Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study

Abstract

ObjectiveThere is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship.MethodsInstrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW).ResultsIVW results confirmed that Anaerotruncus (p = 0.0249), Intestinimonas (p = 0.0237), Lachnoclostridium (p = 0.0245), Lachnospiraceae NC2004 group (p = 0.0083), Olsenella (p = 0.0163), and Peptococcus (p = 0.0472) were protective factors for NAFLD, and Ruminococcus 1 (p = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, Lachnospira (p = 0.0388), Desulfovibrio (p = 0.0252), and Ruminococcus torques group (p = 0.0364), was correlated with a lower risk of ALD, while Ruminococcaceae UCG 002 level was associated with a higher risk of ALD (p = 0.0371). The Alistipes (p = 0.0069) and Ruminococcaceae NK4A214 group (p = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine (p = 0.0076) and phenyllactate (p = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (Op = 0.0244) was found to be positively associated with NAFLD. The phenylacetate (p = 0.0353) and ursodeoxycholate (p = 0.0144) had a protective effect on ALD, while the threonate (p = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine (p = 0.0408) and cholate (p = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate (p = 0.0401) displayed its suggestive protective effect against viral hepatitis.ConclusionIn conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.

Impact of the Mediterranean Diet on the Gut Microbiome of a Well-Defined Cohort of Healthy Individuals

“…We found several microorganisms (e.g., Victivallis , Intestinimonas , and Olsenella ) to be directly correlated with the consumption of foods related to better health, such as olive oil, vegetables, and fruits. These microorganisms have been linked to a healthy response to various diseases [ 60 , 61 ]. In addition, other bacterial genera, such as Faecalicoccus or Clostridium sensu stricto , which had previously been associated with diseases such as immune-mediated inflammatory disease or inflammation [ 62 , 63 ], were positively correlated with glucose and red meat consumption and inversely correlated with olive oil, vegetable, and fruit consumption.…”

Association between gut microbiota and autoimmune cholestatic liver disease, a Mendelian randomization study

“…This was seamlessly complemented by an ensemble of supplementary methodologies, including cML-MA, MR-Egger, Weighted median (WME), Weighted mode (WM), and Simple mode (SM). The imprimatur of a relatively steadfast causal association was imputed when the p -value fell below 0.05 for the IVW methods and concordantly for cML-MA, MR-Egger, WME, WM, and SM when their vectors were aligned ( Zhang et al, 2023 ). Furthermore, a meticulous dissection of the MR-Egger intercept term, denoted as the Egger-intercept, served as a sentinel for horizontal pleiotropy.…”

“…A meticulous screening process was undertaken to identify IVs from a cohort of 211 gut microbes, adhering to the following exclusion criteria: (1) SNPs achieving a significance threshold ( p < 1.0 × 10 −5 ) within the designated locus range were discerningly chosen as potential IVs ( Zhang et al, 2023 ). (2) To guarantee the independence of the included SNPs, linkage disequilibrium (LD) was meticulously expunged using a reference panel sourced from 1,000 Genome Project European samples, with a stringent criterion of r 2 < 0.001 and a window size of 10,000 kb.…”

“…Mendelian randomization (MR) is a methodological approach that leverages genetic variation to construct instrumental variables (IVs) for exposure, thereby facilitating the estimation of causal relationships between said exposure and the onset of a given malady ( Greenland, 2000 ). It is a viable surrogate for Randomized Controlled Trials (RCTs), owing to the randomized assignment of genotypes from progenitors to progeny ( Zhang et al, 2023 ). This randomization process ensures that the association between genetic variants and the resultant outcome remains impervious to common confounding variables, and the causal sequence maintains a plausible trajectory ( Li et al, 2022 ).…”

Assessing the causal relationship between gut microbiota and diabetic nephropathy: insights from two-sample Mendelian randomization

“…Heterogeneity was assessed using Cochran’s Q test with a significance threshold of p < 0.05. The criteria for detecting significant results were defined as follows ( 36 ): (1) the p-value for the IVW analysis was less than 0.05; (2) the direction of the effect obtained in the IVW, WM, MR-Egger regression, and MR-PRESSO methods should be consistent; (3) no significant horizontal pleiotropy was found in the MR-Egger intercept and MR-PRESSO analyses (p > 0.05); (4) the gut bacteria have similar clinical value in different significant phenotypes of DN. In the present study, we determined the statistical significance and potential association between gut bacteria and the risk of developing DN.…”