✪✪✪ Ruan Lingyu Analysis

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Ruan Lingyu Analysis

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Previous studies suggest the direct or indirect involvement of bacterial metabolites, in particular, short-chain fatty acid SCFA and bile acids 32 , 55 in some neurological disorders. In this study, we detected many metabolites significantly altered in AD mice compared to WT mice. Among them, the most significant change occurred in amino acids, particularly those in phenylalanine-related pathways.

We confirmed that the abundance of phenylalanine and isoleucine was increased in the feces and blood of AD mice compared to that of WT mice. Functional assessment both in vitro and in vivo revealed the role of phenylalanine and isoleucine in promoting both differentiation and proliferation of peripheral inflammatory Th1 cells. These findings highlight the role of the abnormal production of phenylalanine and isoleucine by gut microbiota in provoking Th1 cell-dominated neuroinflammation. All these findings allowed us to propose a conceptual advancement in understanding the mechanism of AD pathogenesis.

Its development also requires the systematic interaction between gut, brain and the intermediate inflammatory factors. These amino acids promote the infiltration of peripheral Th1 cells into the brain via blood circulation. The infiltrating peripheral Th1 cells may locally crosstalk with M1 microglial cells in the brain, resulting in pathological neuroinflammation and cognitive impairment Fig. These mechanistic insights into AD pathogenesis may provide a novel therapeutic solution by reconstituting the gut microbiota to favour anti-neuroinflammation responses.

Schematic diagram of gut-brain axis in AD progression and the intervention strategy. The abnormal metabolites production provoke peripheral inflammation, increases the brain infiltration of immune cells which crosstalk with M1 microglial cells in the brain, resulting in pathological neuroinflammation and cognitive impairment left panel. Emerging data have shown that poly- or oligosaccharides have advantages to modulate gut microbiota.

GV is well tolerated with a safety profile comparable to the placebo control. In this study, we found that GV effectively reconditioned gut microbiota, decreased the concentration of phenylalanine and isoleucine in the feces and blood, and reduced Th1-related neuroinflammation in the brain. Of note, GVtreated Tg feces could largely mimic the therapeutic effects of GV treatment per se, while antibiotic treatment abrogated the therapeutic effects of GV These findings provided important evidence showing that the therapeutic effect of GV is primarily via the reconstitution of gut microbiome. As such, GV may provide us an appealing approach of microbiota-centric anti-AD strategies worthy of future investigations.

Our findings may have translational implications for AD diagnosis and therapy. The combination of specific bacteria e. More importantly, the identified microbiota-centric anti-AD effect of GV will open a new therapeutic avenue for AD treatment through remodelling gut microbiota, and guide the future development of effective therapies by exploring the enormous chemical space of carbohydrates.

Meanwhile, our study has several limitations. Though we have revealed the potential role of gut microbiota in the pathogenesis of AD, future studies to identify the key bacteria strains that may account for metabolites and neuroinflammation changes will be critical. Beyond the two key amino acids that have been fully studied in this study, further exploration will be required to understand other mechanistic links connecting gut microbiota and neuroinflammation. Future studies to address these key issues may help gain a better understanding of the pathogenesis of AD and explore the broader therapeutic potential of GV in clinical treatment. GV is a mixture of oligosaccharides with the degree of polymerization dp from 2 to The non-clinical study showed that GV penetrates the blood-brain-barrier BBB in its original form.

GV exhibited a safe and well-tolerated profile in both phase 1 and phase 2 trials. No serious adverse events were observed, with similar incidence rate between GV and placebo group unpublished data. The WT mice C57 were bred in separate cages to avoid microbiota cross transfer. Mice were randomly allocated to different groups before treatment. For time course analysis of Tg mice, male and female Tg mice were sacrificed at 2-, 3-, 5-, 7- and 9-month old. Mouse brains were collected and stained for immune cell analysis and cytokine analysis.

Before the mice were sacrificed, feces were collected for gut microbiota analysis. A behavioral test was performed to monitor cognitive activity after the last treatment. Then, the mouse brains and feces were used for different analyses. For behavior test, Tg mice and WT mice at different months as well as mice after treatment were tested by discrimination learning, as reported previously. Two tests were carried out at 13 months. The mice and age-matched wild-type mice were sacrificed at 3-, 9-, and month old for immune cell analysis. Mouse brains and blood were collected for different analyses. The MWM test is used to measure spatial learning and memory according to a protocol published previously. The animals were released into the water at the desired start position, and the latency to find the platform was timed.

The trace and the number of platform-site crossovers were recorded using a video camera. Working memory was assessed by the Y maze according to the literature with some modifications. The total number of arm entries and alternation behavior were recorded using a video camera. The accuracy of the Y maze was the ratio between the correct alternation and the total alternation.

Discrimination learning. During the habituation phase, the mice had free access to water but limited access to food. During the task, mice need to learn to enter the Cognition Wall through the left entrance three entrances were offered to obtain food one food pellet was rewarded for every fifth entry through the left entrance. All mouse movements were recorded by a computerized tracking system Noldus, Ethovision. Shanghai, China. Microbial DNA was extracted from faecal samples using the E. QC sample was prepared by mixing aliquots of all samples to be a pooled sample and then analyzed using the same method with the analytic samples. The QCs were injected at regular intervals every 10 samples throughout the analytical run to provide a set of data from which repeatability can be assessed.

The mass spectrometric data was collected using an AB Sciex TripleTOF TM mass spectrometer system equipped with an electrospray ionization ESI source operating in either positive or negative ion mode with a capillary voltage 1. We used a previously well-established protocol for the in vitro culture of fecal samples and collected the supernatant. A total of 0. Stained slices were automatically scanned by a high-throughput bright field scanner NanoZoomer 2.

First, concern regarding a change in cognition. Second, impairment in one or more cognitive domains. Third, preservation of independence in functional abilities. All participants underwent a screening process that included a review of their medical history, physical and neurological examinations, laboratory tests, and MRI scans. The clinical assessment of mild cognitive impairment or dementia included neuropsychological tests, as well as behavioral and psychiatric interviews conducted by attending psychiatrists. Based on the assessment, we retained MCI due to AD subjects and others were excluded such as those who had impairment in a single non-memory domain single, non-memory domain MCI subtype and those who had impairment in two or more domains multiple domains, slightly impaired MCI subtype.

Normal control subjects had no history of cognitive decline, neurological disorders, or uncontrolled systemic medical disorders. The sample size for the first cohort Fig. The sample size for the second cohort Fig. A diagnosis of MCI was based on the following criteria, which were adapted from the MCI diagnostic criteria of Petersen: 1 memory complaints, preferably corroborated by a spouse or relative; 2 objective memory impairment; 3 normal general cognitive function; 4 intact activities of daily living; and 5 absence of dementia.

Informed consents were obtained from the subjects and the guardian of the subjects. Information about gender and age etc. Two milliliters of peripheral blood from healthy people or patients were treated with red blood cells lysis buffer. Stained cells were washed twice with PBS. The viability of sorted Th1 cells was further confirmed by Trypan blue staining. After 0.

Mice were treated by adding an antibiotic solution ABX containing ampicillin 0. Solutions and bottles were changed 3 times and once weekly, respectively. The antibiotic activity was confirmed by 16S rRNA gene sequencing. Types of bacteria with a relative abundance of less than 0. The duration of ABX treatment was slightly different based on the experimental settings. In the context of faecal microbia transplantation experiments, mice received 3 days of ABX before undergoing faecal microbia transplantation the next day by oral gavage using animal feeding needles.

FMT was performed by thawing faecal material. After 3 days, 4. The mice were sacrificed 3 days later and used for different analyses. Principal component analysis PCA is a method that simplifies the complexity in high-dimensional data while retaining trends and patterns. PCA reduces data by geometrically projecting them onto lower dimensions called principal components PCs , with the goal of finding the best summary of the data using a limited number of PCs. For correlational analysis, trend changes in the abundance of bacteria were correlated with changes in the frequency of immune cells.

The exact correlation coefficient and the p-value set to 0. TCseq: Time course sequencing data analysis. R package version 1. A standardized z-score transformation was applied to convert the fraction values to z-scores before analysis in all heatmaps. Heatmaps and volcano plots are also plotted using the R packages. The Mouseac database used in Supplementary information, Fig. Other bioinformatics analyses, including the barplot representation of gut microbiota abundance at the family level, lists of significant changing bacteria, etc.

Before tissue collection, the brains were perfused with ice-cold PBS to avoid sampling the circulating blood immune cells, and the brains were removed, chopped into pieces and dissected according to the introduction of the Adult Brain Dissociation Kit Miltenyi, Cat No. Relevant negative control, Fluorescence Minus One FMO control and each fluorescence compensation sample were used to adjust fluorescence compensation and identify the populations of interest. The following steps were conducted by RayBiotech Guangzhou, China. The data were then visualized by a heatmap diagram www. Mice were transcardially perfused with 0. Frozen mouse brain samples were sectioned and collected on PEN membrane slides Leica, In the behavior test, animals were randomly distributed into different groups.

For significantly changing bacteria lists, we used the online platform of the Majorbio I-Sanger Cloud to perform Wilcoxon rank-sum test, and the P -value was based on a two-tailed test with FDR corrected, the significant level was set to 0. Most of the data were analyzed in GraphPad Prism. Cummings, J. Google Scholar. Kodamullil, A. Trial watch: tracing investment in drug development for Alzheimer disease. Drug Discov. Honda, K. The microbiota in adaptive immune homeostasis and disease. Nature , 75—84 Thaiss, C. The microbiome and innate immunity. Nature , 65—74 Blander, J.

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