The incidence of herpes zoster is considerable, with an overall annual incidence of 1.2–3.4 cases per 1000 person-years in the US and 1.85–3.9 cases per 1000 person-years in the UK [6]. Its impact on daily life is significant and is of great importance. Furthermore, herpes zoster can give rise to a condition known as PHN, characterized by enduring dermatomal pain lasting for more than about 3 months after the acute herpes zoster rash. Approximately 20% patients of herpes zoster will experience pain, and of those, 6% will suffer from clinically significant PHN that may last for years or even a lifetime [16]. Despite extensive research, the mechanisms responsible for PHN have not been fully elucidated. The prevailing hypotheses include persistent chronic ganglionitis, neuronal damage resulting from the replication of VZV in ganglia, and altered sodium channels. [17] Although vaccines for herpes zoster are available recently, their coverage remains limited. Surveys indicate a herpes zoster vaccination willingness rate of only 55.74% among 14,066 individuals from 4 WHO regions [18]. Besides, these vaccines do not offer complete prevention against the occurrence of herpes zoster and PHN. Hence, it is crucial to conduct further research on herpes zoster to develop more effective solutions.

The research findings related to gut microbiota hold promise for practical clinical applications, primarily due to the availability of interventions that can influence the composition of gut microbiota. Researchers have already applied fecal microbiota transplantation (FMT) in attempts to treat diseases like Clostridioides difficile infection [19] and IBDs [20, 21]. Interestingly, there was a specific study conducted on patients with Crohn’s disease, where one case of adverse event, namely herpes zoster, was reported in the FMT cohort, while none occurred in the non-FMT cohort. Although it is not certain if this case of herpes zoster was directly related to FMT, it has sparked interest and calls for further investigation [21].

Upon our investigation, the most significant results obtained were related to various genera, with only one family, one order, no class, and one phylum showing significant results attributed to the inherent heterogeneity within these taxa. However, Cyanobacteria, as a phylum, emerged as a factor significantly facilitating occurrence of herpes zoster. Cyanobacteria is well-known in ecological and environmental fields as the only prokaryotes to have developed oxygenic photosynthesis, thereby profoundly influencing the earth’s biological and chemical cycles [22]. However, the non-photosynthetic Cyanobacteria in human gut was just found in recent years. Over the period from 2016 to 2021, ten studies explored the potential association between Cyanobacteria and health issues, and these studies were comprehensively reviewed by Hu et al. [23]. Remarkably, approximately 80% of these studies indicated a higher abundance of Cyanobacteria in individuals with worsened health status, suggesting a possible link between Cyanobacteria and health complications.

Among the significant genera identified, Tyzzerella remains significant even after FDR correction, indicating that this significance is unlikely to be a result of multiple comparisons. Tyzzerella is a relatively new genus, having been reclassified from the Clostridiaceae family to Lachnospiraceae as a distinct genus by Yutin et al. in 2013 [24]. The genus was named in honor of Ernest Tyzzer, a pathologist who first isolated Tyzzerella piliformis, formerly known as Clostridium piliforme, the pathogenic bacteria of Tyzzer’s disease. This disease is an acute epizootic disease affecting mammals, characterized by necrotic liver lesions, and is usually fatal. Although it is found worldwide, infections in humans are rare [25, 26]. As a result, Tyzzerella and its implications may not be well-known among physicians. Although Tyzzerella is not sufficient to cause diseases in humans, there still might be potential effects. In previous studies of human gut microbiota, there are only several mentioned Tyzzerella 3. In detail, it has been found that patients with acute myocardial infraction [27] or those living around mining/smelting areas [28] have a higher abundance of Tyzzerella 3. Moreover, Tyzzerella 3 is associated with a lower frequency but higher severity of postnatal depression [29]. In addition, the only study demonstrated a causal relationship, showing Tyzzerella 3 can inhibit preeclampsia–eclampsia. However, there is currently no information available on the relationship between Tyzzerella 3 and virus-related diseases. Pang et al. published the only article mentioned the relationship between Tyzzerella 3 and immune cells [30]. In spinal cord injury patients, it was found that Tyzzerella 3 is linked to fewer NK cells, but no significant correlations were observed with T cells, which are crucial in the pathogenesis of herpes zoster and PHN. As such, the findings of Tyzzerella 3 in the present study may require further confirmation through additional research, and the underlying mechanisms also remain unclear.

By contrast, there are fewer significant findings for PHN in this study, and none remains significant after FDR correction. Several genera were identified as potentially inhibiting PHN, while only one genus, Odoribacter, was found to facilitate PHN. In other studies, Odoribacter has been reported to improve glucose tolerance and limit inflammation in mice, leading to its consideration as a probiotic [31, 32]. However, the research on Odoribacter is still limited. We cannot confirm whether Odoribacter is beneficial for human health. Nonetheless, based on the findings of the present study, it appears that Odoribacter is not favorable for individuals with PHN.

This study used MR analysis to investigate causality, effectively mitigating the interference of potential confounders and addressing issues of reverse causation. Association studies often struggle to distinguish between two possibilities: whether “herpes zoster causes alterations in gut microbiota” or “changes in gut microbiota contribute to herpes zoster and PHN.” However, the MR analyses conducted in this study provided insight into the direction of causality. As a result, researchers can refer to this study to consider potential new strategies or further exploration with greater confidence.

However, it is important to acknowledge several limitations in this study that warrant consideration. First, the present study analyzed summary-level data, instead of individual-level data, and therefore, cannot make stratified analyses based on covariates such as sex. In addition, two-sample MR studies were designed to evaluating linear associations, thereby not adequately capturing the nonlinear effects of SNPs originating from gut microbiota on herpes zoster and PHN. Finally, the majority of cases included in the analysis are of European descent. As such, the generalization capacity of the findings to other ethnicities may be limited. It should be cautious when extrapolating the results to diverse ethnic groups, and further studies on different populations are warranted.