title: Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly.
abstract: The pathway leading from amyloid-β deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer's disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti-inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1β, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-α]; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n = 40, Amy+) and with no brain amyloidosis (n = 33, Amy-) and also in a group of controls (n = 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1β) compared with both controls and with Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of E. rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC = -9.6, p < 0.001 and FC = +12.8, p < 0.001, respectively) and to Amy- (FC = -7.7, p < 0.001 and FC = +7.4, p = 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1β, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho = 0.60, p < 0.001; rho = 0.57, p < 0.001; and rho = 0.30, p = 0.007, respectively) and a negative correlation with the anti-inflammatory E. rectale (rho = -0.48, p < 0.001; rho = -0.25, p = 0.024; rho = -0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy; King's College London, Institute of Psychiatry, London, UK. Electronic address: acattaneo@fatebenefratelli.eu.
authors: Annamaria
authors: A
authors: Cattaneo
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Nadia
authors: N
authors: Cattane
authors: Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors: Samantha
authors: S
authors: Galluzzi
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Stefania
authors: S
authors: Provasi
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Nicola
authors: N
authors: Lopizzo
authors: Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors: Cristina
authors: C
authors: Festari
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Clarissa
authors: C
authors: Ferrari
authors: Nuclear Medicine, Poliambulanza Foundation, Istituto Ospedaliero, Brescia, Italy.
authors: Ugo Paolo
authors: UP
authors: Guerra
authors: Nuclear Medicine, University of Brescia and Spedali Civili di Brescia, Brescia, Italy.
authors: Barbara
authors: B
authors: Paghera
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy; European Foundation Biomedical Research (FERB), Center of Excellence Alzheimer, Ospedale Briolini, Gazzaniga, Bergamo, Italy.
authors: Cristina
authors: C
authors: Muscio
authors: Department of Medicine and Rehabilitation, Istituto Clinico Sant'Anna, Brescia, Italy.
authors: Angelo
authors: A
authors: Bianchetti
authors: Neurology Unit, Istituto Clinico Città di Brescia, Brescia, Italy.
authors: Giorgio Dalla
authors: GD
authors: Volta
authors: Neurology Unit, Ospedale di Vallecamonica Esine, Brescia, Italy.
authors: Marinella
authors: M
authors: Turla
authors: Neurology Unit, Ospedale di Vallecamonica Esine, Brescia, Italy.
authors: Maria Sofia
authors: MS
authors: Cotelli
authors: Neurology Unit, Ospedale Maggiore di Crema, Cremona, Italy.
authors: Michele
authors: M
authors: Gennuso
authors: Neurology Unit, Ospedale Maggiore di Crema, Cremona, Italy.
authors: Alessandro
authors: A
authors: Prelle
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Orazio
authors: O
authors: Zanetti
authors: Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Giulia
authors: G
authors: Lussignoli
authors: European Foundation Biomedical Research (FERB), Center of Excellence Alzheimer, Ospedale Briolini, Gazzaniga, Bergamo, Italy.
authors: Dario
authors: D
authors: Mirabile
authors: Alzheimer Evaluation Unit, Istituto Ospedaliero di Sospiro ONLUS Foundation, Cremona, Italy.
authors: Daniele
authors: D
authors: Bellandi
authors: Department of Rehabilitation, Casa di Cura Ancelle della Carità, Cremona, Italy.
authors: Simona
authors: S
authors: Gentile
authors: Alzheimer Evaluation Unit, Hospice Santa Maria Ausiliatrice ONLUS Foundation, Bergamo, Italy.
authors: Gloria
authors: G
authors: Belotti
authors: Alzheimer Evaluation Unit, Casa di Cura Figlie di S. Camillo, Cremona, Italy.
authors: Daniele
authors: D
authors: Villani
authors: Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
authors: Taoufiq
authors: T
authors: Harach
authors: Stemedica International SA, Lausanne, Switzerland.
authors: Tristan
authors: T
authors: Bolmont
authors: Neurology Unit, Department of Medical and Experimental Sciences, University of Brescia, Brescia, Italy.
authors: Alessandro
authors: A
authors: Padovani
authors: Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors: Marina
authors: M
authors: Boccardi
authors: Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals, Geneva, Switzerland; Memory Clinic, University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Giovanni B
authors: GB
authors: Frisoni
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000209:etiology / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Brain amyloidosis; Cognitive impairment; Gut microbiota; Inflammation; Neurodegeneration