Neuroimmunomodulation最新文献

Introduction: Chronic stress is a major burden in our society and increases the risk for various somatic and mental diseases, in part via promoting chronic low-grade inflammation. Interestingly, the vulnerability for chronic stress during adulthood varies widely among individuals, with some being more resilient than others. For instance, women, relative to men, are at higher risk for developing typical stress-related diseases, including depression and post-traumatic stress disorder (PTSD). Moreover, the experience of early life adversity (ELA) may increase an individuals' vulnerability for chronic stress during adulthood (CAS), possibly due to its association with chronic inflammation. Because severe consequences of stress-induced immune activation are a dysregulated endochondral ossification, delayed long-bone growth, and bone regeneration following fracture, the aim of this study was to investigate the sex-specific effects of ELA alone or in combination with CAS on bone. As enhancement of an individuals' immunoregulatory potential by repeated administrations of a heat-inactivated preparation of Mycobacterium vaccae NCTC (National Collection of Type Cultures) 11659 has been shown to promote stress resilience in mice, we further aimed to investigate if M. vaccae NCTC 11659 also protects against the negative effects of ELA/CAS on bone.

Methods: Male and female C57BL/6N mice were subjected to ELA using a maternal separation (MS) model. CAS was induced by either using the chronic subordinate colony housing (CSC) paradigm in males or the social instability paradigm (SIP) in females. The effects on bone were evaluated by µCT, histological, and gene expression analysis. M. vaccae NCTC 11659 was administered repeatedly s.c. prior to CAS.

Results: No cumulative impact of ELA and CAS on bone could be detected. Female mice seem to be more susceptible to ELA while male mice to CAS. Importantly, repeated M. vaccae NCTC 11659 administrations were able to mitigate the negative consequences of stress on bone in both sexes.

Conclusion: Our results support the hypotheses that the negative effects of ELA and CAS on bone are highly sex-dependent. Moreover, repeated s.c. administrations with immunoregulatory microorganisms might be a future therapeutic option for stress-related bone disorders.

Introduction: The microbiome-gut-brain axis, by modulating bidirectional immune, metabolic, and neural signaling pathways in the host, has emerged as a target for the prevention and treatment of psychiatric and neurological disorders. Oral administration of the probiotic bacterium Lactobacillus rhamnosus GG (LGG; ATCC 53103) exhibits anti-inflammatory effects, although the precise mechanisms by which LGG benefits host physiology and behavior are not known. The goal of this study was to explore the general effects of LGG on the cerebrospinal fluid (CSF) proteome and a biological signature of anti-inflammatory signaling in the central nervous system (CNS) of undisturbed, adult male rats.

Methods: Liquid chromatography-tandem mass spectrometry-based proteomics were conducted using CSF samples collected after 21 days of oral treatment with live LGG (3.34 × 107 colony-forming units (CFU)/mL in the drinking water (resulting in an estimated delivery of ∼1.17 × 109 CFU/day/rat) or water vehicle. Gene enrichment analysis (using DAVID, v. 6.8) and protein-protein interactions (using STRING, v. 11) were used to explore physiological network changes in CSF. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was performed to assess gene expression changes of anti-inflammatory cytokines in the hippocampus. Genes associated with anti-inflammatory signaling that were analyzed included Il10, Tgfb1, Il4, and IL-4-responsive genes, Cd200, Cd200r1, and Mrc1 (Cd206).

Results: Oral LGG administration altered the abundance of CSF proteins, increasing the abundance of five proteins (cochlin, NPTXR, reelin, Sez6l, and VPS13C) and decreasing the abundance of two proteins (CPQ, IGFBP-7) in the CSF. Simultaneously, LGG increased the expression of Il10 mRNA, encoding the anti-inflammatory cytokine interleukin 10, in the hippocampus.

Conclusion: Oral LGG altered the abundance of CSF proteins associated with extracellular scaffolding, synaptic plasticity, and glutamatergic signaling. These data are consistent with the hypothesis that oral administration of LGG improves memory and cognition, and promotes a physiological resilience to neurodegenerative disease, by increasing glutamatergic signaling and promoting an anti-inflammatory environment in the brain.

Background: Pregnancy and childbirth are accompanied by widespread maternal physiological adaptations and hormonal shifts that have been suggested to result in a period of vulnerability for the development of mood disorders such as postpartum depression (PPD). There is also evidence of peripartum changes in the composition of the gut microbiota, but the potential contribution of intestinal microbes to the adaptations, or subsequent vulnerabilities, during this period are unknown.

Summary: Here, we outline key pathways involved in peripartum adaptations including GABAergic signaling, oxytocin, and immunomodulation that are also associated with susceptibility to mood disorders and present evidence that these pathways are modulated by gut microbes. We also discuss the therapeutic potential of the microbiota-gut-brain axis in PPD and identify future directions for research to help realize this potential.

Key messages: Peripartum adaptations are associated with shifts in gut microbial composition. Disruption of GABAergic, oxytocin, and immunomodulatory pathways may contribute to vulnerability of mood disorders including PPD. These key adaptive pathways are modulated by intestinal microbes suggesting a role for the gut microbiota in determining susceptibility to PPD. More research is needed to confirm relationship between gut microbes and PPD and to gain the mechanistic understanding required to realize the therapeutic potential of microbiota-gut-brain axis in this mood disorder.

Introduction: Common mental disorders, such as anxiety disorders, depression, and posttraumatic stress disorder (PTSD), present a substantial health and economic burden. The gut microbiome has been associated with these psychiatric disorders via the microbiome-gut-brain axis. However, previous studies have focused on the associations between the gut microbiome and common mental disorders in European, North American, and Asian populations. As part of the saNeuroGut Initiative, we assessed associations between gut microbial composition and self-reported symptoms of anxiety, depression, and posttraumatic stress (PTS) among South African adults.

Methods: Participants completed validated, online self-report questionnaires to evaluate symptoms of state anxiety, trait anxiety, depression, and PTSD. Eighty-six stool-derived microbial DNA samples underwent sequencing of the V4 region of the 16S rRNA gene to characterise gut bacterial taxa in the sample.

Results: No significant associations were observed between symptom severity scores and alpha (Shannon and Simpson indices) and beta (Aitchison distances) diversity metrics. Linear regression models revealed that the abundances of Catenibacterium, Collinsella, and Holdemanella were significantly positively associated with the severity of PTS symptoms.

Conclusion: Catenibacterium, Collinsella, and Holdemanella have each previously been associated with various psychiatric disorders, with Catenibacterium having been positively associated with symptoms of PTSD in another South African cohort. This study sheds light on the relationship between the human gut microbiome and symptoms of anxiety, depression, and PTS in a South African adult sample.

Background: The gut microbiota is increasingly recognized as a critical regulator of brain function, influencing neurodevelopment, brain physiology, and disease vulnerability in part through its interactions with microglia, the resident immune cells of the central nervous system. Microbial metabolites, beginning prenatally and persisting throughout the lifespan, modulate fundamental aspects of microglial biology.

Summary: Microglia from germ-free mice exhibit persistent immaturity, altered energy metabolism, and blunted inflammatory responses, which can be partially reversed by microbial colonization or supplementation with specific bacterial metabolites. Short-chain fatty acids, tryptophan-derived indoles, and secondary bile acids have emerged as key microbial mediators that regulate microglial development, metabolism, and immune function, whereas certain inflammatory metabolites, such as trimethylamine n-oxide, disrupt microglial homeostasis, and worsen neurodegeneration.

Key messages: These findings reveal distinct metabolite-driven pathways linking microbial composition to microglial phenotypes, positioning the microbiome as a potential key influencer of neurodevelopmental trajectories and the pathophysiology of psychiatric and neurological disorders. Despite recent advances, major knowledge gaps persist in understanding the precise molecular intermediaries and mechanisms through which metabolite signaling to microglia shapes susceptibility or resilience to brain-based disorders. Understanding both the bacterial metabolomic landscape and its collective impact on microglial programming holds substantial therapeutic promise, offering avenues to target microbial metabolite production or administer them directly to modulate disease susceptibility.

Introduction: Thyroid hormone homeostasis during pregnancy is crucial for proper neurodevelopment and cognitive capacity during adulthood. Accumulating evidence reveals that gestational hypothyroxinemia (HTX) modulates the immune response of the adult offspring.

Methods: In the present study, adult mice gestated in HTX and their euthyroid counterparts were induced with a mild form of experimental autoimmune encephalomyelitis (EAE), a widespread model of multiple sclerosis, and analyzed at baseline and 7 days after EAE induction.

Results: Levels of circulating IL-17 were significantly lower in mice gestated in HTX at both timepoints, while circulating IFN-γ was significantly higher only in mice gestated in HTX, 7 days after EAE induction. A significant increase in type 1 innate lymphoid cells (ILC1) was found only in mice gestated in HTX 7 days after EAE induction, while type 3 innate lymphoid cells (ILC3) populations showed no variation. Interestingly, a significant increase of Th17 CD4+ cells was found only in mice of euthyroid gestation, 7 days after EAE induction.

Conclusion: These results highlight the repercussions of thyroid hormone impairment in utero at adult ages while dissecting on the pathogenesis of EAE in terms of Th1/Th17 balance from an innate immune perspective. These findings contribute to the advancement of our comprehension of the presymptomatic stage of EAE, unveiling new paths for basic and translational research in the field of neuroinflammation.

Background: Postoperative cognitive dysfunction (POCD) affects 10-54% of surgical patients, especially the elderly. It is increasingly recognized as a major perioperative complication driven by neuroinflammatory mechanisms. While physiological postoperative inflammation supports wound healing and recovery, pathological hyperactivation of immune pathways leads to blood-brain barrier disruption, immune cell infiltration, and long-term cognitive impairment.

Summary: This review examines the contribution of innate and adaptive immune cell subsets to POCD pathogenesis. Activated microglia, infiltrating monocytes, and neutrophils initiate neuroinflammatory cascades through cytokine release, while dysregulated T-cell balance (increased Th17 cells, reduced regulatory T cells) exacerbates dysfunction. Key molecular pathways involve damage-associated molecular patterns, complement activation, and impaired neurotrophin signaling. Clinical biomarkers such as IL-6, TNF-α, and S100B show predictive value, with sensitivity of 65-85% and specificity of 75-90%. Current therapeutic strategies include dexmedetomidine, anti-inflammatory agents, and comprehensive perioperative optimization.

Key messages: POCD is a frequent postoperative complication linked to immune dysregulation and neuroinflammation. Both innate and adaptive immune cells play central roles, with microglial polarization and T-cell imbalance as major drivers. Biomarkers such as IL-6, TNF-α, and S100B can support risk stratification and early intervention. Immunomodulatory therapies and perioperative optimization represent promising approaches to reduce POCD incidence and improve patient outcomes.

Background: For over 130 years, scientists have been suggesting that infection and inflammation may play a role in psychosis and other psychiatric disorders. First attempts to treat psychosis by immune-modulating therapies were made early in the last century; however, after the development of antipsychotics in the 1950s, scientific interest shifted away from immunological aspects of psychiatric disorders to the involvement of catecholamines, in particular dopamine, in psychosis.

Summary: Antipsychotic treatment was not as successful as expected, so the 1990s saw renewed interest in inflammation and psychoneuroimmunological research in schizophrenia and beyond. In parallel, advances in immunological research methods allowed immunological and inflammatory mechanisms to be studied in more detail.

Key messages: Clinical studies and meta-analyses have demonstrated positive effects of anti-inflammatory treatment in certain patients with psychiatric disorders. More research is needed to elucidate exactly how immunological mechanisms result in disease pathophysiology, with the aim to improve anti-inflammatory and personalized treatments.

Introduction: Little is known about the effects of a positive human-animal relationship on animal health and resilience. This study investigated the effects of regular positive human-animal interactions on pigs' response to an immune challenge.

Methods: Twenty-four female pigs were recruited at weaning (5 weeks old), and siblings of similar weights were allocated to either the positive contact treatment with positive contacts given by a human to groups of 3 pigs in their home pen or the control treatment only exposed to a human standing immobile and silently in front and outside their home pen. Treatment sessions were applied over 9 consecutive weeks, lasted 10 min per group, and occurred twice daily (morning and afternoon), 3 days a week. At 16 weeks of age, pigs were submitted to an immune challenge, which consisted of a single intravenous administration of lipopolysaccharide (LPS; 2 µg/kg). The sickness behaviours of pigs were observed using scan sampling every 5 min over 6 h post-administration, recording somnolence, vomiting, diarrhoea, cramping, shivering, and panting. Blood samples were taken before the LPS administration, after 1 h and 3 h. Blood plasma was analysed to quantify tumour necrosis factor alpha, interleukins 6 and 10, immunoglobulin A, and cortisol concentrations, and blood serum was analysed to quantify a brain-derived neurotrophic factor. Behavioural and physiological data were statistically analysed using general linear models in R.

Results: Both treatments showed signs of sickness behaviour following LPS administration, but the two treatments did not differ in the frequency, severity of sickness behaviours, or length of recovery or in the blood plasma concentration of cytokines and cortisol measured.

Conclusion: Therefore, regular exposure to positive contacts with a human over several weeks, although leading to the development of a positive human-animal relationship, did not enhance the pigs' response to this immune challenge or the immune parameters measured in this study.