Gut commensal microvesicles reproduce parent bacterial signals to host immune and enteric nervous systems.
Ingestion of a commensal bacteria, Lactobacillus rhamnosus JB-1, has potent immunoregulatory effects, and changes nerve-dependent colon migrating motor complexes (MMCs), enteric nerve function, and behavior. How these alterations occur is unknown. JB-1 microvesicles (MVs) are enriched for heat shock protein components such as chaperonin 60 heat-shock protein isolated from Escherichia coli (GroEL) and reproduce regulatory and neuronal effects in vitro and in vivo. Ingested labeled MVs were detected in murine Peyer's patch (PP) dendritic cells (DCs) within 18 h. After 3 d, PP and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4(+)25(+)Foxp3+ T cells. JB-1, MVs, and GroEL similarly induced phenotypic change in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 and Dectin-1, as well as TLR-2 and -9. JB-1 and MVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial, but not direct neuronal application of, MVs, replicated functional effects of JB-1 on in situ patch-clamped enteric neurons. GroEL and anti-TLR-2 were without effect in this system, suggesting the importance of epithelium neuron signaling and discrimination between pathways for bacteria-neuron and -immune communication. Together these results offer a mechanistic explanation of how Gram-positive commensals and probiotics may influence the host's immune and nervous systems.
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Khalid
K
Al-Nedawi
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
M Firoz
MF
Mian
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Nazia
N
Hossain
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Khalil
K
Karimi
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Yu-Kang
YK
Mao
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Paul
P
Forsythe
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Kevin K
KK
Min
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Andrew M
AM
Stanisz
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Wolfgang A
WA
Kunze
*Division of Nephrology, Departments of Medicine, Psychiatry and Behavioral Neurosciences, and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; and McMaster Brain-Body Institute at St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada bienens@mcmaster.ca.
John
J
Bienenstock
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018834:Chaperonin 60 / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000382:microbiology; D017615:Enteric Nervous System / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000294:innervation*; D007107:Immune System / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D052201:Lacticaseibacillus rhamnosus / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000378:metabolism; D010528:Peristalsis; D010581:Peyer's Patches / Q000382:microbiology; D010641:Phenotype; D019936:Probiotics; D040901:Proteomics; D015398:Signal Transduction
D018834:Chaperonin 60; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type
bacterial microvesicles; immunoregulation