Microbiota-derived succinate promotes enterohaemorrhagic Escherichia coli virulence via lysine succinylation
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Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma
Tumors undergo metabolic reprogramming to meet the energetic, synthetic and redox demands essential for malignancy, often characterized by increased glycolysis and lactate production. However, the role of mitochondrial metabolism in tumor immunity remains unclear. The present study integrates spatial transcriptomics, bulk transcriptomics and proteomics, revealing a strong link between the metabolite succinyl-CoA and tumor immunity as well as the efficacy of anti-programmed cell death protein-1 (PD-1) therapy in patients with melanoma. Elevated succinyl-CoA levels, through α-ketoglutarate or succinate supplementation, enhanced T cell-mediated tumor elimination, both in vitro and in vivo. Mechanistically, succinylation of the ligand of PD-1 (PD-L1) at lysine 129 led to its degradation. Increased carnitine palmitoyltransferase 1A (CPT1A), identified as a succinyltransferase for PD-L1, boosted anti-tumor activity. Preclinically, bezafibrate, a hyperlipidemia drug, upregulated CPT1A and synergized with CTLA-4 monoclonal antibody to inhibit tumor growth. Clinically, higher PD-L1 and lower CPT1A levels in tumors correlated with better anti-PD-1 therapy responses, suggesting potential biomarkers for prediction of treatment efficacy.
Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation
The tuft cell–group 2 innate lymphoid cell (ILC2) circuit orchestrates rapid type 2 responses upon detecting microbially derived succinate and luminal helminths. Our findings delineate key mechanistic steps involving IP3R2 engagement and Ca2+ flux, governing interleukin-25 (IL-25) production by tuft cells triggered by succinate detection. While IL-17RB has a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Supraoptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.
Escherichia Coli K1-colibactin meningitis induces microglial NLRP3/IL-18 exacerbating H3K4me3-synucleinopathy in human inflammatory gut-brain axis
Escherichia coli K1 (E. coli K1) meningitis early occurs in the gastrointestinal and causes severe damage to the central nervous system, including lifelong neurological complications in survivors. However, the cellular mechanism by which E. coli K1 may cause neuropathies is not well understood due to the lack of relevant human multi-organ models for studying multifaceted systemic inflammation across the gut-brain axis. Here, we reconstruct a multicellular model of the human gut-brain axis to identify the neuropathogenic mechanism driven by E. coli K1-colibactin meningitis. We observed that E. coli K1-genotoxic colibactin induced intestinal and peripheral interleukin 6, causing the blood-brain barrier injury and endothelial inflammation via the p38/p65 pathways. Serpin-E1 from the damaged cerebral endothelia induces reactive astrocytes to release IFN-γ, which reduces microglial phagocytosis of E. coli K1 and exacerbates detrimental neuroinflammation via NLRP3/IL-18 axis. Microglial IL-18 elevates neuronal reactive oxidative stress that worsens DNA double-strand breaks in E. coli K1-infected neurons, leading to H3K4 trimethylation and phosphorylation of alpha-synuclein. Our findings suggest therapeutic strategies for post-bacterial meningitis treatment to potentially prevent the initiation of synucleinopathy.
Influence of the early-life gut microbiota on the immune responses to an inhaled allergen
Antibiotics, among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity. We hypothesized that early-life microbiome alterations would lead to increased susceptibility to allergy and asthma. To test this, mouse pups between postnatal days 5–9 were orally exposed to water (control) or to therapeutic doses of azithromycin or amoxicillin. Later in life, these mice were sensitized and challenged with a model allergen, house dust mite (HDM), or saline. Mice with early-life azithromycin exposure that were challenged with HDM had increased IgE and IL-13 production by CD4+ T cells compared to unexposed mice; early-life amoxicillin exposure led to fewer abnormalities. To test that the microbiota contained the immunological cues to alter IgE and cytokine production after HDM challenge, germ-free mice were gavaged with fecal samples of the antibiotic-perturbed microbiota. Gavage of adult germ-free mice did not result in altered HDM responses, however, their offspring, which acquired the antibiotic-perturbed microbiota at birth showed elevated IgE levels and CD4+ cytokines in response to HDM, and altered airway reactivity. These studies indicate that early-life microbiota composition can heighten allergen-driven Th2/Th17 immune pathways and airway responses in an age-dependent manner.
Perturbations in the microbiota-gut-brain axis shaped by social status loss
Social status is closely linked to physiological and psychological states. Loss of social dominance can lead to brain disorders such as depression, but the underlying mechanisms remain unclear. The gut microbiota can sense stress and contribute to brain disorders via the microbiota-gut-brain axis (MGBA). Here, using a forced loss paradigm to demote dominant mice to subordinate ranks, we find that stress alters the composition and function of the gut microbiota, increasing Muribaculaceae abundance and enhancing butanoate metabolism, and gut microbial depletion resists forced loss-induced hierarchical demotion and behavioral alteration. Single-nucleus transcriptomic analysis of the prefrontal cortex (PFC) indicates that social status loss primarily affected interneurons, altering GABAergic synaptic transmission. Weighted gene co-expression network analysis (WGCNA) reveals modules linked to forced loss in the gut microbiota, colon, PFC, and PFC interneurons, suggesting changes in the PI3K-Akt signaling pathway and the glutamatergic synapse. Our findings provide evidence for MGBA perturbations induced by social status loss, offering potential intervention targets for related brain disorders.
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