In this study, using the summary statistics of gut microbiota from the largest GWAS meta-analysis conducted by the MiBioGen consortium and the summary statis-tics of ED from the Bovijn et al. release data, we performed a two-sample MR analysis to evaluate the causal association between gut microbiota and ED. We have identified several gut bacteria are risk factors for the development of ED inculding family Lachnospiraceae、genus Erysipelotrichaceae UCG003、genus Oscillibacter and genus Tyzzerella3, which all belong to the thick-walled phylum, in Other words, these bacteriaes may lead to the occurrence of ED .
Degradation of dietary fiber by the gut microbiota produces organic acids, gases and large amounts of short-chain fatty acids(SCFA). SCFA, as the major end product of human intestinal flora metabolism is the main source of nutrients for intestinal epithelial cells (IEC)(40). It can regulate IEC function through different mechanisms by affecting their proliferation, differentiation, and regulate enteroendocrine cells functions of hormones secretion (41), including sex hormones(42,43), also it have an impact on host cardiovascular and lipid metabolism(40,44–46). Meanwhile, because of Gut-Brain axis, SCFAs can activate G protein coupled receptors , penetrate the blood-brain barrier (47) and have function on the regulation of central nervous system(48,49).Moreover, SCFA can promote the growth of human neural stem cell as well as the differentiation of embryonic stem cells into neural cells, and promote the proliferation of human neural progenitor cells(50,51). While many studies suggested that endocrine hormones, metabolism, vascular and neuromodulation factors affect erectile function(52,53).Acetate, propionate, butyrate and valerate are the main SCFA product. Acetate is the net fermentation product of most intestinal bacteria, whereas butyrate and propionate are produced by more specific bacterial species(44,54,55). The Lachnospiraceae family, Erysipelotrichaceae UCG003 , Tyzzerella3 and Oscillibacter have been found to produce butyrate, furthermore, bacteria of the Lachnospiraceae family, can produce both propionate and butyrate(56–58).
Members of the Lachnospiraceae family are the main producers of SCFA and can affect the host by producing SCFA, converting primary bile acids to secondary bile acids, and promoting colonization resistance to intestinal pathogens (59,60). It was found that increased abundance of the thick-walled phylum was associated with obesity and high BMI, while within the thick-walled phylum, abundance of Lachnospiraceae family was found to be relevant to metabolic disorders(61,62). For example, compared with mice fed by low-fat diet, the abundance of thick-walled bacterial clades, in particular Lachnospiraceae family, was increased in mice fed a high-fat diet(63). A study reveals that the Lachnospiraceae family was involved in the development of obesity and diabetes in mice. Colonization of Lachnospiraceae family in mice resulted in a significant increase of fasting blood glucose levels, liver and mesenteric adipose tissue weight(64,65), Moreover, Lachnospiraceae family play an active role in disrupting glucose metabolism, leading to inflammation and promoting the occurrence of metabolic disorders, diabetes, and colon cancer(66–69). Similarly, the fecal microbiological profile of overweight/obesity and metabolic syndrome showed a positive correlation between Erysipelotrichaceae UCG003 and the HOMA-IR index of the patients(70). In the other hand, genus Oscillibacter showed a remarkable effect in reducing serum triglyceride concentrations and negatively correlated with body mass index (BMI)(71). It is possible that the main metabolic end product of genus Oscillibacter is valerate (72), thus, in addition to the common acetate, butyrate and propionate, valerate may also be involved in host metabolism as SCAFS, causing metabolic disorders that may lead to ED (52,73,74).
A positive correlation has been found between the Lachnospiraceae family (Lachnospiraceae UC and Murimonas) and brain-derived neurotrophic factor (BDNF). And in comparison to healthy controls, gut microbes from depressed patients showed that genus Oscillibacter abundance and low abundance of the Lachnospiraceae family are associated with depression(59,75),which genetic prediction shows a potential causal role in the occurrence of ED(4). Furthermore, genus Oscillibacter type strains’s main end metabolic product is valeric acid, a homologue of the neurotransmitter GABA, which is relevance to depression(72,76). In additional, the abundance of genus Erysipelotrichaceae UCG003 in the intestine of both Alzheimer's dementia patients and Parkinson's patients has been found to be significantly changed(77,78). It also showed significantly lower abundance of the gut microorganism Tyzzerella3 in patients with post-stroke cognitive impairment compared to healthy controls(79). There are few previous studiesabout Tyzzerella3, and it has been suggested that Tyzzerella3’s abundance is associated with preeclampsia-eclampsia . And a reduced Tyzzerella3 abundance is related to acute myocardial infarction. Hypothesis show that this may be correlated with Tyzzerella3’s ability to produce SCFA, however, further studies are needed(80,81). In addition to the above description, compared to healthy controls, long-term metal exposure alters the gut microbiota of inhabitants around mining and smelting areas , resulting in a higher relative abundance of Lachnospiraceae family, Erysipelotrichaceae UCG-003, Tyzzerella3. And this may be due to the association of these gut bacterias with metabolic disorders and inflammation, which needs to be explained by further studies(82).
The strength of this study is that a two-sample MR analysis was performed to determine a clear causal relationship between gut microbes and ED, thereby avoiding confounding and excluding bias by using non-overlapping exposure and outcome summary level data. The horizontal pleiotropy was detected and excluded by applying MR-PRESSO and MR-Egger regression intercept tests(35,80,83).
However, this study also has some limitations which should be noted in the results interpretation.. Since the lowest taxonomic level in the exposure dataset was genus, it was not available to perform further subgroup analyses. So the influence of members of family Lachnospiraceae on ED may be different depending on the species. And this study found that family Lachnospiraceae abundance was associated with ED onset positively, while another study found significantly lower abundance of Lachnospiraceae NK4A136 in family Lachnospiraceae in patients with psychogenic ED(84). Moreover, there may be differences between ethnographic gut microbes, and the participants in this study were European descent because of the GWAS meta-analysis of gut microbiota data, for which the results may be confounded by population stratification. Thus further MR studies on the causal relationship between gut microbiota and ED in non-European populations may need to be considered. Additionally, although reverse MR estimates did not find a causal relationship between ED and gut microbiota, it should not be excluded that ED may influence gut microbes, which need to be confirmed by further studies.