ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

Association of serum 25-hydroxyvitamin D (25(OH)D) levels with the gut microbiota and metabolites in postmenopausal women in China.

BACKGROUND: Vitamin D insufficiency or deficiency is associated with an altered microbiota in older men. However, the relationship between the gut microbiota and 25-hydroxyvitamin D (25(OH)D) levels remains unknown in postmenopausal women. In this study, fecal microbiota profiles for 88 postmenopausal women in the high 25(OH)D (HVD) group (n = 44) and the low 25(OH)D (LVD) group (n = 44) were determined. An integrated 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach was applied to explore the association of serum 25(OH)D levels with the gut microbiota and fecal metabolic phenotype. Adjustments were made using several statistical models for potential confounding variables identified from the literature. RESULTS: The results demonstrated that the community diversity estimated by the Observe, Chao1 and ACE indexes was significantly lower in the LVD group than in the HVD group. Additionally, two kinds of characteristic differences in the microflora were analyzed in the HVD group, and ten kinds of characteristic differences in the microflora were analyzed in the LVD group. We observed that some bacteria belonging to the genera Bifidobacterium, Bacillus, F0332 and Gemella, were enriched in the LVD group, as were other genera, including Lachnoclostridium, UC5_1_2E3, Ruminococcus_gnavus_group and un_f_Lachnospiraceae. Christensenellaceae, Eggerthellaceae and Cloacibacillus were enriched in the HVD group. The L-pyroglutamic acid, inosine, and L-homocysteic acid levels were higher in the HVD group and were negatively correlated with the 1,2-benzenedicarboxylic acid and cholic acid metabolic levels. CONCLUSIONS: These observations provide a better understanding of the relationships between serum 25(OH)D levels and the fecal microbiota and metabolites in postmenopausal women.

The multiple effects of fecal microbiota transplantation on diarrhea-predominant irritable bowel syndrome (IBS-D) patients with anxiety and depression behaviors.

BACKGROUND: Anxiety and depression are complications in Irritable bowel syndrome (IBS) patients. In this study, we recruited 18 IBS patients with mild-modest anxiety and depression behaviors, and after the screening, we defined the FMT treatment group (n = 9) and the control group (n = 9). The IBS symptom severity scale (IBS-SSS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Irritable Bowel Syndrome Quality of Life (IBS-QOL) and Bristol stool scale (BSS) were evaluated one week before FMT (baseline), one-week-, one-month-, two-month-, and three-month-following FMT. Meanwhile, we determined the SCFAs in the patient's feces and serum and continued the metagenomic analysis of the microorganisms in the patient's feces. RESULTS: The results showed that the patient's anxiety and depression behavior gradually improved with FMT treatment. Moreover, the illness and quality of life had also been relieved significantly. The content of isovaleric acid and valeric acid was significantly reduced in the FMT group compared to the Col group. Metagenomic analysis showed that FMT treatment decreased the abundance of Faecalibacterium, Eubacterium and Escherichia. From KEGG functional analysis, we confirmed that the top five abundant pathways were "bacterial chemotaxis, "flagellar assembly", "glycine, serine and threonine metabolism", "apoptosis", and "bacterial invasion of epithelial cells". CONCLUSIONS: FMT treatment can effectively alleviate the anxiety and depression behaviors of IBS-D patients and reduce the IBS-SSS score, indicating that FMT can improve patients' symptoms. The high throughput sequencing results show that Bifidobacterium and Escherichia play the most critical role in the formation and recovery of IBS-D patients. The GC/MS data indicated that faeces isovaleric acid and valeric acid might be more suitable as a metabolic indicator of IBS-D remission. Trial registration ChiCTR, ChiCTR1900024924, Registered 3 August 2019, https://www.chictr.org.cn/showproj.aspx?proj=41676 .

A comprehensive approach to stool donor screening for faecal microbiota transplantation in China.

BACKGROUND: Faecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium difficile infections and chronic gastrointestional infections. However, the risks of FMT and the selection process of suitable donors remain insufficiently characterized. The eligibility rate for screening, underlying microbial basis, and core ethical issues of stool donors for FMT are yet to be elucidated in China. RESULTS: The potential stool donors were screened from December 2017 to December 2019 with the help of an online survey, clinical assessments, and stool and blood testing. Bioinformatics analyses were performed, and the composition and stability of gut microbiota in stool obtained from eligible donors were dynamically observed using metagenomics. Meanwhile, we build a donor microbial evaluation index (DoMEI) for stool donor screening. In the screening process, we also focused on ethical principles and requirements. Of the 2071 participants, 66 donors were selected via the screening process (3.19% success rate). Although there were significant differences in gut microbiota among donors, we found that the changes in the gut microbiota of the same donor were typically more stable than those between donors over time. CONCLUSIONS: DoMEI provides a potential reference index for regular stool donor re-evaluation. In this retrospective study, we summarised the donor recruitment and screening procedure ensuring the safety and tolerability for FMT in China. Based on the latest advances in this field, we carried out rigorous recommendation and method which can assist stool bank and clinicians to screen eligible stool donor for FMT.

Rhynchophylline attenuates migraine in trigeminal nucleus caudalis in nitroglycerin-induced rat model by inhibiting MAPK/NF-кB signaling.

Migraine causes severe health and social issues worldwide. Rhynchophylline (Rhy) is one of the major active components of Uncaria rhynchophylla that is used for the treatment of headache in Traditional Chinese Medicine. In the current study, the effect of Rhy on nitroglycerin (NTG)-induced migraine was assessed and the associated mechanism was also explored to explain its function. Rats were pre-treated with Rhy of two doses (10 mg/kg and 30 mg/kg) and then subjected to NTG to induce migraine symptoms. Thereafter, the electroencephalogram (EEG) signaling, spontaneous behaviors, levels of indicators related to oxidative stress, and expression of calcitonin gene-related peptide (CGRP) were measured to assess the anti-migraine function of Rhy. Moreover, the activities of MAPK/NF-κB pathway under the administrations of Rhy were also detected. The results showed that NTG induced EEG and behavior disorders in rats, which was associated with the initiation of oxidative stress and increased expression of CGRP. Nevertheless, the pre-treatments with Rhy attenuated the damages induced by NTG by reversing the levels of all the above indicators. The results of western blotting demonstrated that the anti-migraine effect of Rhy was accompanied by the inhibition of MAPK/NF-кB pathway. The findings outlined in the current study revealed an alternative mechanism of Rhy in protecting brain tissues against migraine: the agent exerted its effect by suppressing MAPK/NF-кB pathway, which would ameliorate impairments associated with migraine.

Effects of pulsed electromagnetic fields on the expression of NFATc1 and CAII in mouse osteoclast-like cells.

BACKGROUND AND AIMS: Pulsed electromagnetic fields (PEMF) have proven to be an effective noninvasive method in the prevention and treatment of osteoporosis. This study evaluated the effects of PEMF on the expression of the NFATc1, CAII and RANK genes in mouse osteoclast-like cells. METHODS: Bone marrow from bilateral tibiae and femurs was cultured in differentiation medium in the presence of soluble macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). After 5 days, the osteoclast-like cells were confirmed by both tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assays. The osteoclast-like cells were divided into five groups and exposed to the following treatments for 3 days: M-CSF; M-CSF + RANKL; M-CSF + RANKL + osteoprotegerin (OPG), M-CSF + RANKL + premarin (E2); and M-CSF + RANKL + PEMF. The numbers of multinucleated, TRAP-positive osteoclast-like cells and resorption pits formed were determined. The expression of NFATc1, CAII and RANK mRNA was determined with real-time fluorescent quantitative polymerase chain reaction. RESULTS: PEMF substantially reduced the number of osteoclast-like cells in the culture with M-CSF + RANKL. The level of NFATc1, CAII, and RANK mRNA expression was decreased in the M-CSF + RANKL + PEMF group compared to the M-CSF + RANKL group (p = 0.007, p = 0.039, p = 0.001, respectively). The mRNA expression of NFATc1, CAII, and RANK was not higher in the M-CSF + RANKL + OPG group compared to the M-CSF + RANKL + PEMF group (p = 0.682, p = 0.200, p = 0.924, respectively). In addition, there was no difference in the expression of mRNA from NFATc1, CAII, and RANK between the M-CSF + RANKL + PEMF group and the M-CSF + RANKL + E2 group (p = 0.853, p = 0.509, p = 0.664, respectively). CONCLUSIONS: These data suggest that PEMF might modulate the process of osteoclastogenesis and subsequent bone resorption, at least partially, through NFATc1, CAII and RANK.

Trimethylamine-N-oxide promotes osteoclast differentiation and oxidative stress by activating NF-κB pathway.

BACKGROUND: Senile osteoporosis may be caused by an imbalance in intestinal flora and oxidative stress. Trimethylamine-N-oxide (TMAO), a metabolite of dietary choline dependent on gut microbes, has been found to be significantly increased in osteoporosis. However, the role of TMAO in bone loss during osteoporosis remains poorly understood. In this study, we examined the impact of TMAO on osteoclast differentiation and bone resorption in an in vitro setting. METHODS: Osteoclast differentiation was induced by incubating RAW 264.7 cells in the presence of Receptor Activator for Nuclear Factor-κB Ligand (RANKL) and macrophage-stimulating factor (M-CSF). Flow cytometry, TRAP staining assay, CCK-8, and ELISA were employed to investigate the impact of TMAO on osteoclast differentiation and bone resorption activity in vitro. For mechanistic exploration, RT-PCR and Western blotting were utilized to assess the activation of the NF-κB pathway. Additionally, protein levels of secreted cytokines and growth factors were determined using suspension array technology. RESULTS: Our findings demonstrate that TMAO enhances RANKL and M-CSF-induced osteoclast formation and bone resorption in a dose-dependent manner. Mechanistically, TMAO triggers the upregulation of the NF-κB pathway and osteoclast-related genes (NFATc1, c-Fos, NF-κB p65, Traf6, and Cathepsin K). Furthermore, TMAO markedly elevated the levels of oxidative stress and inflammatory factors. CONCLUSIONS: In conclusion, TMAO enhances RANKL and M-CSF-induced osteoclast differentiation and inflammation in RAW 264.7 cells by activating the NF-κB signaling pathway. These findings offer a new rationale for further academic and clinical research on osteoporosis treatment.

Effects of Baduanjin exercise on cognitive frailty, oxidative stress, and chronic inflammation in older adults with cognitive frailty: a randomized controlled trial.

Background: Oxidative stress and chronic inflammation play an important role in the pathogenesis process of cognitive frailty (CF). Regular Baduanjin exercise could improve cognitive frailty in older adults, but it is unclear whether the effect of Baduanjin exercise on improving CF is mediated by modulating circulating oxidative stress and inflammatory process. Method: A total of 102 community-dwelling older adults with CF were recruited and randomly allocated into a 24-week Baduanjin exercise training group or no specific exercise intervention control group at an equal rate. Cognitive function and physical frailty index were assessed using the Montreal Cognitive Assessment (MoCA) and the Edmonton Frail Scale (EFS), as well as the oxidative stress and inflammatory cytokines were measured at baseline and after intervention. Result: After 24 weeks of intervention, the increased MoCA score (2.51 ± 0.32 points, p < 0.001) and the decreased EFS scores (1.94 ± 0.20 points, p = 0.012) in the Baduanjin group were significantly higher than those in the control group. Serum antioxidant SOD levels were increased by 10.03 ± 4.73 U/mL (p < 0.001), and the prooxidative MDA and 8-iso-PGF2α levels were decreased by -1.08 ± 0.80 nmol/mL (p = 0.030) and -86.61 ± 15.03 ng/L (p < 0.001) in the Baduanjin training group; while inflammatory cytokines IFN-γ, IL-2 and IL-4 levels were increased (1.08 ± 0.33 pg./mL, p = 0.034, 2.74 ± 0.75 pg./mL, p = 0.04 and 1.48 ± 0.35 pg./mL, p = 0.042). In addition, a mediation effect that Baduanjin training improved cognitive ability mediated by an increase of circulating IFN-γ and IL-2 levels were observed in this study. Conclusion: Regular Baduanjin exercise training could improve the cognitive frailty of the community-dwelling older adults with CF, and modulate oxidative stress and inflammatory processes by reducing circulating pro-oxidative MDA and 8-iso-PGF2α levels and increasing anti-oxidative SOD levels, as well as impacting inflammatory cytokines IFN-γ, IL-2, and IL-4 levels. Nevertheless, the mechanism of Baduanjin exercise mediating oxidative stress and inflammatory processes should be cautious to be explained. Clinical trial registration: http://www.chictr.org.cn/index.aspx, ChiCTR1800020341.

Whole genome sequencing enables new genetic diagnosis for inherited retinal diseases by identifying pathogenic variants.

Inherited retinal diseases (IRDs) are a group of common primary retinal degenerative disorders. Conventional genetic testing strategies, such as panel-based sequencing and whole exome sequencing (WES), can only elucidate the genetic etiology in approximately 60% of IRD patients. Studies have suggested that unsolved IRD cases could be attributed to previously undetected structural variants (SVs) and intronic variants in IRD-related genes. The aim of our study was to obtain a definitive genetic diagnosis by employing whole genome sequencing (WGS) in IRD cases where the causative genes were inconclusive following an initial screening by panel sequencing. A total of 271 unresolved IRD patients and their available family members (n = 646) were screened using WGS to identify pathogenic SVs and intronic variants in 792 known ocular disease genes. Overall, 13% (34/271) of IRD patients received a confirmed genetic diagnosis, among which 7% were exclusively attributed to SVs, 4% to a combination of single nucleotide variants (SNVs) and SVs while another 2% were linked to intronic variants. 22 SVs, 3 deep-intronic variants, and 2 non-canonical splice-site variants across 14 IRD genes were identified in the entire cohort. Notably, all of these detected SVs and intronic variants were novel pathogenic variants. Among those, 74% (20/27) of variants were found in genes causally linked to Retinitis Pigmentosa (RP), with the gene EYS being the most frequently affected by SVs. The identification of SVs and intronic variants through WGS enhances the genetic diagnostic yield of IRDs and broadens the mutational spectrum of known IRD-associated genes.

Cognitive impairment and risks of osteoporosis: A systematic review and meta-analysis.

OBJECTIVE: To systematically assess the association between osteoporosis and cognitive impairment, and to provide new light on the prevention of cognitive impairment in patients with osteoporosis. METHOD: A comprehensive research of Embase, Cochrane Library, PubMed, Web of Science, CNKI, Wangfang Data and VIP was performed from inception to January 2022, using the search term 'osteoporosis' and 'cognitive impairment'. Literature screening, data extraction and quality evaluation were conducted by two reviewers independently, and meta-analysis was performed by RevMan 5.4 software. RESULTS: A total of 8 studies (136222 participants) were included. Meta-analysis showed that patients with osteoporosis had an increased risk of cognitive impairment [OR=2.01, 95% CI(1.63-2.48), P<0.01]. This initial meta-analysis had significant heterogeneity, and subgroup analysis suggested that potential heterogeneity in different study types, age and outcome indicators. CONCLUSION: Patients with osteoporosis are at increased risk of cognitive impairment, and osteoporosis intervention could prevent or delay the onset of cognitive impairment for those at risk.

Shifts and importance of viable bacteria in treatment of DSS-induced ulcerative colitis mice with FMT.

Background and Aims: Ulcerative colitis (UC) has become a global public health concern, and is in urgent need of novel therapies. Fecal microbiota transplantation (FMT) targeting gut microbiota has recently been applied to the treatment of UC. Despite its recent successes, it is still largely unknown how FMT functionally modulates the gut microbiota and improves the disease. Methods: We prospectively collected fecal samples from the 40 mice (30 mice for dextran sulfate sodium (DSS)-induced, 10 for controls), followed by Propidium monoazide treatment for 16S rRNA gene sequencing. These 30 mice were divided equally into 3 groups, which were transplanted with original donor microbiota (DO), inactivated donor microbiota (DI) and saline, respectively. Subsequently, we used 16S rRNA gene sequencing to analyze the viable gut bacteria of ulcerative colitis (UC) mice and histological analysis to evaluate the effects of fecal microbiota transplantation (FMT) with viable microbiota. Results: We demonstrated that the community structure of viable bacteria was significantly different from fecal bacteria based on total DNA. Furthermore, the intestinal viable microbiota and colonic mucosal structure of mice were significantly changed by DSS induction. The histological analysis showed that only the mice treated with original donor microbiota group (HF) achieved a significant improvement. Compared with inactivated donor microbiota group (IF) and saline (NF), Lactobacillus and Halomonas were significantly enriched in the HF group. Conclusion: We inferred that only live bacteria from human donor reversed the histopathology and symptoms of UC in mice and altered the gut microbiota. The activity of gut microbiota in donor samples should be considered in FMT and that detailed analysis of viable microbiota is essential to understand the mechanisms by which FMT produces therapeutic effects in the future.

Efficacy and safety of fecal microbiota transplantation in the treatment of ulcerative colitis: a systematic review and meta-analysis.

To explore the efficacy and safety of fecal microbiota transplantation (FMT) as a treatment approach for ulcerative colitis (UC), a comprehensive systematic review and meta-analysis of randomized controlled trials was conducted. To collect and evaluate randomized controlled trials of high quality on FMT for UC, we searched a number of databases, including PubMed, Web of Science, Cochrane, Embase, and Medline, for studies published between the establishment of the databases and March 2023. We conducted a meta-analysis of the studies using Review Manager software (version 5.4.1) to determine the differences in rates of remission and adverse reactions between the FMT group and the control group, utilizing the risk ratio (RR) and 95% confidence interval (CI) to combine our findings. A total of 13 randomized controlled trials (RCTs) on the efficacy of FMT in patients with UC were included in the study, in which 580 patients participated, including 293 patients treated with FMT and 287 control subjects. Meta-analysis revealed that clinical remission was significantly better in the FMT group than in the control group [RR = 1.73; 95% CI = (1.41, 2.12); P < 0.00001]; endoscopic remission was significantly better in the FMT group than in the control group [RR = 1.74; 95% CI = (1.24, 2.44); P = 0.001]. Additionally, there were no significant differences in the incidence of adverse reactions between the two groups [RR = 1.00; 95% CI = (0.86, 1.15); P = 0.96]. Fecal microbiota transplantation has shown potential as a therapeutic intervention for inducing clinical remission in ulcerative colitis UC; nevertheless, the attainment of endoscopic remission and the maintenance of long-term remission continue to present challenges. Safety concerns persist throughout the treatment process, necessitating the implementation of measures to augment both safety and success rates.

A deep learning method for foot-type classification using plantar pressure images.

Background: Flat foot deformity is a prevalent and challenging condition often leading to various clinical complications. Accurate identification of abnormal foot types is essential for appropriate interventions. Method: A dataset consisting of 1573 plantar pressure images from 125 individuals was collected. The performance of the You Only Look Once v5 (YOLO-v5) model, improved YOLO-v5 model, and multi-label classification model was evaluated for foot type identification using the collected images. A new dataset was also collected to verify and compare the models. Results: The multi-label classification algorithm based on ResNet-50 outperformed other algorithms. The improved YOLO-v5 model with Squeeze-and-Excitation (SE), the improved YOLO-v5 model with Convolutional Block Attention Module (CBAM), and the multilabel classification model based on ResNet-50 achieved an accuracy of 0.652, 0.717, and 0.826, respectively, which is significantly higher than those obtained using the ordinary plantar-pressure system and the standard YOLO-v5 model. Conclusion: These results indicate that the proposed DL-based multilabel classification model based on ResNet-50 is superior in flat foot type detection and can be used to evaluate the clinical rehabilitation status of patients with abnormal foot types and various foot pathologies when more data on patients with various diseases are available for training.

Altered Gut Microbiota and Short-chain Fatty Acids in Chinese Children with Constipated Autism Spectrum Disorder.

Gastrointestinal symptoms are more prevalent in children with autism spectrum disorder (ASD) than in typically developing (TD) children. Constipation is a significant gastrointestinal comorbidity of ASD, but the associations among constipated autism spectrum disorder (C-ASD), microbiota and short-chain fatty acids (SCFAs) are still debated. We enrolled 80 children, divided into the C-ASD group (n = 40) and the TD group (n = 40). In this study, an integrated 16S rRNA gene sequencing and gas chromatography-mass spectrometry-based metabolomics approach was applied to explore the association of the gut microbiota and SCFAs in C-ASD children in China. The community diversity estimated by the Observe, Chao1, and ACE indices was significantly lower in the C-ASD group than in the TD group. We observed that Ruminococcaceae_UCG_002, Erysipelotrichaceae_UCG_003, Phascolarctobacterium, Megamonas, Ruminiclostridium_5, Parabacteroides, Prevotella_2, Fusobacterium, and Prevotella_9 were enriched in the C-ASD group, and Anaerostipes, Lactobacillus, Ruminococcus_gnavus_group, Lachnospiraceae_NK4A136_group, Ralstonia, Eubacterium_eligens_group, and Ruminococcus_1 were enriched in the TD group. The propionate levels, which were higher in the C-ASD group, were negatively correlated with the abundance of Lactobacillus taxa, but were positively correlated with the severity of ASD symptoms. The random forest model, based on the 16 representative discriminant genera, achieved a high accuracy (AUC = 0.924). In conclusion, we found that C-ASD is related to altered gut microbiota and SCFAs, especially decreased abundance of Lactobacillus and excessive propionate in faeces, which provide new clues to understand C-ASD and biomarkers for the diagnosis and potential strategies for treatment of the disorder. This study was registered in the Chinese Clinical Trial Registry ( www.chictr.org.cn ; trial registration number ChiCTR2100052106; date of registration: October 17, 2021).

A Matching Strategy To Guide Donor Selection for Ulcerative Colitis in Fecal Microbiota Transplantation: Meta-Analysis and Analytic Hierarchy Process.

Fecal microbiota transplantation (FMT) targeting gut microbiota has recently been applied to the treatment of ulcerative colitis (UC). However, preliminary trials showed that only a subset of patients responded to FMT, and the heterogeneity in donor gut microbiota probably played important roles in patients' responses, implying the significance of matching an appropriate donor to a specified patient. We developed a strategy to build a donor-recipient matching model to guide rational donor selection for UC in FMT. We collected and uniformly reanalyzed 656 fecal 16S rRNA gene sequencing samples (350 from UC patients and 306 from healthy subjects) from 9 studies. Significantly lower α-diversity indexes were observed in UC patients by random effects model. Thirty-four bacterial genera and 34 predicted pathways were identified with significant odds ratios and classification potentials for UC patients. Based on six bacterial indicators, including richness, overall distance, genera, and pathways (beneficial and harmful), the analytic hierarchy process-based donor-recipient matching model was set to rank and select appropriate donors for patients with UC. Finally, the model showed favorable classification powers (>70%) for FMT effectiveness in two previous clinical trials. This study revealed the dysbiosis of fecal bacterial diversity, composition, and predicted pathways of patients with UC by meta-analysis and hereby developed a donor-recipient matching strategy to guide donor selection for UC in FMT. This strategy can also be applied to other diseases associated with gut microbiota. IMPORTANCE Modulation of gut microbiota by FMT from donors has been applied to the treatment of UC and yielded variable effectiveness in clinical trials. One possibility is that this variable effectiveness was related to donor selection, as a patient's response to FMT may rely on the capability of the used donor's microbiota to restore the specific gut disturbances of the patient. However, the biggest issues on the practical level are what should be considered in the selection process and how to set up such a donor-recipient matching model. In this study, we presented a bacterial profile-based donor-recipient matching strategy to guide donor selection for UC in FMT by first meta-analysis of 656 fecal 16S rRNA gene sequencing samples from 9 studies to identify significant indicators and then setting up the model by an analytic hierarchy process. The applicability and accuracy of this model were verified in the data sets from two previous FMT clinical studies. Our data indicate that the donor-recipient matching model built in this study enables researchers to rationally select donors for UC patients in FMT clinical practice, although it needs more samples and prospective trials for validation. The strategy adopted in this study to leverage existing data sets to build donor-recipient matching models for precision FMT is feasible for other diseases associated with gut microbiota.

Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

OPG inhibits gene expression of RANK and CAII in mouse osteoclast-like cell.

This study was designed to determine the effects of the osteoprotegerin (OPG) on the mRNA expression of carbonic anhydrase II (CAII) and the receptor activator of NF-κB (RANK) in mouse osteoclast-like cells. Marrow cells were harvested from femora and tibiae of mouse and cultured in 6-well chamber slides. After 1 day of incubation, the marrow cells were exposed to M-CSF (25 ng/ml), RANKL (50 ng/ml), and different concentrations of OPG (50, 75, and 100 ng/ml, respectively) for 3 days. Osteoclast-like cells were confirmed by both tartrate-resistant acid phosphatase (TRAP) stain and bone resorption assay. The expression of RANK and CAIImRNA was determined with real-time fluorescent quantitative polymerase chain reaction. The numbers of multinucleated, TRAP-positive osteoclast-like cells, and resorption pits formed were observed. Compared with the M-CSF + RANKL group, RANKmRNA expression was statistically decreased in the M-CSF and M-CSF + RANKL + OPG (100 ng/ml) groups (P = 0.004, P = 0.024, respectively); Compared with the M-CSF, M-CSF + RANKL, and M-CSF + RANKL + OPG (100 ng/ml) group, CAIImRNA expression in the M-CSF + RANKL + OPG (75 ng/ml) groups was statistically decreased (P = 0.001, P = 0.008, and P = 0.036, respectively). These data suggest that OPG could regulate the expression of RANK and CA II mRNA in the marrow culture system.

Gut Microbiota Characteristics of People with Obesity by Meta-Analysis of Existing Datasets.

Obesity is a complex chronic, relapsing, progressive disease. Association studies have linked microbiome alterations with obesity and overweight. However, the results are not always consistent. An integrated analysis of 4282 fecal samples (2236 control (normal weight) group, 1152 overweight, and 894 simple obesity) was performed to identify obesity-associated microbial markers. Based on a random effects model and a fixed effects model, we calculated the odds ratios of the metrics, including bacterial alpha-diversity, beta-diversity, Bacteroidetes/Firmicutes ratio, common genera, and common pathways, between the simple obesity and control groups as well as the overweight and control groups. The random forest model was trained based on a single dataset at the genus level. Feature selection based on feature importance ranked by mean decrease accuracy and leave-one-out cross-validation was conducted to improve the predictive performance of the models. Chao1 and evenness possessed significant ORs higher than 1.0 between the obesity and control groups. Significant bacterial community differences were observed between the simple obesity and the control. The ratio of Bacteroidetes/Firmicutes was significantly higher in simple obesity patients. The relative abundance of Lachnoclostridium and Faecalitalea were higher in people with simple obesity, while 23 genera, including Christensenellaceae_R-7_group, Akkermansia, Alistipes, and Butyricimonas, etc., were significantly lower. The random forest model achieved a high accuracy (AUC = 0.83). The adenine and adenosine salvage pathway (PWY-6609) and the L-histidine degradation I pathway (HISDEG-PWY) were clustered in obese patients, while amino acid biosynthesis and degradation pathways (HISDEG-PWY, DAPLYSINESYN-PWY) were decreased. This study identified obesity microbial biomarkers, providing fertile targets for the management of obesity.

Multiomics Study Reveals Enterococcus and Subdoligranulum Are Beneficial to Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a life-threatening disease for premature infants with low body weight. Due to its fragile gut microbiome and successful treatment of fecal microbiota transplantation (FMT) for intestinal disease, we aimed to reveal the multiple-omics changes after FMT and/or sulperazone treatment. In this study, 2-week-old newborn rabbits were used to simulate the NEC model and grouped into healthy control, NEC, sulperazone treatment, FTM treatment, and FMT and sulperazone combination treatment. We evaluated the intestinal pathology and survival to define the benefit from each treatment and performed microbiome and transcriptome analysis to reveal the changes in microcosmic level, which could be helpful to understand the pathogenesis of NEC and develop new strategy. We found NEC rabbits benefit more from the combination of FMT and sulperazone treatment. Combination treatment reverses a lot of microorganisms dysregulated by NEC and showed the most similar transcript profiler with healthy control. Moreover, a combination of FMT and sulperazone significantly prolonged the survival of NEC rabbits. Function enrichment showed that metabolism and viral life cycle are the most significant changes in NEC. FMT is a common therapy method for NEC. Meanwhile, in the severe situation of NEC with intestinal infection, the first therapy strategy is preferred the third-generation cephalosporin, among which sulperazone is used widely and the effect is remarkable. So, we used sulperazone to treat the rabbits with the NEC. In this research, we aim to explore the different effects on NEC between FMT and sulperazone as well as the combination. Considering the microbiome and transcriptome result, we make a conclusion that the Enterococcus and Subdoligranulum benefits NEC by influencing the bacterial phages and butyrate production, respectively.