Emerging evidence demonstrates that alterations to the gut microbiota can affect mood, suggesting that the microbiota–gut–brain (MGB) axis contributes to the pathogenesis of depression. Many of these pathways overlap with the way in which the gut microbiota are thought to contribute to metabolic disease progression and obesity. In rodents, prebiotics and probiotics have been shown to modulate the composition and function of the gut microbiota. Together with germ-free rodent models, probiotics have provided compelling evidence for a causal relationship between microbes, microbial metabolites, and altered neurochemical signalling and inflammatory pathways in the brain. In humans, probiotic supplementation has demonstrated modest antidepressant effects in individuals with depressive symptoms, though more studies in clinically relevant populations are needed. This review critically discusses the role of the MGB axis in depression pathophysiology, integrating preclinical and clinical evidence, as well as the putative routes of communication between the microbiota–gut interface and the brain. A critical overview of the current approaches to investigating microbiome changes in depression is provided. To effectively translate preclinical breakthroughs in MGB axis research into novel therapies, rigorous placebo-controlled trials alongside a mechanistic and biochemical understanding of prebiotic and probiotic action are required from future research.

Maternal obesity disturbs brain–gut–microbiota interactions and induces negative affect in the offspring, but its impact on gut and brain metabolism in the offspring (F1) are unknown. Here, we tested whether perinatal intake of a multispecies probiotic could mitigate the abnormal emotional behavior in the juvenile and adult offspring of obese dams. Untargeted NMR-based metabolomic profiling and gene-expression analysis throughout the gut–brain axis were then used to investigate the biology underpinning behavioral changes in the dams and their offspring. Prolonged high-fat diet feeding reduced maternal gut short-chain fatty acid abundance, increased markers of peripheral inflammation, and decreased the abundance of neuroactive metabolites in maternal milk during nursing. Both juvenile (postnatal day [PND] 21) and adult (PND112) offspring of obese dams exhibited increased anxiety-like behavior, which were prevented by perinatal probiotic exposure. Maternal probiotic treatment increased gut butyrate and brain lactate in the juvenile and adult offspring and increased the expression of prefrontal cortex PFKFB3, a marker of glycolytic metabolism in astrocytes. PFKFB3 expression correlated with the increase in gut butyrate in the juvenile and adult offspring. Maternal obesity reduced synaptophysin expression in the adult offspring, while perinatal probiotic exposure increased expression of brain-derived neurotrophic factor. Finally, we showed that the resilience of juvenile and adult offspring to anxiety-like behavior was most prominently associated with increased brain lactate abundance, independent of maternal group. Taken together, we show that maternal probiotic supplementation exerts a long-lasting effect on offspring neuroplasticity and the offspring gut–liver–brain metabolome, increasing resilience to emotional dysfunction induced by maternal obesity. Significance Maternal obesity is a growing public health concern and is linked to an increased risk of neurodevelopmental and psychiatric disorders in humans. Despite accumulating evidence for the important role maternal microbes play during gestation and nursing, the longitudinal effect of maternal nutrition on offspring metabolism across the gut–brain axis at different ages remains unexplored. We provide evidence for the protective efficacy of perinatal probiotic exposure against increased anxiety-like behaviors induced by maternal obesity. Protection was maintained into adulthood, which may be mediated by the enhancement of brain energy metabolites and an increase in gut butyrate. These findings reveal the importance and long-lasting role of maternally derived microbiota and metabolites in increasing resilience to mood disorders in the offspring.

Antimicrobial resistance (AMR) poses a profound threat to modern healthcare, with vancomycin-resistant Enterococcus faecium (VREfm) emerging as a particularly resilient and clinically significant pathogen. This mini-review examines the biological mechanisms underpinning VREfm resistance, including biofilm formation, stress tolerance, and the acquisition of resistance genes such as vanA and vanB. It also explores the behavioural, social, and healthcare system factors that facilitate VREfm transmission, highlighting disparities in burden across vulnerable populations and low-resource settings. Prevention strategies are mapped across the disease pathway, spanning primary, secondary, and tertiary levels, with a particular focus on the role and evolving challenges of antimicrobial stewardship programmes (ASP). We highlight emerging threats, such as rifaximin-induced cross-resistance to daptomycin, which challenge conventional stewardship paradigms. Finally, we propose future directions to enhance global surveillance, promote equitable stewardship interventions, and accelerate the development of innovative therapies. Addressing VREfm requires a coordinated, multidisciplinary effort to safeguard the efficacy of existing antimicrobials and protect at-risk patient populations.

Endotoxemia and sepsis induce neuroinflammation and increase the risk of neurodegenerative disorders although the mechanism by which peripheral infection leads to brain inflammation is not well understood. While circulating serum lipoproteins are known immunometabolites with the potential to modulate the acute phase response and cross the blood brain barrier, their contribution to neuroinflammation during systemic infection is unknown. The objective of this study was to elucidate the mechanisms by which lipoprotein subclasses modulate lipopolysaccharide (LPS)-induced neuroinflammation. Adult C57BL/6 mice were divided into 6 treatment groups, including a sterile saline vehicle control group (n = 9), an LPS group (n = 11), a premixed LPS + HDL group (n = 6), a premixed LPS + LDL group (n = 5), a HDL only group (n = 6) and an LDL only group (n = 3). In all cases injections were administered intraperitoneally. LPS was administered at 0.5 mg/kg, and lipoproteins were administered at 20 mg/kg. Behavioural testing and tissue collection was performed 6 h post-injection. The magnitude of peripheral and central inflammation was determined by qPCR of pro-inflammatory genes in fresh liver and brain. Metabolite profiles of liver, plasma and brain were determined by ¹H NMR. Endotoxin concentration in the brain was measured by the Limulus Amoebocyte Lysate (LAL) assay. Co-administration of LPS + HDL exacerbated both peripheral and central inflammation, whilst LPS + LDL attenuated this inflammation. Metabolomic analysis identified several metabolites significantly associated with LPS-induced inflammation, which were partially rescued by LDL, but not HDL. Endotoxin was detected at significantly greater concentrations in the brains of animals that received LPS + HDL compared to LPS + saline, but not those that received LPS + LDL. These results suggest that HDL may promote neuroinflammation through direct shuttling of endotoxin to the brain. In contrast, LDL was shown to have anti-neuroinflammatory properties in this study. Our results indicate that lipoproteins may be useful targets in neuroinflammation and neurodegeneration associated with endotoxemia and sepsis.

Infants with attenuated type III IFN (IFN-λ) responses are at increased risk of severe lower respiratory tract infection (sLRI). The IL-28Rα–chain and IL-10Rβ–chain form a heterodimeric receptor complex, necessary for IFN-λ signaling. Therefore, to better understand the immunopathogenic mechanisms through which an IFN-λ^lo microenvironment predisposes to a sLRI, we inoculated neonatal wild-type and IL-28R–deficient (IL-28R^−/−) mice with pneumonia virus of mice, a rodent-specific pneumovirus. Infected IL-28R^−/− neonates displayed an early, pronounced, and persistent neutrophilia that was associated with enhanced reactive oxygen species (ROS) production, NETosis, and mucus hypersecretion. Targeted deletion of the IL-28R in neutrophils was sufficient to increase neutrophil activation, ROS production, NET formation, and mucus production in the airways. Inhibition of protein-arginine deiminase type 4 (PAD4), a regulator of NETosis, had no effect on myeloperoxidase expression, citrullinated histones, and the magnitude of the inflammatory response in the lungs of infected IL-28R^−/− mice. In contrast, inhibition of ROS production decreased NET formation, cellular inflammation, and mucus hypersecretion. These data suggest that IFN-λ signaling in neutrophils dampens ROS-induced NETosis, limiting the magnitude of the inflammatory response and mucus production. Therapeutics that promote IFN-λ signaling may confer protection against sLRI. Key Points IFN-λ limits neutrophil-induced immunopathology during severe viral bronchiolitis. IFN-λ signaling in neutrophils regulates ROS production. IFN-λ signaling in neutrophils regulates PAD4-independent NETosis.