Cognition and gut microbiota in schizophrenia spectrum and mood disorders: A systematic review.

FRILEUX, M., BOLTRI M. and al. Cognition and Gut microbiota in schizophrenia spectrum and mood disorders: a Systematic Review. NEUROSCI BIOBEHAV REV (1) 2024 Schizophrenia spectrum disorders and major mood disorders are associated with cognitive impairments. Recent studies suggest a link between gut microbiota composition and cognitive functioning. Here, we review the relationship between gut microbiota and cognition in these disorders. To do this, we conducted a systematic review, searching Cochrane Central Register of Controlled Trials, EBSCOhost, Embase, Pubmed, Scopus, and Web of Science. Studies were included if they investigated the relationship between gut microbiota composition and cognitive function through neuropsychological assessments in patients with bipolar, depressive, schizophrenia spectrum, and other psychotic disorders. Ten studies were identified. Findings underscore a link between gut dysbiosis and cognitive impairment. This relationship identified specific taxa (Haemophilus, Bacteroides, and Alistipes) as potential contributors to bolstered cognitive performance. Conversely, Candida albicans, Toxoplasma gondii, Streptococcus and Deinococcus were associated with diminished performance on cognitive assessments. Prebiotics and probiotics interventions were associated with cognitive enhancements, particularly executive functions. These results emphasize the role of gut microbiota in cognition, prompting further exploration of the underlying mechanisms paving the way toward precision psychiatry.

Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome.

BACKGROUND: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. OBJECTIVES: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. DESIGN: Cross-sectional study. SETTING: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). PARTICIPANTS: Control participants of the Luxembourg Parkinson's Study. MEASUREMENTS: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0-10, 11-16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. RESULTS: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15-0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. CONCLUSIONS: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.

Exertional heat stroke-induced changes in gut microbiota cause cognitive impairment in mice.

BACKGROUND: The incidence of exertional heat stroke (EHS) escalates during periods of elevated temperatures, potentially leading to persistent cognitive impairment postrecovery. Currently, effective prophylactic or therapeutic measures against EHS are nonexistent. METHODS: The selection of days 14 and 23 postinduction for detailed examination was guided by TEM of neuronal cells and HE staining of intestinal villi and the hippocampal regions. Fecal specimens from the ileum and cecum at these designated times were analyzed for changes in gut microbiota and metabolic products. Bioinformatic analyses facilitated the identification of pivotal microbial species and metabolites. The influence of supplementing these identified microorganisms on behavioral outcomes and the expression of functional proteins within the hippocampus was subsequently assessed. RESULTS: TEM analyses of neurons, coupled with HE staining of intestinal villi and the hippocampal region, indicated substantial recovery in intestinal morphology and neuronal injury on Day 14, indicating this time point for subsequent microbial and metabolomic analyses. Notably, a reduction in the Lactobacillaceae family, particularly Lactobacillus murinus, was observed. Functional annotation of 16S rDNA sequences suggested diminished lipid metabolism and glycan biosynthesis and metabolism in EHS models. Mice receiving this intervention (EHS + probiotics group) exhibited markedly reduced cognitive impairment and increased expression of BDNF/TrKB pathway molecules in the hippocampus during behavioral assessment on Day 28. CONCLUSION: Probiotic supplementation, specifically with Lactobacillus spp., appears to mitigate EHS-induced cognitive impairment, potentially through the modulation of the BDNF/TrKB signaling pathway within the hippocampus, illustrating the therapeutic potential of targeting the gut-brain axis.

Role of the gut microbiota in complications after ischemic stroke.

Ischemic stroke (IS) is a serious central nervous system disease. Post-IS complications, such as post-stroke cognitive impairment (PSCI), post-stroke depression (PSD), hemorrhagic transformation (HT), gastrointestinal dysfunction, cardiovascular events, and post-stroke infection (PSI), result in neurological deficits. The microbiota-gut-brain axis (MGBA) facilitates bidirectional signal transduction and communication between the intestines and the brain. Recent studies have reported alterations in gut microbiota diversity post-IS, suggesting the involvement of gut microbiota in post-IS complications through various mechanisms such as bacterial translocation, immune regulation, and production of gut bacterial metabolites, thereby affecting disease prognosis. In this review, to provide insights into the prevention and treatment of post-IS complications and improvement of the long-term prognosis of IS, we summarize the interaction between the gut microbiota and IS, along with the effects of the gut microbiota on post-IS complications.

The relationship between the gut microbiota and oxidative stress in the cognitive function of schizophrenia: A pilot study in China.

Cognitive impairment is a core symptom of schizophrenia. The gut microbiota (GM) and oxidative stress may play important roles in the pathophysiological mechanisms of cognitive impairment. This study aimed to explore the relationship between GM and oxidative stress in the cognitive function of schizophrenia. GM obtained by 16S RNA sequencing and serum superoxide dismutase (SOD) levels from schizophrenia patients (N = 68) and healthy controls (HCs, N = 72) were analyzed. All psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Correlation analysis was used to explore the relationship between GM, SOD, and cognitive function. Machine learning models were used to identify potential biomarkers. Compared to HCs, the relative abundances of Collinsella, undefined Ruminococcus, Lactobacillus, Eubacterium, Mogibacterium, Desulfovibrio, Bulleidia, Succinivibrio, Corynebacterium, and Atopobium were higher in patients with schizophrenia, but Faecalibacterium, Anaerostipes, Turicibacter, and Ruminococcus were lower. In patients with schizophrenia, the positive factor, general factor, and total score of MCCB positively correlated with Lactobacillus, Collinsella, and Lactobacillus, respectively; SOD negatively correlated with Eubacterium, Collinsella, Lactobacillus, Corynebacterium, Bulleidia, Mogibacterium, and Succinivibrio, but positively correlated with Faecalibacterium, Ruminococcus, and MCCB verbal learning index scores; Faecalibacterium and Turicibacter were positively correlated with MCCB visual learning index scores and speed of processing index scores, respectively. Our findings revealed a correlation between SOD and GM and confirmed that cognitive dysfunction in patients with schizophrenia involves abnormal SOD levels and GM changes.

Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

Current Understanding of the Roles of Gut-Brain Axis in the Cognitive Deficits Caused by Perinatal Stress Exposure.

The term 'perinatal environment' refers to the period surrounding birth, which plays a crucial role in brain development. It has been suggested that dynamic communication between the neuro-immune system and gut microbiota is essential in maintaining adequate brain function. This interaction depends on the mother's status during pregnancy and/or the newborn environment. Here, we show experimental and clinical evidence that indicates that the perinatal period is a critical window in which stress-induced immune activation and altered microbiota compositions produce lasting behavioral consequences, although a clear causative relationship has not yet been established. In addition, we discuss potential early treatments for preventing the deleterious effect of perinatal stress exposure. In this sense, early environmental enrichment exposure (including exercise) and melatonin use in the perinatal period could be valuable in improving the negative consequences of early adversities. The evidence presented in this review encourages the realization of studies investigating the beneficial role of melatonin administration and environmental enrichment exposure in mitigating cognitive alteration in offspring under perinatal stress exposure. On the other hand, direct evidence of microbiota restoration as the main mechanism behind the beneficial effects of this treatment has not been fully demonstrated and should be explored in future studies.

Bifidobacterium breve HNXY26M4 Attenuates Cognitive Deficits and Neuroinflammation by Regulating the Gut-Brain Axis in APP/PS1 Mice.

Alzheimer's disease (AD) is a neurodegenerative disease, pathological markers of which are amyloid plaques and neurofibrillary tangles. As a key node of gut-brain axis, gut microbiota is increasingly associated with changes in cognitive behaviors and brain function. Psychobiotics are known to benefit patients with neurodegenerative diseases by the production and deliberation of neuroactive substances. However, psychobiotics are strain-specific probiotics, and their neuroprotective effects on the brain and modulation effects on the gut microbiome are not generalizable. In this study, we investigated the effects of Bifidobacterium breve HNXY26M4 in APP/PS1 mice. By assessing the alterations associated with brain function, we found that B. breve HNXY26M4 attenuated cognitive deficits and suppressed neuroinflammation and synaptic dysfunction in APP/PS1 mice. Moreover, by determining the modulation effects of B. breve HNXY26M4 on gut homeostasis, we identified that B. breve HNXY26M4 supplementation restored the composition of gut microbiota and short-chain fatty acids, as well as enhanced the function of the intestinal barrier. These findings indicate that microbiome-derived acetate and butyrate modulated by B. breve HNXY26M4 administration may be transported to the brain through the blood-brain barrier, and thus confer neuroprotective effects against AD-associated brain deficits and inflammation via the gut-brain axis.

Lactobacillaceae improve cognitive dysfunction via regulating gut microbiota and suppressing Aß deposits and neuroinflammation in APP/PS1 mice.

Alzheimer's disease (AD), the most prevalent neurodegenerative disease, has a significant relationship with alteration of the gut microbiota (GM), and the GM-gut-brain axis has been explored to find novel therapeutic approaches for AD. The present study aimed to evaluate the effect of human Lactobacillaceae (HLL) on cognitive function in APP/PS1 mice. The results showed that HLL treatment significantly improved the cognitive function of mice via MWM and NOR tests. Furthermore, the expression of Aß plaques, tau phosphorylation and neuroinflammation were markedly reduced in the hippocampus. Meanwhile, HLL treatment significantly increased the activity of GSH-PX and decreased the expression levels of IL-6 and MDA in the brain, and simultaneously increased the abundance of beneficial bacteria and restrained pathogenic bacteria in the intestine. Interestingly, significant correlations were observed between significant changes in abundance of GMs and AD-related markers. Collectively, these findings reveal that HLL is a promising therapeutic agent and potential probiotics, which might improve the cognitive function and AD pathologies.

Comparing the gut microbiome of obese, African American, older adults with and without mild cognitive impairment.

Those with mild cognitive impairment (MCI), a precursor to dementia, have a gut microbiome distinct from healthy individuals, but this has only been shown in healthy individuals, not in those exhibiting several risk factors for dementia. Using amplicon 16S rRNA gene sequencing in a case-control study of 60 older (ages 55-76), obese, predominately female, African American adults, those with MCI (cases) had different gut microbiota profiles than controls. While microbial community diversity was similar between cases and controls, the abundances of specific microbial taxa weren't, such as Parabacteroides distasonis (lower in cases) and Dialister invisus (higher in cases). These differences disappeared after adjusting for markers of oxidative stress and systemic inflammation. Cognitive scores were positively correlated with levels of Akkermansia muciniphila, a bacterium associated with reduced inflammation. Our study shows that gut microbial composition may be associated with inflammation, oxidative stress, and MCI in those at high risk for dementia.

Predicting the Rapid Progression of Mild Cognitive Impairment by Intestinal Flora and Blood Indicators through Machine Learning Method.

INTRODUCTION: The aim of the work was to establish a prediction model of mild cognitive impairment (MCI) progression based on intestinal flora by machine learning method. METHOD: A total of 1,013 patients were recruited, in which 87 patients with MCI finished a two-year follow-up. To establish a prediction model, 61 patients were randomly divided into a training set and 26 patients were divided into a testing set. A total of 121 features including demographic characteristics, hematological indicators, and intestinal flora abundance were analyzed. RESULTS: Of the 87 patients who finished a two-year follow-up, 44 presented rapid progression. Model 1 was established based on 121 features with the accuracy 85%, sensitivity 85%, and specificity 83%. Model 2 was based on the first fifteen features of model 1 (triglyceride, uric acid, alanine transaminase, F-Clostridiaceae, G-Megamonas, S-Megamonas, G-Shigella, G-Shigella, S-Shigella, average hemoglobin concentration, G-Alistipes, S-Collinsella, median cell count, average hemoglobin volume, low-density lipoprotein), with the accuracy 97%, sensitivity 92%, and specificity 100%. Model 3 was based on the first ten features of model 1, with the accuracy 97%, sensitivity 86%, and specificity 100%. Other models based on the demographic characteristics, hematological indicators, or intestinal flora abundance features presented lower sensitivity and specificity. CONCLUSION: The 15 features (including intestinal flora abundance) could establish an effective model for predicting rapid MCI progression.

Altered Gut Microbiota and Its Clinical Relevance in Mild Cognitive Impairment and Alzheimer's Disease: Shanghai Aging Study and Shanghai Memory Study.

Altered gut microbiota has been reported in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Previous research has suggested that specific bacterial species might be associated with the decline of cognitive function. However, the evidence was insufficient, and the results were inconsistent. To determine whether there is an alteration of gut microbiota in patients with MCI and AD and to investigate its correlation with clinical characteristics, the fecal samples from 94 cognitively normal controls (NC), 125 participants with MCI, and 83 patients with AD were collected and analyzed by 16S ribosomal RNA sequencing. The overall microbial compositions and specific taxa were compared. The clinical relevance was analyzed. There was no significant overall difference in the alpha and beta diversity among the three groups. Patients with AD or MCI had increased bacterial taxa including Erysipelatoclostridiaceae, Erysipelotrichales, Patescibacteria, Saccharimonadales, and Saccharimonadia, compared with NC group (p < 0.05), which were positively correlated with APOE 4 carrier status and Clinical Dementia Rating (correlation coefficient: 0.11~0.31, p < 0.05), and negatively associated with memory (correlation coefficient: −0.19~−0.16, p < 0.01). Our results supported the hypothesis that intestinal microorganisms change in MCI and AD. The alteration in specific taxa correlated closely with clinical manifestations, indicating the potential role in AD pathogenesis.

Axillary Microbiota Is Associated with Cognitive Impairment in Parkinson's Disease Patients.

Cognitive impairment (CI) is among the most common non-motor symptoms of Parkinson's disease (PD), with a substantially negative impact on patient management and outcome. The development and progression of CI exhibits high interindividual variability, which requires better diagnostic and monitoring strategies. PD patients often display sweating disorders resulting from autonomic dysfunction, which has been associated with CI. Because the axillary microbiota is known to change with humidity level and sweat composition, we hypothesized that the axillary microbiota of PD patients shifts in association with CI progression, and thus can be used as a proxy for classification of CI stages in PD. We compared the axillary microbiota compositions of 103 PD patients (55 PD patients with dementia [PDD] and 48 PD patients with mild cognitive impairment [PD-MCI]) and 26 cognitively normal healthy controls (HC). We found that axillary microbiota profiles differentiate HC, PD-MCI, and PDD groups based on differential ranking analysis, and detected an increasing trend in the log ratio of Corynebacterium to Anaerococcus in progression from HC to PDD. In addition, phylogenetic factorization revealed that the depletion of the Anaerococcus, Peptoniphilus, and W5053 genera is associated with PD-MCI and PDD. Moreover, functional predictions suggested significant increases in myo-inositol degradation, ergothioneine biosynthesis, propionate biosynthesis, menaquinone biosynthesis, and the proportion of aerobic bacteria and biofilm formation capacity, in parallel to increasing CI. Our results suggest that alterations in axillary microbiota are associated with CI in PD. Thus, axillary microbiota has the potential to be exploited as a noninvasive tool in the development of novel strategies. IMPORTANCE Parkinson's disease (PD) is the second most common neurodegenerative disease. Cognitive impairment (CI) in PD has significant negative impacts on life quality of patients. The emergence and progression of cognitive impairment shows high variability among PD patients, and thus requires better diagnostic and monitoring strategies. Recent findings indicate a close link between autonomic dysfunction and cognitive impairment. Since thermoregulatory dysfunction and skin changes are among the main manifestations of autonomic dysfunction in PD, we hypothesized that alterations in the axillary microbiota may be useful for tracking cognitive impairment stages in PD. To our knowledge, this the first study characterizing the axillary microbiota of PD patients and exploring its association with cognitive impairment stages in PD. Future studies should include larger cohorts and multicenter studies to validate our results and investigate potential biological mechanisms.

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy.

Patients who recover from nosocomial pneumonia oftentimes exhibit long-lasting cognitive impairment comparable with what is observed in Alzheimer's disease patients. We previously hypothesized that the lung endothelium contributes to infection-related neurocognitive dysfunction, because bacteria-exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long-term potentiation in the hippocampus. However, the full-length lung and endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection-induced endothelial cytotoxic tau triggers neuronal tau aggregation. Here, we demonstrate that lung endothelial cells express a big tau isoform and three additional tau isoforms that are similar to neuronal tau, each containing four microtubule-binding repeat domains, and that tau is expressed in lung capillaries in vivo. To test whether infection elicits endothelial tau capable of causing transmissible tau aggregation, the cells were infected with Pseudomonas aeruginosa. The infection-induced tau released from endothelium into the medium-induced neuronal tau aggregation in reporter cells, including reporter cells that express either the four microtubule-binding repeat domains or the full-length tau. Infection-induced release of pathological tau variant(s) from endothelium, and the ability of the endothelial-derived tau to cause neuronal tau aggregation, was abolished in tau knockout cells. After bacterial lung infection, brain homogenates from WT mice, but not from tau knockout mice, initiated tau aggregation. Thus, we conclude that bacterial pneumonia initiates the release of lung endothelial-derived cytotoxic tau, which is capable of propagating a neuronal tauopathy.

Fecal Volatile Organic Compounds and Microbiota Associated with the Progression of Cognitive Impairment in Alzheimer's Disease.

Metabolites produced by an altered gut microbiota might mediate the effects in the brain. Among metabolites, the fecal volatile organic compounds (VOCs) are considered to be potential biomarkers. In this study, we examined both the VOCs and bacterial taxa in the feces from healthy subjects and Alzheimer's disease (AD) patients at early and middle stages. Remarkably, 29 fecal VOCs and 13 bacterial genera were differentiated from the healthy subjects and the AD patients. In general, higher amounts of acids and esters were found in in the feces of the AD patients and terpenes, sulfur compounds and aldehydes in the healthy subjects. At the early stage of AD, the most relevant VOCs with a higher abundance were short-chain fatty acids and their producing bacteria, Faecalibacterium and Lachnoclostridium. Coinciding with the development of dementia in the AD patients, parallel rises of heptanoic acid and Peptococcus were observed. At a more advanced stage of AD, the microbiota and volatiles shifted towards a profile in the feces with increases in hexanoic acid, Ruminococcus and Blautia. The most remarkable VOCs that were associated with the healthy subjects were 4-ethyl-phenol and dodecanol, together with their possible producers Clostridium and Coprococcus. Our results revealed a VOCs and microbiota crosstalk in AD development and their profiles in the feces were specific depending on the stage of AD. Additionally, some of the most significant fecal VOCs identified in our study could be used as potential biomarkers for the initiation and progression of AD.

Elderly Patients with Mild Cognitive Impairment Exhibit Altered Gut Microbiota Profiles.

BACKGROUND: As a transitional state between normal aging and Alzheimer's disease (AD), mild cognitive impairment (MCI) is characterized by a worse cognitive decline than that of natural aging. The association between AD and gut microbiota has been reported in a number of studies; however, microbial research regarding MCI remains limited. METHODS: This study examined 48 participants, of whom 22 were MCI cases and 26 were normal control cases. Fecal samples were collected for 16S ribosomal RNA (rRNA) quantitative arrays and bioinformatics analysis. RESULTS: A principal coordinates analysis (PCoA) and nonmetric multidimensional scaling (NMDS) both demonstrated that the microbial composition of participants with MCI deviated from that of healthy control participants. Multiple bacterial species were significantly increased (e.g., Staphylococcus intermedius) or decreased (e.g., Bacteroides salyersiae) in samples from the MCI group. CONCLUSION: The composition of gut microbiota differed between normal control and MCI cases. This is the first study to identify a signature series of species in the gut microbiota of individuals with MCI. The results provide a new direction for the future development of an early diagnosis and probiotic regimen.

Predictive Value of Gut Microbiome for Cognitive Impairment in Patients with Hypertension.

A connection exists between hypertension (HTN) and cognitive impairment (CI) or gut microbiota (GM) and neuropsychiatric disease. However, the link between GM and HTNCI has not been illustrated. This study endeavoured to profile the landscape of GM in HTNCI patients and evaluate the value of GM as HTNCI biomarkers. We recruited 128 patients with hypertension and assigned them to two groups of different MoCA scores. Clinical and biological data were recorded. GM composition was illustrated with 16S ribosomal RNA sequencing, and the dominant species were identified by linear discriminant analysis Effect Size (LEfSe). It showed higher abundance of TM7 and lower abundances of Veillonella and Peptoniphilus in the HTNCI group than in the HTN without cognitive impairment (HTNnCI) group. We next clarified the link between GM and MoCA scores or HTNCI factors. KEGG analysis revealed the involvement of decreased bile secretion. An evident correlation showed up between HTNCI and Veillonella abundance (P = 0.0340). We concluded that some representative GM species, especially Veillonella, could predict cognitive impairment in hypertension patients, making them potential benchmarks of HTNCI.

Lactobacillus rhamnosus and Bifidobacterium longum alleviate colitis and cognitive impairment in mice by regulating IFN-γ to IL-10 and TNF-α to IL-10 expression ratios.

Gut lactobacilli and bifidobacteria on the immune homeostasis. Therefore, to understand the mechanism in vivo, we selected human fecal Lactobacillus rhamnosus NK210 and Bifidobacterium longum NK219, which strongly suppressed the IFN-γ to IL-10 expression (IIE) ratio in lipopolysaccharide-stimulated macrophages. Thereafter, we examined their effects on the endotoxin, antibiotics, or antitumor drug-stimulated immune imbalance in mice. Intraperitoneal injection of lipopolysaccharide and oral gavage of ampicillin increased IFN-γ and TNF-α expression in the spleen, colon, and hippocampus, while IL-10 expression decreased. However, intraperitoneal injection of cyclophosphamide suppressed IFN-γ, TNF-α, and IL-10 expression. LPS exposure induced splenic natural killer cell cytotoxicity against YAC-1 cells (sNK-C) and peritoneal macrophage phagocytosis against Candida albicans (pMA-P) activities, while cyclophosphamide and ampicillin treatments suppressed sNK-C and pMA-P activities. However, LPS, ampicillin, cyclophosphamide all increased IIE and TNF-α to IL-10 expression (TIE) ratios. Oral administration of NK210 and/or NK219 significantly reduced LPS-induced sNK-C, pMA-P, and IFN-γ expression, while cyclophosphamide- or ampicillin-suppressed sNK-C and pMA-P activities, cyclophosphamide-suppressed IFN-γ, TNF-α, and IL-10 expression, and ampicillin-suppressed IL-10 expression increased. Nevertheless, they suppressed LPS-, ampicillin-, or cyclophosphamide-induced IIE and TIE ratios, cognitive impairment, and gut dysbiosis. In particular, NK219, but not NK210, increased the IIE expression ratio in vitro and in vivo, and enhanced sNK-C and pMA-P activities in normal control mice, while cognitive function and gut microbiota composition were not significantly affected. These findings suggest that NK210, Lactobacillus sp, and NK219, Bifidobacterium additively or synergistically alleviate gut dysbiosis, inflammation, and cognitive impairment with immune imbalance by controlling IIE and TIE ratios.

Identification of Faecalibacterium prausnitzii strains for gut microbiome-based intervention in Alzheimer's-type dementia.

Evidence linking the gut-brain axis to Alzheimer's disease (AD) is accumulating, but the characteristics of causally important microbes are poorly understood. We perform a fecal microbiome analysis in healthy subjects and those with mild cognitive impairment (MCI) and AD. We find that Faecalibacterium prausnitzii (F. prausnitzii) correlates with cognitive scores and decreases in the MCI group compared with the healthy group. Two isolated strains from the healthy group, live Fp360 and pasteurized Fp14, improve cognitive impairment in an AD mouse model. Whole-genome comparison of isolated strains reveals specific orthologs that are found only in the effective strains and are more abundant in the healthy group compared with the MCI group. Metabolome and RNA sequencing analyses of mouse brains provides mechanistic insights into the relationship between the efficacy of pasteurized Fp14, oxidative stress, and mitochondrial function. We conclude that F. prausnitzii strains with these specific orthologs are candidates for gut microbiome-based intervention in Alzheimer's-type dementia.

The imbalance of Th17/Treg via STAT3 activation modulates cognitive impairment in P. gingivalis LPS-induced periodontitis mice.

Periodontitis is one of the most common oral diseases worldwide, and it is associated with various systemic diseases, including cognitive diseases. STAT3 regulates the inflammatory cascade and influences adaptive immunity by modulating Th17/Treg cell differentiation. In this study, we aimed to explore the effect of adaptive immunity inside and outside the brain on the association between periodontitis and cognitive impairment and understand the role of the STAT3 signaling pathway. We established Porphyromonas gingivalis LPS-induced periodontitis mice models by injecting P. gingivalis LPS into the gingival sulcus of mice. Behavioral tests showed that learning and memory abilities were impaired. The flow cytometry data showed an imbalance in the Th17/Treg ratio in the blood and brain samples of the mice. The expression of Th17-related cytokines (IL-1ß, IL-17A, IL-21, and IL-22) increased, whereas that of Treg-related cytokines (IL-2 and IL-10) decreased in both the blood and the brain. The level of LPS increased and the STAT3 signaling pathway was activated during this process. These effects were reversed by C188-9, a STAT3 inhibitor. In conclusion, P. gingivalis LPS-induced periodontitis may promote the occurrence and progression of cognitive impairment by modulating the Th17/Treg balance inside and outside the brain. The STAT3 signaling pathway may have immunoregulatory effects on the mouth-to-brain axis.