Brain-spleen axis in health and diseases: A review and future perspective

Wang, Tong; Liao, Lei; Fan, Xiaoxuan; Chang, Lijia; Hashimoto, Kenji

doi:10.1016/j.brainresbull.2022.02.008

Cited by 76 publications

(43 citation statements)

References 162 publications

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“…It is also of interest to examine whether pain might affect depression-like behaviors in CIA mice or ABX-treated mice after FMT from RA patients. Third, the recent studies demonstrated the role of subdiaphragmatic vagus nerve on the depression-like behaviors in ABX-treated mice after FMT of depression-related microbes [ 20 , 22 , 24 , 55 , 56 ]. Further study on the role of subdiaphragmatic vagus nerve on depression-like behaviors in rodents after FMT from RA patients is needed.…”

Section: Discussionmentioning

confidence: 99%

Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation

Zhang

Tang

et al. 2022

Transl Psychiatry

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Depression is common in patients with rheumatoid arthritis (RA); however, the precise mechanisms underlying a link between depression and RA remain unclear. Accumulating evidence suggests the role of gut–microbiota–brain axis in depression. In this study, we investigated whether collagen-induced arthritis (CIA) mice produce depression-like behaviors and abnormal composition of gut microbiota. Furthermore, we investigated whether fecal microbiota transplantation (FMT) from RA patients causes depression-like phenotypes in antibiotic cocktail (ABX)-treated mice. CIA mice displayed depression-like behaviors, increased blood levels of pro-inflammatory cytokine interleukin-6 (IL-6), decreased expression of synaptic proteins in the prefrontal cortex (PFC), and abnormal composition of gut microbiota. Furthermore, FMT from RA patients caused depression-like phenotypes, alterations of gut microbiota composition, increased levels of IL-6 and tumor necrosis factor-α (TNF-α), and downregulation of synaptic proteins in the PFC compared to FMT from healthy controls. There were correlations between relative abundance of microbiota and plasma cytokines, expression of synaptic proteins in the PFC or depression-like behaviors. Interestingly, FMT from RA patients induced T cells differentiation in Peyer’s patches and spleen. Reduced percentage of Treg cells with an increase of Th1/Th2 index was observed in the mice after FMT from RA patients. These findings suggest that CIA mice exhibit depression-like behaviors, systemic inflammation, and abnormal composition of gut microbiota, and that FMT from RA patients produces depression-like behaviors in ABX-treated mice via T cells differentiation. Therefore, abnormalities in gut microbiota in RA patients may contribute to depression via gut–microbiota–brain axis.

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Section: Discussionmentioning

confidence: 99%

Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation

Zhang

Tang

et al. 2022

Transl Psychiatry

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“…Starting at 10 M on, we observed a significant increase in CD3 + /LRRK2 + cells in G2019S SNpc compared to WT counterparts. Moreover, LRRK2 G2019S synergized with LPS and IFN-γ in SPMs to promote greater levels of TNF-α and IL-6 release starting at 6 M. Given the recently recognized role of the brain-spleen axis, [159][160][161] these data would suggest a potential early role of the peripheral immune system in LRRK2-related neurodegeneration. In line with these data, we found a significant increase in the serum levels of IL-6, IFN-γ, IL1-beta, IL-2, IL-4 and IL-17 in G2019S LPS-treated mice at 6 M. These results indicate an overactivation of the peripheral immune system in G2019S mice subjected to low-grade inflammation during ageing.…”

Section: Discussionmentioning

confidence: 83%

LRRK2-G2019S Synergizes With Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation That Precede Nigrostriatal Degeneration

Marchetti

Giachino

Tirolo

et al. 2022

Preprint

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). The incomplete penetrance of LRRK2 mutations suggest that additional hits are required for disease onset. We hypothesized that chronic low-grade inflammation interacts with LRRK2 G2019S, the most frequent PD-associated mutation, to activate peripheral and central immune reactions and drive age-dependent neurodegeneration. We exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide and performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, peripheral monocyte infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines as well as increased CD4+ T-cell infiltration and α-synuclein aggregation in the colon. Peripheral immune activation and colonic α-synuclein aggregation preceded brain inflammation and degeneration. Our study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers.

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“…Considering the spleen's key role in the immune system [18][19][20][21] , we investigated how splenectomy affects psoriasis-like pathology and skin inflammation of IMQ-treated mice. Unexpectedly, splenectomy did not change the psoriasis-like phenotype in IMQ-treated mice.…”

Section: Discussionmentioning

confidence: 99%

“…Topical application of IMQ to back skin causes splenomegaly in rodents 9,[13][14][15][16][17] . Given the key role of immune system in the spleen [18][19][20][21] , the spleen may play a role in psoriasis-like skin inflammation of IMQ-treated mice by modulating the immune system. However, how the spleen and splenectomy contribute to the psoriasis-like phenotype of IMQ-treated mice is unknown.…”

Section: Effects Of Splenectomy On Skin Inflammation and Psoriasis-li...mentioning

confidence: 99%

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice

Shinno-Hashimoto

Eguchi

Sakamoto

et al. 2022

Sci Rep

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Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

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Brain-spleen axis in health and diseases: A review and future perspective

Cited by 76 publications

References 162 publications

Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation

Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation

LRRK2-G2019S Synergizes With Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation That Precede Nigrostriatal Degeneration

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice

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