Astragalus polysaccharide promotes the regeneration of intestinal stem cells through HIF-1 signalling pathway.

Ionizing radiation (IR)-induced intestinal injury is usually accompanied by high lethality. Intestinal stem cells (ISCs) are critical and responsible for the regeneration of the damaged intestine. Astragalus polysaccharide (APS), one of the main active ingredients of Astragalus membranaceus (AM), has a variety of biological functions. This study was aimed to investigate the potential effects of APS on IR-induced intestine injury via promoting the regeneration of ISCs. We have established models of IR-induced intestinal injury and our results showed that APS played great radioprotective effects on the intestine. APS improved the survival rate of irradiated mice, reversed the radiation damage of intestinal tissue, increased the survival rate of intestinal crypts, the number of ISCs and the expression of intestinal tight junction-related proteins after IR. Moreover, APS promoted the cell viability while inhibited the apoptosis of MODE-K. Through organoid experiments, we found that APS promoted the regeneration of ISCs. Remarkably, the results of network pharmacology, RNA sequencing and RT-PCR assays showed that APS significantly upregulated the HIF-1 signalling pathway, and HIF-1 inhibitor destroyed the radioprotection of APS. Our findings suggested that APS promotes the regeneration of ISCs through HIF-1 signalling pathway, and it may be an effective radioprotective agent for IR-induced intestinal injury.

Cryptotanshinone alleviates radiation-induced lung fibrosis via modulation of gut microbiota and bile acid metabolism.

Cryptotanshinone (CPT), a major biological active ingredient extracted from root of Salvia miltiorrhiza (Danshen), has shown several pharmacological activities. However, the effect of CPT on radiation-induced lung fibrosis (RILF) is unknown. In this study, we explored the protective effects of CPT on RILF from gut-lung axis angle, specifically focusing on the bile acid (BA)-gut microbiota axis. We found that CPT could inhibit the process of epithelial mesenchymal transformation (EMT) and suppress inflammation to reduce the deposition of extracellular matrix in lung fibrosis in mice induced by radiation. In addition, 16S rDNA gene sequencing and BAs-targeted metabolomics analysis demonstrated that CPT could improve the dysbiosis of gut microbiota and BA metabolites in RILF mice. CPT significantly enriched the proportion of the beneficial genera Enterorhabdus and Akkermansia, and depleted that of Erysipelatoclostridium, which were correlated with increased intestinal levels of several farnesoid X receptor (FXR) natural agonists, such as deoxycholic acid and lithocholic acid, activating the FXR pathway. Taken together, these results suggested that CPT can regulate radiation-induced disruption of gut microbiota and BAs metabolism of mice, and reduce the radiation-induced lung inflammation and fibrosis. Thus, CPT may be a promising drug candidate for treating RILF.

[Chemical constituents in Dolomiaea plants and their pharmacological activities: a review].

Dolomiaea plants are perennial herbs in the Asteraceae family with a long medicinal history. They are rich in chemical constituents, mainly including sesquiterpenes, phenylpropanoids, triterpenes, and steroids. The extracts and chemical constituents of Dolomiaea plants have various pharmacological effects, such as anti-inflammatory, antibacterial, antitumor, anti-gastric ulcer, hepatoprotective and choleretic effects. However, there are few reports on Dolomiaea plants. This study systematically reviewed the research progress on the chemical constituents and pharmacological effects of Dolomiaea plants to provide references for the further development and research of Dolomiaea plants.

Mendelian randomization study of causal link from gut microbiota to colorectal cancer.

Recent studies have shown the relevance of gut microbiota in the occurrence and development of colorectal cancer (CRC), but the causal relationship remains unclear in the human population. The present study aims to assess the causal relationship from the gut microbiota to CRC and to identify specific causal microbe taxa via genome-wide association study (GWAS) summary statistics based two-sample Mendelian randomization (MR) analyses. Microbiome GWAS (MGWAS) in the TwinsUK 1,126 twin pairs was used as discovery exposure sample, and MGWAS in 1,812 northern German participants was used as replication exposure sample. GWAS of CRC in 387,156 participants from the UK Biobank (UKB) was used as the outcome sample. Bacteria were grouped into taxa features at both family and genus levels. In the discovery sample, a total of 30 bacteria features including 15 families and 15 genera were analyzed. Five features, including 2 families (Verrucomicrobiaceae and Enterobacteriaceae) and 3 genera (Akkermansia, Blautia, and Ruminococcus), were nominally significant. In the replication sample, the genus Blautia (discovery beta=-0.01, P = 0.04) was successfully replicated (replication beta=-0.18, P = 0.01) with consistent effect direction. Our findings identified genus Blautia that was causally associated with CRC, thus offering novel insights into the microbiota-mediated CRC development mechanism.

Potential role of gut microbiota and its metabolites in radiation-induced intestinal damage.

Radiation-induced intestinal damage (RIID) is a serious disease with limited effective treatment. Nuclear explosion, nuclear release, nuclear application and especially radiation therapy are all highly likely to cause radioactive intestinal damage. The intestinal microecology is an organic whole with a symbiotic relationship formed by the interaction between a relatively stable microbial community living in the intestinal tract and the host. Imbalance and disorders of intestinal microecology are related to the occurrence and development of multiple systemic diseases, especially intestinal diseases. Increasing evidence indicates that the gut microbiota and its metabolites play an important role in the pathogenesis and prevention of RIID. Radiation leads to gut microbiota imbalance, including a decrease in the number of beneficial bacteria and an increase in the number of harmful bacteria that cause RIID. In this review, we describe the pathological mechanisms of RIID, the changes in intestinal microbiota, the metabolites induced by radiation, and their mechanism in RIID. Finally, the mechanisms of various methods for regulating the microbiota in the treatment of RIID are summarized.

[Metabonomics and its application in Chinese medicine processing].

Chinese medicine processing is a procedure to process medicinal materials under the guidance of traditional Chinese medicine(TCM) theories by using unique methods in China. The medicinal materials can only be used clinically after proper processing. With the development of the modernization of TCM, it is difficult to solve the problems in the inheritance, development, and internationalization of Chinese medicine processing. Metabonomics, a new omics technology developed at the end of the last century, is used to infer the physiological or pathological conditions of the organism with the methods such as NMR and LC-MS via investigating the changes in endogenous small molecule metabolic network after the organism is stimulated by external environment. Metabonomics coincides with the holistic view of TCM because it displays the characteristics of integrity, comprehensiveness, and dynamics, and it has been widely applied in the field of Chinese medicine processing in recent years. This study summarized the application of metabonomics in the processing mechanism and quality control of Chinese medicine processing and prospected the development of this technology in the field of Chinese medicine processing.

[Application of metabonomics in study of traditional Chinese medicine syndrome:a review].

Syndrome is a nonlinear "internal-excess external-deficiency", "dynamic spatial-temporal" and "multi-dimensional" complex system and thus only by using a versatile method can the connotation be expounded. Metabonomics, which is dynamic, holistic, and systematic, is consistent with the overall mode of traditional Chinese medicine(TCM)(holistic view and syndrome differentiation and treatment). Therefore, metabonomics is very important for the research on the differentiation, material basis, and metabolic pathways of syndromes, and efficacy on syndromes. This study reviewed the application of metabonomics in the study of TCM syndromes in recent years, which is expected to objectify the research on TCM syndromes.

Identification of pleiotropic loci underlying hip bone mineral density and trunk lean mass.

Bone mineral density (BMD) and lean body mass (LBM) not only have a considerable heritability each, but also are genetically correlated. However, common genetic determinants shared by both traits are largely unknown. In the present study, we performed a bivariate genome-wide association study (GWAS) meta-analysis of hip BMD and trunk lean mass (TLM) in 11,335 subjects from 6 samples, and performed replication in estimated heel BMD and TLM in 215,234 UK Biobank (UKB) participants. We identified 2 loci that nearly attained the genome-wide significance (GWS, p < 5.0 × 10-8) level in the discovery GWAS meta-analysis and that were successfully replicated in the UKB sample: 11p15.2 (lead SNP rs12800228, discovery p = 2.88 × 10-7, replication p = 1.95 × 10-4) and 18q21.32 (rs489693, discovery p = 1.67 × 10-7, replication p = 1.17 × 10-3). The above 2 pleiotropic loci may play a pleiotropic role for hip BMD and TLM development. So our findings provide useful insights that further enhance our understanding of genetic interplay between BMD and LBM.

Mendelian Randomization Analysis Reveals Causal Effects of the Human Gut Microbiota on Abdominal Obesity.

BACKGROUND: Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined. OBJECTIVES: The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity. METHODS: Gut microbiota GWAS in 1126 twin pairs (age range, 18-89 years; 89% were females) from the TwinsUK study were used as exposure data. The primary outcome tested was trunk fat mass (TFM) GWAS in 492,805 participants (age range, 40-69 years; 54% were females) from the UK Biobank. The gut microbiota were classified at family, genus, and species levels. A feature was defined as a distinct family, genus, or species. MR analysis was mainly performed by an inverse variance-weighted test or Wald ratio test, depending on the number of instrumental variables (IVs) involved. A sensitivity analysis was performed on significant results by a weighted median test and a weighted genetic risk score (GRS) analysis. RESULTS: Results of MR analyses provided evidence of a causal association between 3 microbiota features and TFM, including 1 family [Lachnosiraceae; P = 0.02; ß = 0.001 (SEE, 4.28 × 10-4)], 1 genus [Bifidobacterium; P = 5.0 × 10-9; ß = -0.08 (SEE, 0.14)], and 1 species [Prausnitzii; P = 0.03; ß = -0.007 (SEE, 0.003)]. Both the weighted median test and GRS analysis successfully validated the association of the genetically predicted family, Lachnosiraceae (Pweighted median = 0.03; PGRS = 0.004). CONCLUSIONS: Our findings provided evidence of a causal association between gut microbiota and TFM in UK adults and identified specific bacteria taxa that may regulate the fat metabolism, thus offering new direction for the treatment of obesity.

Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10-7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10-7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10-3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10-7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10-7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10-3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10-23 and 1.18 × 10-11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

Four pleiotropic loci associated with fat mass and lean mass.

BACKGROUND: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated. METHODS: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097). RESULTS: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10-8) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, pdiscovery = 3.32 × 10-8, preplication = 4.07 × 10-13), 5q13.1 (rs4976033, pdiscovery = 1.93 × 10-9, preplication = 6.35 × 10-7), 12q24.31 (rs4765528, pdiscovery = 7.19 × 10-12, preplication = 1.88 × 10-11) and 18q21.32 (rs371326986, pdiscovery = 9.04 × 10-9, preplication = 2.35 × 10-95). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development. CONCLUSIONS: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.

Bacopaside I alleviates depressive-like behaviors by modulating the gut microbiome and host metabolism in CUMS-induced mice.

Bacopaside I (BSI) is a natural compound that is difficult to absorb orally but has been shown to have antidepressant effects. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of BSI. Therefore, this study aimed to investigate the potential mechanism of BSI in the treatment of depression via the microbiota-gut-brain axis and to validate it in a fecal microbiota transplantation model. The antidepressant effect of BSI was established in CUMS-induced mice using behavioral tests and measurement of changes in hypothalamicpituitaryadrenal (HPA) axis-related hormones. The improvement of stress-induced gut-brain axis damage by BSI was observed by histopathological sections and enzyme-linked immunosorbent assay (ELISA). 16 S rDNA sequencing analysis indicated that BSI could modulate the abundance of gut microbiota and increase the abundance of probiotic bacteria. We also observed an increase in short-chain fatty acids, particularly acetic acid. In addition, BSI could modulate the disruption of lipid metabolism induced by CUMS. Fecal microbiota transplantation further confirmed that disruption of the microbiota-gut-brain axis is closely associated with the development of depression, and that the microbiota regulated by BSI exerts a partial antidepressant effect. In conclusion, BSI exerts antidepressant effects by remodeling gut microbiota, specifically through the Lactobacillus and Streptococcus-acetic acid-neurotrophin signaling pathways. Furthermore, BSI can repair damage to the gut-brain axis, regulate HPA axis dysfunction, and maintain immune homeostasis.

Characterization and Discrimination of Ophiopogonis Radix with Different Levels of Sulfur Fumigation Based on UPLC-QTOF-MS Combined Molecular Networking with Multivariate Statistical Analysis.

Ophiopogonis Radix, also known as "Maidong" (MD) in China, is frequently sulfur-fumigated (SF) in the pretreatment process of MD to improve the appearance and facilitate preservation. However, the process leads to changes in chemical composition, so it is essential to develop an approach to identify the chemical characteristics between nonfumigated and sulfur-fumigated products. This paper provided a practical method based on UPLC-QTOF-MS combined Global Natural Products Social Molecular Networking (GNPS) with multivariate statistical analysis for the characterization and discrimination of MD with different levels of sulfur fumigation, high concentration sulfur fumigation (HS), low concentration sulfur fumigation (LS) and without sulfur fumigation (WS). First, a number of 98 compounds were identified in those MD samples. Additionally, the results of Principal component analysis (PCA) and Orthogonal partial least-squares-discriminant analysis (OPLS-DA) demonstrated that there were significant chemical differences in the chemical composition of MD with different degrees of SF. Finally, fourteen and sixteen chemical markers were identified upon the comparison between HS and WS, LS and WS, respectively. Overall, these results can be able to discriminate MD with different levels of SF as well as establish a solid foundation for further quality control and pharmacological research.

Integrated transcriptomic and metabolomic profiles reveal the protective mechanism of modified Danggui Buxue decoction on radiation-induced leukopenia in mice.

Leukopenia caused by radiation hinders the continuous treatment of cancers. Danggui Buxue Decoction (DBD) has been widely used in clinical owing to low toxicity and definite therapeutic effects to increase leukocytes. Meanwhile, icaritin (ICT) has also been proved to have the effect of boosting peripheral blood cells proliferation. However, there is no study to prove the efficacy of MDBD (Modified Danggui Buxue Decoction), a derivative herbal formula composed of DBD and ICT, in the treatment of radiation-induced leukopenia. In this study, we performed a model of 3.5 Gy whole-body radiation to induce leukopenia in mice. The results of pharmacodynamic studies demonstrated that MDBD could significantly increase the white blood cells in peripheral blood by improving the activity of bone marrow nuclear cells, reducing bone marrow damage, modulating spleen index, and regulating hematopoietic factors to alleviate leukopenia. We also analyzed the integrated results of metabolomics and transcriptomics and found that MDBD could relieve leukopenia and alleviate bone marrow damage by targeting steroid biosynthesis and IL-17 signaling pathway, in which the key genes are Jun, Cxcl2 and Egr1. Therefore, our study provides a basis for the effectiveness and compatibility in the combination of traditional Chinese medicine formula and small molecule drugs.

LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors of the digestive system. As a hallmark of cancer, energy-related metabolic reprogramming is manipulated by multiple factors, including long non-coding RNAs (lncRNAs). Notably, lncRNA CCAT1 has been identified as a crucial regulator in tumor progression. Nevertheless, the precise molecular mechanisms underlying the involvement of CCAT1 in metabolic reprogramming of GC remain unclear. METHODS: Gain- and loss-of-function experiments were performed to evaluate the roles of CCAT1 in tumorigenesis and glycolysis of GC. Bioinformatics analyses and mechanistic experiments, such as mass spectrometry (MS), RNA-pulldown, and RNA immunoprecipitation (RIP), were employed to reveal the potential interacting protein of CCAT1 and elucidate the regulatory mechanism of CCAT1 in GC glycolysis. Moreover, the nude mice xenograft assay was used to evaluate the effect of CCAT1 on GC cells in vivo. RESULTS: In this study, we identified that CCAT1 expression was significantly elevated in the tissues and plasma exosomes of GC patients, as well as GC cell lines. Functional experiments showed that the knockdown of CCAT1 resulted in a substantial decrease in the proliferation, migration and invasion of GC cells both in vitro and in vivo through decreasing the expression of glycolytic enzymes and glycolytic rate. Conversely, overexpression of CCAT1 exhibited contrasting effects. Mechanistically, CCAT1 interacted with PTBP1 and effectively maintained its stability by inhibiting the ubiquitin-mediated degradation process. As a critical splicing factor, PTBP1 facilitated the transition from PKM1 to PKM2, thereby augmenting the glycolytic activity of GC cells and ultimately fostering the progression of GC. CONCLUSIONS: Our findings demonstrate that CCAT1 plays a significant role in promoting the proliferation, migration, and invasion of GC cells through the PTBP1/PKM2/glycolysis pathway, thus suggesting CCAT1's potential as a biomarker and therapeutic target for GC.

Astragalus polysaccharide ameliorated complex factor-induced chronic fatigue syndrome by modulating the gut microbiota and metabolites in mice.

Chronic fatigue syndrome (CFS) is a debilitating disease with no symptomatic treatment. Astragalus polysaccharide (APS), a component derived from the traditional Chinese medicine A. membranaceus, has significant anti-fatigue activity. However, the mechanisms underlying the potential beneficial effects of APS on CFS remain poorly understood. A CFS model of 6-week-old C57BL/6 male mice was established using the multiple-factor method. These mice underwent examinations for behavior, oxidative stress and inflammatory indicators in brain and intestinal tissues, and ileum histomorphology. 16 S rDNA sequencing analysis indicated that APS regulated the abundance of gut microbiota and increased production of short chain fatty acids (SCFAs) and anti-inflammatory bacteria. In addition, APS reversed the abnormal expression of Nrf2, NF-κB, and their downstream factors in the brain-gut axis and alleviated the reduction in SCFAs in the cecal content caused by CFS. Further, APS modulated the changes in serum metabolic pathways induced by CFS. Finally, it was verified that butyrate exerted antioxidant and anti-inflammatory effects in neuronal cells. In conclusion, APS could increase the SCFAs content by regulating the gut microbiota, and SCFAs (especially butyrate) can further regulate the oxidative stress and inflammation in the brain, thus alleviating CFS. This study explored the efficacy and mechanism of APS for CFS from the perspective of gut-brain axis and provides a reference to further explore the efficacy of APS and the role of SCFAs in the central nervous system.

Identification of chemical components and rat serum metabolites in Danggui Buxue decoction based on UPLC-Q-TOF-MS, the UNIFI platform and molecular networks.

Danggui Buxue Decoction (DBD), consisting of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (Huangqi, HQ) and Angelica sinensis (Oliv.) Diels (Danggui, DG), is a traditional Chinese medicine (TCM) formula with the function of tonifying Qi and promoting blood. In this study, ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was used to comprehensively identify the chemical constituents in DBD and those entering into the rat serum after gastric perfusion. A combination of the UNIFI platform and Global Natural Product Social molecular networking (GNPS) was used to analyze the chemical composition of DBD. As a result, 207 compounds were unambiguously or tentatively identified including 60 flavonoids, 38 saponins, 35 organic acids, 26 phthalides, 12 phenylpropanoids, 11 amino acids and 25 others. Furthermore, a total of 80 compounds, including 29 prototype components and 51 exogenous metabolites, were detected in the serum of rats. Phase I reactions (oxidation, reduction, and hydration), phase II reactions (methylation, sulfation, and glucuronidation), and their combinations were the main metabolic pathways of DBD. The results provided fundamental information for further studying the pharmacological mechanisms of DBD, as well as its quality control research.

Comprehensive Metabolic Profiling of Euphorbiasteroid in Rats by Integrating UPLC-Q/TOF-MS and NMR as Well as Microbial Biotransformation.

Euphorbiasteroid, a lathyrane-type diterpene from Euphorbiae semen (the seeds of Euphorbia lathyris L.), has been shown to have a variety of pharmacological effects such as anti-tumor and anti-obesity. This study aims to investigate the metabolic profiles of euphorbiasteroid in rats and rat liver microsomes (RLMs) and Cunninghamella elegans bio-110930 by integrating ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q/TOF-MS), UNIFI software, and NMR techniques. A total of 31 metabolites were identified in rats. Twelve metabolites (M1-M5, M8, M12-M13, M16, M24-M25, and M29) were matched to the metabolites obtained by RLMs incubation and the microbial transformation of C. elegans bio-110930 and their structures were exactly determined through analysis of NMR spectroscopic data. In addition, the metabolic pathways of euphorbiasteroid were then clarified, mainly including hydroxylation, hydrolysis, oxygenation, sulfonation, and glycosylation. Finally, three metabolites, M3 (20-hydroxyl euphorbiasteroid), M24 (epoxylathyrol) and M25 (15-deacetyl euphorbiasteroid), showed significant cytotoxicity against four human cell lines with IC50 values from 3.60 µM to 40.74 µM. This is the first systematic investigation into the in vivo metabolic pathways of euphorbiasteroid and the cytotoxicity of its metabolites, which will be beneficial for better predicting the metabolism profile of euphorbiasteroid in humans and understanding its possible toxic material basis.

Mendelian randomization analysis identified causal Association of Childhood Obesity with adult major depressive disorder.

BACKGROUND: Childhood obesity is associated with adult major depressive disorder (MDD), but their causality is not clear. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to explore the causality of childhood body mass index (BMI) and childhood obesity on MDD, followed by a multivariable MR (MVMR) analysis to investigate the potential role of adult BMI in mediating such effect. We accessed genome-wide association summary statistics of childhood BMI, childhood obesity, adult BMI and adult MDD from the Early Growth Genetics consortium (nBMI  = 47 541, nobesity  = 24 160), the Genetic Investigation of Anthropometric Traits consortium (nadult_BMI  = âˆ¼700 000) and the Psychiatric Genomics consortium (nMDD  = 500 199), respectively. The MR-PRESSO test was performed to remove SNPs with potential pleiotropic effect. The MR analysis was performed by inverse-variance weighted test. Further sensitivity analyses, including the MR-Egger intercept test and leave-one-out analysis, were performed to evaluate the reliability of the results. RESULTS: Our study found that childhood obesity might increase the odds of developing MDD in adults (OR = 1.03, 95% CI: 1.01-1.06, p = 2.6 × 10-3 ). Children with higher BMI were more likely to develop MDD in adulthood, with an OR of 1.12 per standard deviation score (SDS) increase in BMI (95% CI: 1.07-1.17, p = 4.4 × 10-7 ). Sensitivity analyses verified the reliability of the causality between childhood BMI/obesity and MDD. Further MVMR results revealed that the impact of childhood BMI on MDD risk was predominantly mediated by adult BMI. CONCLUSION: Our findings provided evidence of a causal relationship between childhood BMI/obesity and adult MDD, thus providing new insights into the prevention of MDD.