Bridging the brain and gut: neuroimmune mechanisms of neuroinflammation and therapeutic insights

Abstract

The central nervous system (CNS) and the immune system are profoundly interconnected, engaging in a continuous dynamic exchange that regulates homeostasis, immune surveillance, and responses to injury. These interactions occur through diverse mechanisms, ranging from microglial activation and cytokine signaling to peripheral immune cell infiltration. When disrupted, this balance contributes to neurodegenerative processes, affecting cognitive function and neuronal survival. This mini-review examines the cellular and molecular foundations of neuroimmune communication, focusing on how neuroimmune interactions influence the onset and progression of neurodegenerative disorders such as Alzheimer's disease. Key mechanisms include barrier systems, gut-brain interactions, and circadian rhythm regulation, all playing a crucial role in modulating neuroinflammatory responses. The gut-brain axis plays a pivotal role in modulating CNS function, as alterations in gut microbiota composition can trigger neuroinflammatory pathways, affect systemic immunity, and influence disease susceptibility. Both innate and adaptive immune responses are instrumental in shaping disease trajectory, highlighting the complex interplay between systemic and neural immune components. The blood-brain barrier and glymphatic system modulate immune cell trafficking and waste clearance, influencing CNS pathology. Additionally, circadian rhythm and sleep patterns regulate neuroimmune balance, with disruptions exacerbating inflammation and neurodegeneration. Neuroimmune crosstalk manifests through a spectrum of pathways, each capable of either promoting resilience or accelerating neurodegeneration. By unraveling these connections, we can gain new insights into potential strategies to modulate immune responses and restore homeostasis. This investigation underlines the necessity of integrative approaches that target immune modulation, microbiota regulation, and circadian alignment to mitigate neurodegenerative disease progression and improve therapeutic outcomes.

Keywords: AD; cytokines; glial cells; gut-brain interactions; immune cells; neurodegenerative diseases; neuroinflammation; neurons.

FIGURE 1

The simplified illustration of the barrier systems regulating CNS immune homeostasis and waste clearance. (A) BBB serves as a selective interface between the peripheral circulation and the CNS, formed by endothelial cells, tight junctions, pericytes, and astrocytic endfeet. Under homeostatic conditions, only specific peripheral immune cells, such as patrolling monocytes and subsets of T cells, can enter the CNS through controlled mechanisms. In neurodegenerative diseases like AD, chronic inflammation, oxidative stress, and endothelial dysfunction compromise BBB integrity, increasing permeability and allowing infiltration of activated monocytes and peripheral immune cells, along with pro-inflammatory cytokines, which drive neuroinflammation, impair Aβ clearance, and promote its aggregation. (B) The meningeal lymphatic system located within the meninges—comprising the dura, arachnoid, and pia mater—contains functional lymphatic vessels that facilitate the drainage of CNS-derived antigens and immune cells to cervical lymph nodes. In AD, impaired meningeal lymphatic function hinders antigen clearance, leading to chronic immune activation, waste aggregation, and sustained neuroinflammation. (C) The glymphatic system, a perivascular network regulated by CSF-ISF flow and astrocytic aquaporin channels, is responsible for clearing metabolic waste, including toxic Aβ and tau aggregates. Glymphatic dysfunction, commonly observed in aging and AD, leads to waste accumulation, exacerbating disease pathology. AC, astrocyte; aAC, activated astrocyte; Aβ, Amyloid β plaque; aIP, amyloid-like protein; aMG, activated microglia; aMo, activated monocyte; 9APC, antigen-presenting cell; BBB, blood-brain barrier; BP, brain parenchyma; cBBB, compromised blood-brain barrier; CSF, cerebrospinal fluid; dN, degenerating neuron; ISF, interstitial fluid; MG, microglia; Mo, monocytes; N, neuron; PC, pericytes; pIC, peripheral immune cells; proIC, pro-inflammatory cytokines; TJ, tight junctions; Treg, regulatory T cell.

FIGURE 2

The simplified illustration of the gut-brain axis in a healthy state (left) and under neurodegenerative conditions in AD (right). In the healthy brain (top left, blue area), an intact BBB regulates immune cell trafficking and prevents excessive neuroinflammation. Microglia remain in a homeostatic state, and neuroprotective metabolites and SCFAs support neuronal function and anti-inflammatory responses. The vagus nerve enables bidirectional communication between the gut and brain that help maintain neuronal homeostasis. Additionally, melatonin, primarily produced by the pineal gland and also synthesized in the gut, regulates circadian rhythms, enhances BBB integrity, and exerts antioxidant and anti-inflammatory effects, contributing to neuronal protection. In the healthy gut (bottom left, blue area), a balanced microbiota composition supports gut barrier integrity, regulate immune response through Tregs, and produces SCFAs that modulate neuroimmune interactions. In contrast, during neurodegeneration (top right, red area), a compromised BBB allows infiltration of peripheral immune cells and pro-inflammatory cytokines, leading to glial cell activation, oxidative stress, and Aβ-plaque formation. The vagus nerve’s regulatory function is impaired, supporting inflammatory signaling and exacerbating neuroinflammation. Simultaneously, gut dysbiosis (bottom right, red area) increases intestinal permeability, allowing bacterial endotoxins like LPS to enter circulation, triggering systemic inflammation and BBB disruption. Dysbiotic microbes also release amyloid-like proteins, promoting cross-seeding with brain-derived Aβ and further driving neurodegeneration. Aβ, Amyloid β plaque; aAC, activated astrocyte; aIC, anti-inflammatory cytokines; aIP, amyloid-like protein; aMG, activated microglia; AC, astrocyte; BBB, blood-brain barrier; cBBB, compromised blood-brain barrier; dN, degenerating neuron; LPS, lipopolysaccharide; Mel, melatonin; MG, microglia; Mf-1, macrophage type 1; N, neuron; pIC, peripheral immune cells; proIC, pro-inflammatory cytokines; SCFA, short-chain fatty acids; Treg, regulatory T cell.