversion capability may impact gut Viral infections are involved in a variety of glomerular diseases
health, increase inflammation and intestinal permeability, thereby (Sallustio et al., 2023). The gut virome, particularly the part
further affecting the overall health of the patients. Gut microbiota dominated by bacteriophages, plays a crucial role in the ecological
dysbiosis, especially in the context of kidney disease, by reducing balance of gut microbiota. These bacteriophages, by invading and
beneficial microbes producing SCFAs and increasing protein- replicating within bacterial hosts, not only regulate the population of
fermenting microbes, may lead to the production of uremic toxins, specific bacterial groups to maintain microbial diversity but also
endotoxemia, systemic inflammation, and various complications significantly influence the host’s immune system regulation. Studies
associated with CKD, thus exacerbating the progression of kidney have reported that bacteriophages can activate the host’s immune
disease (Pan and Kang, 2017). However, research by Mitrović et al. has response via the TLR9 sensing pathway, promoting the production of
shown that the use of Synbiotic can effectively reduce the serum levels cytokines such as IL-12, IL-6, IL-10, and IFN-γ (Gogokhia et al.,

Frontiers in Microbiology 09 frontiersin.org

Liu et al. 10.3389/fmicb.2024.1356478

2019; Sweere et al., 2019). Bacteriophages can also enter the systemic metabolomics, genomics, and in vitro cultures are needed to further
circulation through intestinal epithelial cells and then affect the investigate its specific mechanisms of action. Lastly, the GWAS data
human immune system by modulating the release of cytokines and we used primarily involved European populations, which may not
the activity of T and B cells (Popescu et al., 2021). Research by Fan be generalizable to other ethnic groups. Moreover, our exposure data
et al. (2023) revealed an imbalance in the gut virome in patients with focused on the genus level of microbial communities, indicating that
diabetic nephropathy (DN), characterized by a significant decrease future research should delve deeper into species or strain-level
in overall viral richness and diversity. Notably, levels of Shigella phage analyses. We believe that as research progresses, modern medicine
and Xylella phage were elevated in the guts of DN patients. Further may develop new therapeutic strategies to prevent or treat various
analysis of the functional aspects of the gut virome found multiple kidney diseases, including CRF, by improving the interaction between
viral functional losses in DN patients, particularly a weakened ability the gut and the kidney axis.
of bacteriophages to lyse their bacterial hosts. This reduction in
function could have important implications for the ecological balance
of the gut microbiota. 5 Conclusion
Archaea represent a unique form of life, distinct from bacteria and
eukaryotes, possessing special biological characteristics and metabolic The results of this study suggest that the genera Escherichia-
pathways. Despite their relatively low abundance in the human body, Shigella and Howardella are potential risk factors for CRF,
archaea play a crucial role in maintaining human health and highlighting their significance in CRF. Future interventions for
environmental balance (Mafra et al., 2022). Particularly in the human patients with CRF could potentially include dietary modifications,
gut, methanogenic archaea, such as Methanobrevibacter smithii, probiotics, and fecal transplantation to slow the progression of the
dominate. These archaea not only promote the development of other disease. However, our research can only infer part of the causation.
microbes by consuming hydrogen, maintaining the stability and The onset and progression of CRF are also related to many other
diversity of the gut microbial community, but also regulate the factors beyond the gut microbiota, and further in-depth, large-scale
structure and function of the gut microbiome through their unique studies are needed to fully elucidate their specific mechanisms
metabolic products (e.g., methane), significantly impacting host of action.
health. Trimethylamine-N-oxide (TMAO) has been shown to promote
oxidative stress, inflammation, and the progression of CKD (Borges
et al., 2016; Castillo-Rodriguez et al., 2018), and is an independent Data availability statement
predictor of the burden of coronary artery atherosclerosis and
mortality (Stubbs et al., 2016). Research has reported that The original contributions presented in the study are included in
methanogenic archaea can reduce the conversion of trimethylamine the article/Supplementary material, further inquiries can be directed
(TMA) to TMAO (Brugère et al., 2013), thereby decreasing the to the corresponding author.
production of TMAO associated with health issues such as
cardiovascular diseases CKD, and trimethylaminuria. Therefore,
modulating the metabolic activity of archaea, especially increasing Author contributions
beneficial archaeal populations, may help mitigate inflammation and
treat related disease states. This reveals the potential positive role of XL: Conceptualization, Data curation, Methodology, Writing –
archaea in regulating the gut microbiome, reducing the generation of original draft, Writing – review & editing. JM: Data curation,
harmful metabolic products, and combating chronic inflammation Methodology, Writing – review & editing. XY: Formal analysis,
and related diseases through possible other mechanisms, such as Methodology, Writing – review & editing. LP: Conceptualization,
modulating host immune responses, offering a new perspective for the Writing – review & editing. YoZ: Formal analysis, Writing – review &
treatment of related diseases. editing. YiZ: Supervision, Writing – review & editing. GS: Supervision,
In summary, our study addresses the current gaps in research on Writing – review & editing.
the gut microbiota in CRF and identifies gut genera with potential
causal relationships to CRF, offering more possibilities for future
targeted gut interventions to prevent or treat CRF. However, our Funding
research has certain limitations. Firstly, since our data were derived
from public databases, which only provided aggregated data related to The author(s) declare that no financial support was received for
single nucleotide polymorphisms without information on individual the research, authorship, and/or publication of this article.
confounding factors such as age, gender, and antibiotic usage, we were
unable to conduct more detailed subgroup analyses. Secondly, our
study merely infers the causal relationship between gut microbiota Acknowledgments
and CRF from a theoretical perspective, with a focus on the correlation
analysis between gut genera and CRF. The gut microbiome is a We want to acknowledge all the volunteers who participated in
complex system influenced by diet, medication, environment, and this study, and we also thank MiBioGen consortium and large-scale
other factors (Stepkowski et al., 2017; Asnicar et al., 2021). Future consortia or studies for providing gut microbiota and chronic renal
large-scale randomized controlled trials incorporating metagenomics, failure GWAS summary statistics data for our analyses.

Frontiers in Microbiology 10 frontiersin.org

Liu et al. 10.3389/fmicb.2024.1356478

Conflict of interest organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or claim
The authors declare that the research was conducted in the that may be made by its manufacturer, is not guaranteed or endorsed
absence of any commercial or financial relationships that could by the publisher.
be construed as a potential conflict of interest.

Supplementary material
Publisher’s note
The Supplementary material for this article can be found online
All claims expressed in this article are solely those of the authors at: https://www.frontiersin.org/articles/10.3389/fmicb.2024.1356478/
and do not necessarily represent those of their affiliated full#supplementary-material

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