Deviated and early unsustainable stunted development of gut microbiota in children with autism spectrum disorder.

OBJECTIVE: Recent studies have provided insights into the gut microbiota in autism spectrum disorder (ASD); however, these studies were restricted owing to limited sampling at the unitary stage of childhood. Herein, we aimed to reveal developmental characteristics of gut microbiota in a large cohort of subjects with ASD combined with interindividual factors impacting gut microbiota. DESIGN: A large cohort of 773 subjects with ASD (aged 16 months to 19 years), 429 neurotypical (NT) development subjects (aged 11 months to 15 years) were emolyed to determine the dynamics change of gut microbiota across different ages using 16S rRNA sequencing. RESULT: In subjects with ASD, we observed a distinct but progressive deviation in the development of gut microbiota characterised by persistently decreased alpha diversity, early unsustainable immature microbiota, altered aboudance of 20 operational taxonomic units (OTUs), decreased taxon detection rate and 325 deregulated microbial metabolic functions with age-dependent patterns. We further revealed microbial relationships that have changed extensively in ASD before 3 years of age, which were associated with the severity of behaviour, sleep and GI symptoms in the ASD group. This analysis demonstrated that a signature of the combination of 2 OTUs, Veillonella and Enterobacteriaceae, and 17 microbial metabolic functions efficiently discriminated ASD from NT subjects in both the discovery (area under the curve (AUC)=0.86), and validation 1 (AUC=0.78), 2 (AUC=0.82) and 3 (AUC=0.67) sets. CONCLUSION: Our large cohort combined with clinical symptom analysis highlights the key regulator of gut microbiota in the pathogenesis of ASD and emphasises the importance of monitoring and targeting the gut microbiome in future clinical applications of ASD.

KDM5 interacts with Foxo to modulate cellular levels of oxidative stress.

Increased cellular levels of oxidative stress are implicated in a large number of human diseases. Here we describe the transcription co-factor KDM5 (also known as Lid) as a new critical regulator of cellular redox state. Moreover, this occurs through a novel KDM5 activity whereby it alters the ability of the transcription factor Foxo to bind to DNA. Our microarray analyses of kdm5 mutants revealed a striking enrichment for genes required to regulate cellular levels of oxidative stress. Consistent with this, loss of kdm5 results in increased sensitivity to treatment with oxidizers, elevated levels of oxidized proteins, and increased mutation load. KDM5 activates oxidative stress resistance genes by interacting with Foxo to facilitate its recruitment to KDM5-Foxo co-regulated genes. Significantly, this occurs independently of KDM5's well-characterized demethylase activity. Instead, KDM5 interacts with the lysine deacetylase HDAC4 to promote Foxo deacetylation, which affects Foxo DNA binding.

Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism.

BACKGROUND: Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. METHODS: Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. RESULTS: Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. CONCLUSIONS: This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.

Lactobacillus plantarum L168 improves hyperoxia-induced pulmonary inflammation and hypoalveolarization in a rat model of bronchopulmonary dysplasia.

Alteration of gut microbiota can affect chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, through abnormal immune and inflammatory responses. Previous studies have shown a feasible connection between gut microbiota and bronchopulmonary dysplasia (BPD) in preterm infants. However, whether BPD can be ameliorated by restoring the gut microbiota remains unclear. In preterm infants with BPD, we found variance in the diversity and structure of gut microbiota. Similarly, BPD rats showed gut dysbiosis, characterized by a deficiency of Lactobacillus, which was abundant in normal rats. We therefore explored the effect and potential mechanism of action of a probiotic strain, Lactobacillus plantarum L168, in improving BPD. The BPD rats were treated with L. plantarum L168 by gavage for 2 weeks, and the effect was evaluated by lung histopathology, lung function, and serum inflammatory markers. Subsequently, we observed reduced lung injury and improved lung development in BPD rats exposed to L. plantarum L168. Further evaluation revealed that L. plantarum L168 improved intestinal permeability in BPD rats. Serum metabolomics showed altered inflammation-associated metabolites following L. plantarum L168 intervention, notably a marked increase in anti-inflammatory metabolites. In agreement with the metabolites analysis, RNA-seq analysis of the intestine and lung showed that inflammation and immune-related genes were down-regulated. Based on the information from RNA-seq, we validated that L. plantarum L168 might improve BPD relating to down-regulation of TLR4 /NF-κB /CCL4 pathway. Together, our findings suggest the potential of L. plantarum L168 to provide probiotic-based therapeutic strategies for BPD.

Global analysis of the differentially expressed miRNAs of prostate cancer in Chinese patients.

BACKGROUND: Our recent study showed the global physiological function of the differentially expressed genes of prostate cancer in Chinese patients was different from that of other non-Chinese populations. microRNA are estimated to regulate the expression of greater than 60% of all protein-coding genes. To further investigate the global association between the transcript abundance of miRNAs and their target mRNAs in Chinese patients, we used microRNA microarray approach combined with bioinformatics and clinical-pathological assay to investigate the miRNA profile and evaluate the potential of miRNAs as diagnostic and prognostic markers in Chinese patients. RESULTS: A total of 28 miRNAs (fold change ≥ 1.5; P ≤ 0.05) were differentially expressed between tumor tissue and adjacent benign tissue of 4 prostate cancer patients.10 top Differentially expressed miRNAs were validated by qRT-PCR using all 20 tissue pairs. Compared to the miRNA profile of non-Chinese populations, the current study showed that miR-23b, miR-220, miR-221, miR-222, and miR-205 maybe common critical therapeutic targets in different populations. The integrated analysis for mRNA microarray and miRNA microarray showed the effects of specifically inhibiting and/or enhancing the function of miRNAs on the gene transcription level. The current studies also identified 15 specific expressed miRNAs in Chinese patients. The clinical feature statistics revealed that miR-374b and miR-19a have significant correlations with clinical-pathological features in Chinese patients. CONCLUSIONS: Our findings showed Chinese prostate cancer patients have a common and specific miRNA expression profile compared with non-Chinese populations. The miR-374b is down-regulated in prostate cancer tissue, and it can be identified as an independent predictor of biochemical recurrence-free survival.

The microbiota-gut-brain axis and neurodevelopmental disorders.

The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis, regulating various physiological processes. In recent years, the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated. The gut microbiota is commonly considered to regulate neurodevelopment through three pathways, the immune pathway, the neuronal pathway, and the endocrine/systemic pathway, with overlaps and crosstalks in between. Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, and Rett Syndrome. Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders (NDDs). This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs. Furthermore, we analyzed both the current state of research progress and discuss future perspectives in this field.

QMD: A new method to quantify microbial absolute abundance differences between groups.

A new method, quantification of microbial absolute abundance differences (QMD), was proposed to estimate the microbial absolute abundance changes of each taxon under different conditions based on the microbial relative abundance. Compared with other methods, QMD displayed greater confidence in understanding microbiome dynamics between groups. We also provide QMD software to investigate common deviations and achieve a better understanding of microbiota changes under different conditions.

DVT: a high-throughput analysis pipeline for locomotion and social behavior in adult Drosophila melanogaster.

BACKGROUND: Drosophila melanogaster is excellent animal model for understanding the molecular basis of human neurological and motor disorders. The experimental conditions and chamber design varied between studies. Moreover, most previously established paradigms focus on fly trace detection algorithm development. A comprehensive understanding on how fly behaves in the chamber is still lacking. RESULTS: In this report, we established 74 unique behavior metrics quantifying spatiotemporal characteristics of adult fly locomotion and social behaviors, of which 49 were newly proposed. By the aiding of the developed analysis pipeline, Drosophila video tracking (DVT), we identified siginificantly different patterns of fly behavior confronted with different chamber height, fly density, illumination and experimental time. Meanwhile, three fly strains which are widely used as control lines, Canton-S(CS), w1118 and Oregon-R (OR), were found to exhibit distinct motion explosiveness and exercise endurance. CONCLUSIONS: We believe the proposed behavior metrics set and pipeline should help identify subtle spatial and temporal differences of drosophila behavior confronted with different environmental factors or gene variants.

Multi-Omics Analysis Reveals Intratumor Microbes as Immunomodulators in Colorectal Cancer.

Recent studies indicated that intratumor microbes are an essential part of the tumor microenvironment. Here, we performed an integrated analysis of genetic, epigenetic, and intratumor microbial factors to unravel the potential remodeling mechanisms of immune-cell infiltration (ICI) and tumorigenesis of colorectal cancer (CRC). We identified the components and structure of the intratumor microbiome as primary contributors to the difference in survival between ICI subtypes. Multiple tumor-infiltrating immune cells (TIICs) and immune-related genes were associated with intratumor microbial abundance. Additionally, we found that Clostridium was enriched in CRC patients who were nonsensitive to immune checkpoint blockade (ICB) therapy. We further provided clues that the intratumor microbes might influence the response to ICB therapy by mediating TIICs, especially MAIT (mucosa-associated invariant T) cells. Finally, three ICB-related TIICs and 22 of their associated microbes showed the potential to predict the response to ICB therapy (area under the receiver operating characteristic curve [AUC] = 89%). Our findings highlight the crucial role of intratumor microbes in affecting immune-cell infiltration patterns, prognosis, and therapy response of CRC and provide insights for improving current immunotherapeutic treatment strategies and prognosis for CRC patients. IMPORTANCE Using the multi-omics data from The Cancer Genome Atlas (TCGA) colorectal cancer (CRC) cohort, we estimated the tumor microenvironment (TME) infiltration patterns of patients and unraveled the interplay of gene expression, epigenetic modification, and the intratumor microbiome. This study suggests the impact of intratumor microbes on maintaining the tumor immune microenvironment in the pathogenesis of CRC and modulating the response to immune checkpoint blockade (ICB) therapy. We identified a set of combined features, including 3 ICB-related tumor-infiltrating immune cells (TIICs) and 22 of their associated microbes, that are predictive of ICB responses.

Akkermansia muciniphila and Lactobacillus plantarum ameliorate systemic lupus erythematosus by possibly regulating immune response and remodeling gut microbiota.

Systemic lupus erythematosus (SLE), characterized by persistent inflammation, is a complex autoimmune disorder that affects all organs, challenging clinical treatment. Dysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Modulating the gut microbiome is proposed as a promising approach for fine-running parts of the immune system, relieving systematic inflammation in multiple diseases. This study demonstrated that the administration of Akkermansia muciniphila and Lactobacillus plantarum contributed to an anti-inflammatory environment by decreasing IL-6 and IL-17 and increasing IL-10 levels in the circulation. The treatment of A. muciniphila and L. plantarum restored the intestinal barrier integrity to a different extent. In addition, both strains reduced the deposit of IgG in the kidney and improved renal function significantly. Further studies revealed distinct remodeling roles of A. muciniphila and L. plantarum administration on the gut microbiome. This work demonstrated essential mechanisms of how A. muciniphila and L. plantarum remodel gut microbiota and regulate the immune responses in the SLE mice model. IMPORTANCE Several pieces of research have demonstrated that certain probiotic strains contribute to regulating excessive inflammation and restoring tolerances in the SLE animal model. More animal trials combined with clinical studies are urgently needed to further elucidate the mechanisms for the effect of specific probiotic bacteria in preventing SLE symptoms and developing novel therapeutic targets. In this study, we explored the role of A. muciniphila and L. plantarum in ameliorating the SLE disease activity. Both A. muciniphila and L. plantarum treatment relieved the systemic inflammation and improved renal function in the SLE mouse model. We demonstrated that A. muciniphila and L. plantarum contributed to an anti-inflammatory environment by regulating cytokine levels in the circulation, restoring the intestinal barrier integrity, and remodeling the gut microbiome, however, to a different extent.

Biglycan regulated colorectal cancer progress by modulating enteric neuron-derived IL-10 and abundance of Bacteroides thetaiotaomicron.

Biglycan (BGN) is a proteoglycan with branch chains and highly expressed in enteric neurons in the tumor tissue of colorectal cancer (CRC), which is negatively associated with survival rates in patients with CRC. However, how the proteoglycan promotes the progress of CRC through interacting with bacteria and regulating the immune response of enteric neurons remains largely unknown. In the present study, we found that biglycan deficiency changed tumor distribution in a colitis-associated colon cancer model. Furthermore, we revealed that BGN deficiency inhibits tumor growth in an allograft tumor model and the migration of cancer cell by upregulating interleukin-10 expression in enteric neurons. Significantly, we demonstrated that biglycan deficiency enriched the abundance of Bacteroides thetaiotaomicron through competing with it for chondroitin sulfate to inhibit CRC progress. Our work provided new insights into the interaction between host proteoglycan and gut microbiota as well as the role of enteric neurons in the tumor microenvironment.

Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity.

Previous studies have shown that Lactobacillus species play a role in ameliorating colorectal cancer (CRC) in a mouse model. However, the underlying mechanisms remain largely unknown. Here, we found that administration of a probiotic strain, Lactobacillus plantarum L168 and its metabolite, indole-3-lactic acid, ameliorated intestinal inflammation, tumor growth, and gut dysbiosis. Mechanistically, we indicated that indole-3-lactic acid accelerated IL12a production in dendritic cells by enhancing H3K27ac binding at the enhancer regions of IL12a that contributed to priming CD8+ T cell immunity against tumor growth. Furthermore, indole-3-lactic acid was found to transcriptionally inhibit Saa3 expression related to cholesterol metabolism of CD8+ T cells through changing chromatin accessibility and subsequent enhancing function of tumor-infiltrating CD8+ T cells. Together, our findings provide new insights into the epigenetic regulation of probiotics-mediated anti-tumor immunity and suggest the potential of L. plantarum L168 and indole-3-lactic acid to develop therapeutic strategies for patients with CRC.

Efficacy of fecal microbiota transplantation in patients with Parkinson's disease: clinical trial results from a randomized, placebo-controlled design.

The occurrence and development of Parkinson's disease (PD) have been demonstrated to be related to gut dysbiosis, however, the impact of fecal microbiota transplantation (FMT) on microbiota engraftment in PD patients is uncertain. We performed a randomized, placebo-controlled trial at the Department of Neurology, Army Medical University Southwest Hospital in China (ChiCTR1900021405) from February 2019 to December 2019. Fifty-six participants with mild to moderate PD (Hoehn-Yahr stage 1-3) were randomly assigned to the FMT and placebo group, 27 patients in the FMT group and 27 in the placebo group completed the whole trial. During the follow-up, no severe adverse effect was observed, and patients with FMT treatment showed significant improvement in PD-related autonomic symptoms compared with the placebo group at the end of this trial (MDS-UPDRS total score, group×time effect, B = -6.56 [-12.98, -0.13], P < 0.05). Additionally, FMT improved gastrointestinal disorders and a marked increase in the complexity of the microecological system in patients. This study demonstrated that FMT through oral administration is clinically feasible and has the potential to improve the effectiveness of current medications in the clinical symptoms of PD patients.

Consistent activation of the ß-catenin pathway by Salmonella type-three secretion effector protein AvrA in chronically infected intestine.

Salmonella infection is a common public health problem that can become chronic and increase the risk of cancer. Live, mutated Salmonella is used to target cancer cells. However, few studies have addressed chronic Salmonella infection in vivo. AvrA is a Salmonella type-three secretion effector that is multifunctional, inhibiting intestinal inflammation and enhancing proliferation. ß-catenin is a key player in intestinal renewal, inflammation, and tumorigenesis. We hypothesize that in Salmonella-infected intestine, AvrA chronically activates the ß-catenin pathway and increases cell proliferation, thus deregulating the intestinal responses to bacterial infection. We followed mice with Salmonella infection for 27 wk and investigated the physiological effects and role of AvrA on ß-catenin in chronically infected intestine. We found that AvrA persistently regulated ß-catenin posttranslational modifications, including phosphorylation and acetylation. Moreover, the upstream regulator Akt, transcription factors, T cell factors, nuclear ß-catenin, and ß-catenin target genes were enhanced in mice infected with Salmonella-expressing AvrA. AvrA has a chronic functional role in promoting intestinal renewal. In summary, we have uncovered an essential role of Salmonella AvrA in chronically activating ß-catenin and impacting intestinal renewal in small intestine and colon. Our study emphasizes the importance of AvrA in chronic bacterial infection.

Fecal microbiota transplantation from young donor mice improves ovarian function in aged mice.

Advanced maternal age is characterized by declines in the quantity and quality of oocytes in the ovaries, and the aging process is accompanied by changes in gut microbiota composition. However, little is known about the relationship between gut microbiota and ovarian aging. By using fecal microbiota transplantation (FMT) to transplant material from young (5-week-old) into aged (42-week-old) mice, we find that the composition of gut microbiota in FMT-treated mice presents a "younger-like phenotype" and an increase of commensal bacteria, such as Bifidobacterium and Ruminococcaceae. Moreover, the FMT-treated mice show increased anti-inflammatory cytokine IL-4 and decreased pro-inflammatory cytokine IFN-γ. Fertility tests for assessing ovarian function reveal that the first litter size of female FMT-treated mice is significantly higher than that of the non-FMT group. Morphology analysis demonstrates a dramatic decrease in follicle atresia and apoptosis as well as an increase in cellular proliferation in the ovaries of the FMT-treated mice. Our results also show that FMT improves the immune microenvironment in aged ovaries, with decreased macrophages and macrophage-derived multinucleated giant cells (MNGCs). These results suggest that FMT from young donors could be a good choice for delaying ovarian aging.

Combined treatment with Rg1 and adipose-derived stem cells alleviates DSS-induced colitis in a mouse model.

BACKGROUND: Inflammatory bowel diseases, consisting of Crohn's disease and ulcerative colitis constitute chronic inflammatory conditions that may compromise the whole gastrointestinal tract as well as the colonic mucosa. Currently, there are no curative interventions for IBD, and all available treatments have side effects that limit their use. Adipose-derived stem cell (ADSC) treatment is a prospective treatment option for IBD. Previous findings indicated that ginsenoside (Rg1) dampened inflammatory diseases like colitis by inhibiting the binding of LPS to TLR4 on macrophages and restoring the Th17/Treg ratio. The purpose of this work was to investigate whether Rg1 can increase the influence of ADSC in a mouse model of colitis triggered by dextran sulfate sodium (DSS). METHODS: ADSC was intravenously inoculated into mice with DSS-triggered colitis, while Rg1 was delivered via oral gavage. Colon inflammation was assessed via body weight, colon length along with H&E staining. Serum cytokine levels were measured using ELISA. Besides, flow cytometry was adopted to determine the percentage, as well as FMI of immune cells in the spleen. The effects of simultaneous Rg1 and ADSC treatment on TLR4-MyD88 signaling were assessed via immunofluorescence. RESULTS: Rg1 and ADSC effectively alleviated the impacts of colon inflammation, weight loss, and colon length reduction along with histological score. Treatment with Rg1 and ADSC reduced serum levels of the proinflammatory cytokines, IL-1ß, TNF-α, IL-6, IL-4, and IL-17A and upregulated the level of immunosuppressive cytokine, IL-10. Compared with ADSC or Rg1 alone, combined treatment with Rg1 and ADSC significantly improved the structure of microbial community. Additionally, treatment with Rg1 plus ADSC selectively elevated the level of splenic regulatory T (Treg) cells and downregulated the proportion of T helper type 17 (Th17) cells, indicating restoration of intestinal homeostasis. Besides, we established that the combination of ADSC + Rg1 restored immunological balance more effectively than either ADSC or Rg1 alone, illustrating that Rg1's modulatory function on the gut microbiota may boost the impact of ADSCs in restoration of the immune balance. ADSC combined with Rg1 might downregulate the expression of TLR4 and MyD88, thereby suppressing TLR4-MyD8 signaling. The immunofluorescence results also suggested that co-therapy with Rg-1 and ADSC may optimize treatment strategies of IBD. CONCLUSIONS: Here, we find that the combination of Rg1 and ADSC alleviates DSS-induced colitis in a mouse model more efficiently than ADSC alone, indicating that Rg1 enhances the effect of ADSC against colitis.

Characterization of Changes and Driver Microbes in Gut Microbiota During Healthy Aging Using A Captive Monkey Model.

Recent population studies have significantly advanced our understanding of how age shapes the gut microbiota. However, the actual role of age could be inevitably confounded due to the complex and variable environmental factors in human populations. A well-controlled environment is thus necessary to reduce undesirable confounding effects, and recapitulate age-dependent changes in the gut microbiota of healthy primates. Herein we performed 16S rRNA gene sequencing, characterized the age-associated gut microbial profiles from infant to elderly crab-eating macaques reared in captivity, and systemically revealed the lifelong dynamic changes of the primate gut microbiota. While the most significant age-associated taxa were mainly found as commensals such as Faecalibacterium, the abundance of a group of suspicious pathogens such as Helicobacter was exclusively increased in infants, underlining their potential role in host development. Importantly, topology analysis indicated that the network connectivity of gut microbiota was even more age-dependent than taxonomic diversity, and its tremendous decline with age could probably be linked to healthy aging. Moreover, we identified key driver microbes responsible for such age-dependent network changes, which were further linked to altered metabolic functions of lipids, carbohydrates, and amino acids, as well as phenotypes in the microbial community. The current study thus demonstrates the lifelong age-dependent changes and their driver microbes in the primate gut microbiota, and provides new insights into their roles in the development and healthy aging of their hosts.

Prospective Study Reveals Host Microbial Determinants of Clinical Response to Fecal Microbiota Transplant Therapy in Type 2 Diabetes Patients.

Background: Increasing evidence shows that alterations in gut microbiome (GM) contribute to the development of type 2 diabetes mellitus (T2DM), and fecal microbiota transplantation (FMT) successfully treats various human diseases. However, the benefits of FMT therapy to T2DM patients remain unknown. Methods: We enrolled 17 patients with T2DM for nonblinded, one-armed intervention trial of FMT. A total of 20 healthy individuals were recruited as the baseline control. HbA1c% and metabolic parameter change were evaluated in 17 T2DM patients 12 weeks after they received FMT from healthy donors. The GM composition was characterized by 16S rRNA gene amplicon sequencing from fecal samples prior to and 12 weeks after FMT treatment. Results: We found that the GM of T2DM patients was reconstituted by FMT. We observed a statistically significant decrease in HbA1c% (from 7.565 ± 0.148 to 7.190 ± 0.210, p<0.01), blood glucose (from 8.483 ± 0.497 to 7.286 ± 0.454 mmol/L, p<0.01), and uric acid (from 309.4 ± 21.5 to 259.1 ± 15.8 µmol/L, p<0.01) while a significant increase in postprandial C-peptide (from 4.503 ± 0.600 to 5.471 ± 0.728 ng/ml, p<0.01) at 12 weeks after FMT. Closely evaluating the changes in these assays, we found individual variability in response to FMT treatment. Out of 17 T2DM patients, 11 were found to significantly improve T2DM symptoms. The FMT responders have significantly higher levels of the family Rikenellaceae and the genus Anaerotruncus (family Ruminococcaceae) in their pretreated fecal in comparison to nonresponders, which could predict the clinical response with an area under the curve of 0.83. Conclusion: Our findings suggest that certain T2DM patients can potentially benefit from FMT, and the pretreated abundance of Rikenellaceae and Anaerotruncus in the fecal of patients may serve as potential biomarkers for selecting T2DM patients to receive FMT.

Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration.

Gut microbes participate in pathogenesis by interacting with the host genome through epigenetic mechanisms, such as long non-coding RNAs. However, the mechanisms by which the microbiota induce expression alteration of long non-coding RNAs remains unclear. Here, we quantified the transcriptome alteration of human colon cell lines after being infected by a common enteric pathogen Salmonella typhimurium SL1344. We observed a widespread lncRNAs expression alteration. Among them, the elevated expression of LINC00152 was verified and proved to be induced by enteric bacteria-derived lipopolysaccharide (LPS). The inducible LINC00152 were found to inhibit Salmonella invasion and inflammation response. LINC00152 was overexpressed in tumors of the clinical CRC samples compared with adjacent normal tissues. Accordingly, we also demonstrated that overexpression of LINC00152 promoted the migration and invasion of colorectal cancer cells. Consistently, we observed an increased abundance of gram-negative bacteria and LPS in tumors tissue. Taken together, the above data implicated that enriched gram-negative bacteria in tumor tissue might promote tumor growth through modulating the expression of LINC00152. Furthermore, we demonstrated that LPS upregulated the expression of LINC00152 by introducing histone lactylation on its promoter and decreasing the binding efficiency of the repressor, YY1, to it. Our results provide new insights into how enterobacteria affect host epigenetics in human disease.

The landscape in the gut microbiome of long-lived families reveals new insights on longevity and aging - relevant neural and immune function.

Human longevity has a strong familial and genetic component. Dynamic characteristics of the gut microbiome during aging associated with longevity, neural, and immune function remained unknown. Here, we aim to reveal the synergistic changes in gut microbiome associated with decline in neural and immune system with aging and further obtain insights into the establishment of microbiome homeostasis that can benefit human longevity. Based on 16S rRNA and metagenomics sequencing data for 32 longevity families including three generations, centenarians, elderly, and young groups, we found centenarians showed increased diversity of gut microbiota, severely damaged connection among bacteria, depleted in microbial-associated essential amino acid function, and increased abundance of anti-inflammatory bacteria in comparison to young and elderly groups. Some potential probiotic species, such as Desulfovibrio piger, Gordonibacter pamelaeae, Odoribacter splanchnicus, and Ruminococcaceae bacterium D5 were enriched with aging, which might possibly support health maintenance. The level of Amyloid-ß (Aß) and brain-derived neurotrophic factor (BDNF) related to neural function showed increased and decreased with aging, respectively. The elevated level of inflammatory factors was observed in centenarians compared with young and elderly groups. The enriched Bacteroides fragilis in centenarians might promote longevity through up-regulating anti-inflammatory factor IL-10 expression to mediate the critical balance between health and disease. Impressively, the associated analysis for gut microbiota with the level of Aß, BDNF, and inflammatory factors suggests Bifidobacterium pseudocatenulatum could be a particularly beneficial bacteria in the improvement of impaired neural and immune function. Our results provide a rationale for targeting the gut microbiome in future clinical applications of aging-related diseases and extending life span.Abbreviations: 16S rRNA: 16S ribosomal RNA; MAGs: Metagenome-assembled genomes; ASVs: Amplicon sequence variants; DNA: Deoxyribonucleic acid; FDR: False discovery rate: KEGG: Kyoto Encyclopedia of Genes and Genomes; PCoA: Principal coordinates analysis; PCR: Polymerase chain reaction; PICRUSt: Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; Aß: Amyloid-ß (Aß); BDNF: Brain-derived neurotrophic factor.