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A novel SUCNR1 inhibitor alleviates dysbiosis through inhibition of host responses without direct interaction with host microbiota

Thomas, Scott C; Guo, Yuqi; Xu, Fangxi; Saxena, Deepak; Li, Xin
Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein-coupled receptor, SUCNR1. Modulating succinate-induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis-induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host-microbial community structure, with enrichment in succinate producers and consumers and mucin-degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels.
PMID: 37715517
ISSN: 2041-1014
CID: 5593302

Getting off tract: contributions of intraorgan microbiota to cancer in extraintestinal organs

Thomas, Scott C; Miller, George; Li, Xin; Saxena, Deepak
The gastrointestinal ecosystem has received the most attention when examining the contributions of the human microbiome to health and disease. This concentration of effort is logical due to the overwhelming abundance of microbes in the gut coupled with the relative ease of sampling compared with other organs. However, the intestines are intimately connected to multiple extraintestinal organs, providing an opportunity for homeostatic microbial colonisation and pathogenesis in organs traditionally thought to be sterile or only transiently harbouring microbiota. These habitats are challenging to sample, and their low microbial biomass among large amounts of host tissue can make study challenging. Nevertheless, recent findings have shown that many extraintestinal organs that are intimately linked to the gut harbour stable microbiomes, which are colonised from the gut in selective manners and have highlighted not just the influence of the bacteriome but that of the mycobiome and virome on oncogenesis and health.
PMID: 37918889
ISSN: 1468-3288
CID: 5611712

Metformin regulates bone marrow stromal cells to accelerate bone healing in diabetic mice

Guo, Yuqi; Wei, Jianlu; Liu, Chuanju; Li, Xin; Yan, Wenbo
Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.
PMID: 37417730
ISSN: 2050-084x
CID: 5535222

Risk factors associated with low bone mineral density in children with idiopathic scoliosis: a scoping review

Yang, Yuqi; Chen, Zhengquan; Huang, Zefan; Tao, Jing; Li, Xin; Zhou, Xuan; Du, Qing
BACKGROUND:Children with idiopathic scoliosis (IS) have a high risk of osteoporosis and IS with low bone mineral density (BMD) are susceptible to curve progression. This review aims to explore the risk factors of low BMD in children with IS. METHODS:Studies were retrieved from 5 databases that were published up to January 2022. Search terms are keywords in titles or abstracts, including subject headings related to "Scoliosis", "Bone Mineral Density", and "Risk Factors". Observational studies on risk factors of low BMD in children with IS were enrolled in this review. The number of studies, sample size, outcome measures, research type, endocrine, and lifestyle-related factors, gene/signal pathway, and other contents were extracted for qualitative analysis. RESULTS:A total of 56 studies were included in this scoping review. Thirty studies involved genetic factors that may affect BMD, including the Vitamin-D receptor gene, RANK/RANKL signal pathway, the function of mesenchymal stem cells, Runx2, Interleukin-6 (IL-6), and miR-145/β-catenin pathway. Eight studies mentioned the influence of endocrine factors on BMD, and the results showed that serum levels of IL-6, leptin and its metabolites, and ghrelin in children with IS were different from the age-matched controls. In addition, there were 18 articles on lifestyle-related factors related to low BMD in children with IS, consisting of physical activity, calcium intake, Vitamin D level, and body composition. CONCLUSIONS:Genetic, endocrine, and lifestyle-related factors might relate to low BMD and even osteoporosis in IS. To prevent osteoporosis, the effectiveness of regular screening for low BMD risk factors in children with IS needs to be investigated. Additionally, clear risk factors suggest strategies for bone intervention. Future studies should consider the effectiveness of calcium and vitamin D supplements and physical activity in BMD improvement.
PMID: 36670417
ISSN: 1471-2474
CID: 5410792

Bone mineral density in children and young adults with idiopathic scoliosis: a systematic review and meta-analysis

Yang, Yuqi; Han, Xiaoli; Chen, Zhengquan; Li, Xin; Zhu, Xiaoqing; Yuan, Haiyan; Huang, Zefan; Zhou, Xuan; Du, Qing
PURPOSE/OBJECTIVE:Osteoporosis is a risk factor for idiopathic scoliosis (IS) progression, but it is still unclear whether IS patients have bone mineral density (BMD) loss and a higher risk of osteoporosis than asymptomatic people. This systematic review aims to explore the differences in BMD and prevalence of osteoporosis between the IS group and the control group. METHODS:We searched 5 health science-related databases. Studies that were published up to February 2022 and written in English and Chinese languages were included. The primary outcome measures consisted of BMD z score, the prevalence of osteoporosis and osteopenia, and areal and volumetric BMD. Bone morphometry, trabecular microarchitecture, and quantitative ultrasound measures were included in the secondary outcome measures. The odds ratio (OR) and the weighted mean difference (WMD) with a 95% confidence interval (CI) were used to pool the data. RESULTS:A total of 32 case-control studies were included. The pooled analysis revealed significant differences between the IS group and the control group in BMD z score (WMD -1.191; 95% CI  - 1.651 to -0.732, p  <  0.001). Subgroup analysis showed significance in both female (WMD -1.031; 95% CI -1.496 to -0.566, p  <  0.001) and male participants (WMD -1.516; 95% CI -2.401 to -0.632, p  =  0.001). The prevalence of osteoporosis and osteopenia in the group with IS was significantly higher than in the control group (OR  =  6.813, 95% CI 2.815-16.489, p  <  0.001; OR 1.879; 95% CI 1.548-2.281, p  <  0.000). BMD measures by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography showed a significant decrease in the IS group (all p  <  0.05), but no significant difference was found in the speed of sound measured by quantitative ultrasound between the two groups (p > 0.05). CONCLUSION/CONCLUSIONS:Both the male and female IS patients had a generalized lower BMD and an increased prevalence of osteopenia and osteoporosis than the control group. Future research should focus on the validity of quantitative ultrasound in BMD screening. To control the risk of progression in IS patients, regular BMD scans and targeted intervention are necessary for IS patients during clinical practice.
PMID: 36450863
ISSN: 1432-0932
CID: 5394302

The tumor mycobiome: A paradigm shift in cancer pathogenesis

Li, Xin; Saxena, Deepak
Distinct fungal communities or "mycobiomes" have been found in individual tumor types and are known to contribute to carcinogenesis. Two new studies present a comprehensive picture of the tumor-associated mycobiomes from a variety of human cancers. These studies reveal that fungi, although in low abundance, are ubiquitous across all major human cancers and that specific mycobiome types can be predictive of survival.
PMID: 36179665
ISSN: 1097-4172
CID: 5334672

Targeting the succinate receptor effectively inhibits periodontitis

Guo, Yuqi; Xu, Fangxi; Thomas, Scott C; Zhang, Yanli; Paul, Bidisha; Sakilam, Satish; Chae, Sungpil; Li, Patty; Almeter, Caleb; Kamer, Angela R; Arora, Paramjit; Graves, Dana T; Saxena, Deepak; Li, Xin
Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone loss. Here, we report an abnormal elevation of succinate in the subgingival plaque of subjects with severe PD. Succinate activates succinate receptor-1 (SUCNR1) and stimulates inflammation. We detected SUCNR1 expression in the human and mouse periodontium and hypothesize that succinate activates SUCNR1 to accelerate periodontitis through the inflammatory response. Administration of exogenous succinate enhanced periodontal disease, whereas SUCNR1 knockout mice were protected from inflammation, oral dysbiosis, and subsequent periodontal bone loss in two different models of periodontitis. Therapeutic studies demonstrated that a SUCNR1 antagonist inhibited inflammatory events and osteoclastogenesis in vitro and reduced periodontal bone loss in vivo. Our study reveals succinate's effect on periodontitis pathogenesis and provides a topical treatment for this disease.
PMID: 36130514
ISSN: 2211-1247
CID: 5333132

Serum metabolomic signatures of plant-based diets and incident chronic kidney disease

Kim, Hyunju; Yu, Bing; Li, Xin; Wong, Kari E; Boerwinkle, Eric; Seidelmann, Sara B; Levey, Andrew S; Rhee, Eugene P; Coresh, Josef; Rebholz, Casey M
BACKGROUND:Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms. OBJECTIVES:Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study. METHODS:We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (n1 = 1762; n2 = 1960). We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile compared to the lower 4 quintiles of PDIs, and whether PDI- and CKD-related metabolites predicted incident CKD beyond the CKD prediction model. RESULTS:We identified 82 significant PDI-metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026-0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006). CONCLUSIONS:In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.
PMID: 35218183
ISSN: 1938-3207
CID: 5586502

Neuroinflammation: A Distal Consequence of Periodontitis

Li, X; Kiprowska, M; Kansara, T; Kansara, P; Li, P
Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and contributes to the development of neurodegenerative diseases. The precise etiology of the most common neurodegenerative disorders, such as sporadic Alzheimer's, Parkinson's diseases and multiple sclerosis (AD, PD, and MS, respectively), remains to be revealed. Chronic neuroinflammation is a well-recognized component of these disorders, and evidence suggests that systemic inflammation is a possible stimulus for neuroinflammation development. Systemic inflammation can lead to deleterious consequences on the brain if the inflammation is sufficiently severe or if the brain shows vulnerabilities due to genetic predisposition, aging, or neurodegenerative diseases. It has been proposed that periodontal disease can initiate or contribute to the AD pathogenesis through multiple pathways, including key periodontal pathogens. Dysbiotic oral bacteria can release bacterial products into the bloodstream and eventually cross the brain-blood barrier; these bacteria can also cause alterations to gut microbiota that enhance inflammation and potentially affect brain function via the gut-brain axis. The trigeminal nerve has been suggested as another route for connecting oral bacterial products to the brain. PD and MS are often preceded by gastrointestinal symptoms or aberrant gut microbiome composition, and alterations in the enteric nervous system accompany the disease. Clinical evidence has suggested that patients with periodontitis are at a higher risk of developing PD and MS. This nexus among the brain, periodontal disease, and systemic inflammation heralds new ways in which microglial cells, the main innate immune cells, and astrocytes, the crucial regulators of innate and adaptive immune responses in the brain, contribute to brain pathology. Currently, the lack of understanding of the pathogenesis of neurodegeneration is hindering treatment development. However, we may prevent this pathogenesis by tackling one of its possible contributors (periodontitis) for systemic inflammation through simple preventive oral hygiene measures.
PMID: 35708472
ISSN: 1544-0591
CID: 5282712

Intrahepatic microbes govern liver immunity by programming NKT cells

Leinwand, Joshua C; Paul, Bidisha; Chen, Ruonan; Xu, Fangxi; Sierra, Maria A; Paluru, Madan M; Nanduri, Sumant; Alcantara Hirsch, Carolina G; Shadaloey, Sorin Aa; Yang, Fan; Adam, Salma A; Li, Qianhao; Bandel, Michelle; Gakhal, Inderdeep; Appiah, Lara; Guo, Yuqi; Vardhan, Mridula; Flaminio, Zia J; Grodman, Emilie R; Mermelstein, Ari; Wang, Wei; Diskin, Brian; Aykut, Berk; Khan, Mohammed; Werba, Gregor; Pushalkar, Smruti; McKinstry, Mia; Kluger, Zachary; Park, Jaimie J; Hsieh, Brandon; Dancel-Manning, Kristen; Liang, Feng-Xia; Park, James S; Saxena, Anjana; Li, Xin; Theise, Neil D; Saxena, Deepak; Miller, George
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial - glycosphingolipid - NKT - CCL5 axis that underlies hepatic immunity.
PMID: 35175938
ISSN: 1558-8238
CID: 5163572