Peihong Li’s research while affiliated with Xiangya Hospital of Central South University and other places

Background Insomnia is a common neurological disorder that exhibits connections with the gut microbiota; however, the exact causal relationship remains unclear. Methods We conducted a Mendelian randomization (MR) study to systematically evaluate the causal effects of genus‐level gut microbiota on insomnia risk in individuals of European ancestry. Summary‐level datasets on gut microbiota were sourced from the genome‐wide association study (GWAS) of MiBioGen, while datasets on insomnia were obtained from the GWAS of Neale Lab and FinnGen. The primary analytical approach used was the inverse‐variance weighted (IVW) method, supplemented by MR‐Egger, maximum likelihood, MR‐robust adjusted profile score, and weighted median. Sensitivity analyses were conducted to ensure robustness. ResultsThe microbial taxa Enterorhabdus , Family XIII AD3011 group , Paraprevotella , and Lachnospiraceae UCG004 were associated with an increased risk of insomnia, whereas Coprococcus1 , Coprobacter, Desulfovibrio, Flavonifractor, Olsenella, Odoribacter , and Oscillibacter were linked to a decreased risk. Regarding the insomnia phenotype characterized by trouble falling asleep, the microbial taxon Eisenbergiella was correlated with an increased risk, while Haemophilus and the Eubacterium brachy group were associated with a reduced risk. Furthermore, for the insomnia phenotype characterized by waking too early, the microbial taxa Family XIII UCG001 , Lachnospiraceae FCS020 group , and Olsenella were linked to an increased risk, whereas the Eubacterium brachy group and Victivallis were associated with a lower risk. The results remained robust across all sensitivity analyses. Conclusion Our MR study identified multiple genus‐level gut microbial taxa that may exhibit potential causal effects on insomnia from a genetic perspective. These findings provide evidence supporting the theory of the microbiota‐gut‐brain axis and offer new insights into potential prevention and therapeutic targets for insomnia.

The blockade of the interleukin 6 receptor (IL-6R) demonstrates significant potential in various autoimmune diseases (ADs); however, the underlying therapeutic efficacy associated with this approach remains elusive. We conducted a comprehensive Mendelian randomization (MR) analysis based on large-scale genome-wide association studies to investigate the causal relationships between genetically proxied IL-6R blockade weighted by serum C-reactive protein levels and eighteen common ADs. Rheumatoid arthritis, COVID-19 infection, and COVID-19 critical illness were utilized as positive controls. The inverse-variance weighted (IVW) method was utilized as the primary analytical tool, while genetic colocalization analysis was conducted to further substantiate the causalities. Genetically proxied IL-6R blockade exhibited causally protective effects on all positive control diseases. After Bonferroni correction to IVW estimates, genetically proxied IL-6R blockade may significantly increase the risk of asthma (OR=1.031, P=2.15×10⁻¹²) and eczema (OR=1.066, P=5.92×10⁻²²), while reducing the risk of ankylosing spondylitis (OR=0.341, P=1.39×10⁻⁵), Crohn's disease (OR=0.556, P=2.21×10⁻³), and type 1 diabetes (OR=0.410, P=1.78×10⁻⁷). Additionally, genetically proxied IL-6R blockade would suggestively reduce the risk of multiple sclerosis (OR=0.713, P=1.13×10⁻²). The results were robust under sensitivity analysis. For genetic colocalization analysis, we identified a shared causal variant rs531479718 linking serum C-reactive protein levels and asthma (posterior probability H4=0.998). Overall, our MR study demonstrated that genetically proxied IL-6R blockade may be causally associated with an increased risk of asthma and eczema, while concurrently diminishing the risk of ankylosing spondylitis, Crohn's disease, type 1 diabetes, and multiple sclerosis. These findings carry substantial implications for informing the therapeutic utilization of IL-6R blockade in the management of ADs.

Background Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. Methods Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. Results Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10− 5) and slower walking pace (OR = 0.918, P = 6.06 × 10− 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10− 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10− 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10− 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10− 6). Meta-analysis further supported the robustness of these causal associations. Conclusions Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Background: Migraine is a common and burdensome neurological disorder. The causal relationship between sedentary behaviours (SBs) and migraine remains instinct. We aimed to evaluate the roles of SBs including watching TV, using computer and driving in the risk of migraine. Methods: We conducted a univariable and multivariable Mendelian randomization (MR) study based on summary datasets of large genome-wide association studies. The inverse variance weighted method was utilized as the primary analytical tool. Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier and leave-one-out were conducted as sensitivity analysis. Additionally, we performed a meta-analysis to combine the causal estimates. Results: In the discovery analysis, we identified causal associations between time spent watching TV and an increased risk of migraine (p = 0.015) and migraine without aura (MO) (p = 0.002). Such causalities with increasing risk of migraine (p = 0.005), and MO (p = 0.006) were further verified using summary datasets from another study in the replication analysis. There was no significant causal association found between time spent using computer, driving and migraine or its two subtypes. The meta-analysis and multivariable MR analysis also strongly supported the causal relationships between time spent watching TV and an increased risk of migraine (p = 0.0003 and p = 0.034), as well as MO (p < 0.0001 and p = 0.0004), respectively. These findings were robust under all sensitivity analysis. Conclusions: Our study suggested that time spent watching TV may be causally associated with an increased risk of migraine, particularly MO. Large-scale and well-designed cohort studies may be warranted for further validation. Significance statement: This study represents the first attempt to investigate whether a causal relationship exists between SBs and migraine. Utilizing MR analysis helps mitigate reverse causation bias and confounding factors commonly encountered in observational cohorts, thereby enhancing the robustness of derived causal associations. Our MR analysis revealed that time spent watching TV may serve as a potential risk factor for migraine, particularly MO.

Background Despite numerous investigations into the relationship between physical activities (PA) and epilepsy, the causal effects remain contentious. Thus, we conducted a two‐sample Mendelian randomization (MR) study to assess the potential causality. Methods Single‐nucleotide polymorphisms (SNPs) predisposed to self‐reported moderate and vigorous physical activities (MPA and VPA) and overall acceleration average (OAA) calculated through wrist‐worn accelerometers were selected as exposure instrumental variables. Five subtypes of epilepsy, including all epilepsy, focal epilepsy and generalized epilepsy (with or without each other), focal epilepsy‐strict definition and generalized epilepsy‐strict definition (without overlap), were chosen as the outcomes. The MR study utilized the inverse‐variance weighted (IVW) method as the primary analytical tool, supplemented by MR‐Egger, simple mode, weighted mode, and weighted median methods. Cochran's Q and MR‐Egger intercept tests were employed to assess heterogeneity and pleiotropy, while MR pleiotropy residual sum and outlier and leave‐one‐out analyses were conducted to identify potential SNP outliers. Results The study indicated that OAA was genetically linked to a decreased risk of both focal epilepsy (OR = 0.812, 95% CI: 0.687–0.960, p = .015, IVW) and focal epilepsy‐strict definition (OR = 0.732, 95% CI: 0.596–0.900, p = .003, IVW; OR = 0.749, 95% CI: 0.573−0.979, p = .035, Weighted median). Genetically predicted MPA and VPA did not exhibit a causal association with all epilepsy or its subtypes (p>.05). No evidence of heterogeneity, pleiotropy, or SNP outlier was observed. Conclusions Our findings suggested that PA with accelerometer monitoring may potentially reduce the risk of focal epilepsy, while there is no evidence supporting causal association between self‐reported MPA or VPA and either focal or generalized epilepsy.

Mucormycosis is an invasive opportunistic fungal infection, which may be lethal and mostly affects patients with immunodeficiency or diabetes mellitus. Among Mucorales fungi, Rhizopus spp. is the most common cause of mucormycosis, followed by genera such as Mucor and Lichtheimia. Here we report a patient with severe COVID-19 infection who developed nasal pain, facial swelling, prominent black eschar on the nasal root. CT scan revealed pansinusitis along the maxillary, ethmoidal, and sphenoid sinuses. Mixed mold infection with Rhizopus microsporus and Mucor racemosus was detected by blood metagenomics next-generation sequencing (mNGS) and later nasal mucosa histological investigation confirmed mucormycosis. Severe COVID-19 infection led to the patient's thrombocytopenia and leukopenia. Later disseminated mucormycosis aggravated the infection and sepsis eventually resulted in death. It is the first case report of mucormycosis in which R. microsporus and M. racemosus as the etiologic agents were found simultaneously in one patient. COVID-19 infection combined with disseminated mucormycosisis can be fatal and mNGS is a fast, sensitive and accurate diagnostic method for fungi detection.

Study Objectives Narcolepsy type 1 (NT1), characterized by cataplexy and orexin deficiency, is a rare and frequently debilitating neurological disorder. It has been noted to have connections with the gut microbiota, yet the exact causal relationships remain unclear. Methods We conducted a comprehensive bidirectional Mendelian randomization (MR) study to rigorously investigate the causal links between the gut microbiota and NT1, utilizing genetic datasets from the MiBioGen consortium and FinnGen consortium, respectively. The inverse-variance weighted (IVW) method was employed to obtain the primary MR estimates, supplemented by several alternative methods as well as sensitivity analyses including Cochran's Q, MR-Egger, MR pleiotropy residual sum and outlier, leave-one-out, and genetic colocalization. Results Our findings indicated that an increased relative abundance of five genera including Blautia (P=4.47E-5), Collinsella (P=0.036), Gordonibacter (P=0.047), Hungatella (P=0.015), and Lachnospiraceae UCG010 (P=0.027) may be associated with a decreased risk of NT1. Conversely, an increased relative abundance of class Betaproteobacteria (P=0.032), genus Alloprevotella (P=0.009) and genus Ruminiclostridium6 (P=0.029) may potentially heighten the risk of NT1. The onset of NT1 may lead to a decrease in the relative abundance of genus Eubacterium eligens group (P=0.022), while a increase in the family Family XI (P=0.009), genus Hungatella (P=0.005), genus Prevotella (P=0.013), and unknown genus id.2001 (P=0.019). These findings remained robust under all sensitivity analyses. Conclusions Our results offer robust evidence for the bidirectional causal links between particular gut microbial taxa and NT1, underscoring the significance of the microbiota-gut-brain axis in the pathological process of NT1.

Background Myasthenia gravis (MG) is an autoimmune disease observed to have connections with gut microbiome. We aimed to systematically assess the causal relationships between gut microbiome, gut microbiome-derived metabolites, and MG using Mendelian randomization (MR) approach. Methods Summary-level genetic datasets from large-scale genome-wide association studies regarding 196 gut microbial taxa from the MiBioGen consortium (n=18,340), 72 derived metabolites from the TwinsUK and KORA studies (n=7,824), and antiacetylcholine receptor (AChR) antibody-positive MG (case=1,873, control=36,370) were employed for MR causal estimates. The inverse-variance weighted (IVW) method was utilized as the main analysis with MR-Egger, maximum likelihood, simple mode, and weighted median as complements. The tests of Cochran’s Q, MR-Egger intercept, Steiger, MR-PRESSO and leave-one-out were implemented for sensitivity analyses. Results The forward MR estimates of IVW revealed significant causal associations of the abundance of phylum Actinobacteria, class Gammaproteobacteria, family Defluviitaleac, family Family XIII, and family Peptococcaceae with a reduced risk of MG. Conversely, the abundance of phylum Lentisphaerae, order Mollicutes RF9, order Victivallales, and genus Faecalibacterium was causally associated with an increased risk of MG. The reversed MR analysis proved negative causal correlations between the MG and the abundance of family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum. Regarding the derived metabolites, the IVW estimates revealed that elevated levels of beta-hydroxyisovalerate and methionine were causally associated with a decreased risk of MG, while increased levels of choline and kynurenine were linked to an increased risk of MG. Furthermore, genetically predicted MG was associated with a decreased level of cholesterol. The results obtained from complementary MR methods were similar. These findings remained robust in all sensitivity analyses. Conclusion Our MR findings support the causal effects of specific gut microbiome taxa and derived metabolites on AChR antibody-positive MG, and vice versa, yielding novel insights into prevention and therapy targets of MG. Future studies may be warranted for validation and pursuing the precise mechanisms.