Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Lasconi, Chiara; Pahl, Matthew C; Cousminer, Diana L.; Doege, Claudia A.; Chesi, Alessandra; Hodge, Kenyaita M.; Leonard, Michelle E.; Lu, Sumei; Johnson, Matthew E.; Su, Chun; Hammond, Reza; Pippin, James A.; Terry, Natalie A.; Ghanem, Louis; Leibel, Rudolph L.; Wells, Andrew D.; Grant, Struan F.A.

doi:10.1016/j.jcmgh.2020.10.004

Cited by 19 publications

(23 citation statements)

References 102 publications

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“…Furthermore, in the clinical context, adverse life events and emotional conflicts, often associated with anxiety and depression, represent causal factors for the exacerbation of symptoms as well as of IBD relapses [24,189]. A recent study based on the integration of 3D genomic data with publicly available GWAS data for depression and IBD traits to identify genetic commonalities is highly suggestive for the existence of potential genetic relationships between IBD and stress-induced depression, involving key stress regulator hypothalamic genes [190]. In IBD, stress-induced brain-gut perturbations are associated with mast cell-mediated pro-inflammatory responses in the periphery and the CNS and with a complex array of neuroendocrine and autonomic reflexes consequent to HPA axis activation, increased pro-inflammatory sympathetic outflow, and decreased anti-inflammatory vagal outflow, mainly under the control of the prefrontal cortex and amygdala [24].…”

Section: Hormonal Connections: the Hpa Axis And Stress Responsementioning

confidence: 99%

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

Banfi

Moro

Bosi

et al. 2021

IJMS

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The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the “gut–brain axis” and renamed the “microbiota–gut–brain axis”, considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota–gut–brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as “postbiotics”, such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.

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Section: Hormonal Connections: the Hpa Axis And Stress Responsementioning

confidence: 99%

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

Banfi

Moro

Bosi

et al. 2021

IJMS

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“…We also performed a more relaxed search in neural cell types only without requiring the SNP or the gene promoter to reside in open chromatin and investigating both the index SNP (rs143080277) and a proxy SNP (rs144636993; r 2 ∼0.5 ( D’ =1) in the 1000 Genomes European [EUR] populations). One loop was observed between one loop between rs144636993 and an alternative promoter of the same short isoform (NM_001004720.3) of NCK2 in ESC-derived hypothalamic neurons 51 , however neither the SNP nor the promoter were found to be open ( Supplementary Figure 8b ).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

Naj

Leonenko

Jian

et al. 2021

Preprint

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Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer's Project (IGAP). Existing genotype data were imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimer's Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10-12), SHARPIN (P=1.56×10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10-8), APH1B (P=2.10×10-13), and CLNK (P=2.24×10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

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“…Dysregulation in the hypothalamus has been found to play a critical role in stress and depression during IBD (41). Targeting certain neurons in the hypothalamus rather than the whole brain potentially provides a more effective treatment for anxiety than conventional therapy (19).…”

Section: Results 3 Colitic Mice Show Brain Inflammation With Cd4 + T Cell Accumulation and Astrogliosis In The Hypothalamusmentioning

confidence: 99%

RORγt-Expressing Pathogenic CD4⁺T Cells Cause Brain Inflammation During Chronic Colitis

Mickael

Chakraborti

Umfress

et al. 2021

Preprint

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Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn's Disease (CD) and Ulcerative Colitis (UC) patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease (IBD) patients remains unknown. Studies have linked the Th17 subset of CD4+T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis (MS), ischemic brain injury, and Alzheimer's disease. To better understand how CD4+T lymphocytes, contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4+T cells infiltrate the brain of colitic Rag1-/- mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4+T cells expressed Th17 cell transcription factor RORγt and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naive CD4+T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1-/- recipients, with significantly less brain infiltration of CD4+T cells. These findings suggest that pathogenic RORγt+CD4+T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.

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Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Cited by 19 publications

References 102 publications

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

RORγt-Expressing Pathogenic CD4⁺T Cells Cause Brain Inflammation During Chronic Colitis

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Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease

Cited by 19 publications

References 102 publications

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

RORγt-Expressing Pathogenic CD4+T Cells Cause Brain Inflammation During Chronic Colitis

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RORγt-Expressing Pathogenic CD4⁺T Cells Cause Brain Inflammation During Chronic Colitis