Inflammasome Signaling Regulates the Microbial-Neuroimmune Axis and Visceral Pain in Mice.

Mònica Aguilera,Lauren Pawley,John F Cryan,Donjete Simnica,Ken Nally,Valerio Rossini,Siobhan M O’Mahony,Valeria D Felice,Fergus Shanahan,Silvia Melgar,Ana Hickey,Aine Fanning,Amy Moloney,Lorraine Mccarthy,Fiona Grady

doi:10.3390/ijms22158336

Abstract

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain–gut interactions, but their role in microbiota–neuro–immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut–neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.

Highlights

The resident microbiota of the gut plays a critical role in regulating the physiology, metabolism, immune function, and nutrition of the host
Recent research shows a bidirectional interplay between inflammasome multiprotein complexes—such as the NLRP3-inflammasome—and the gut microbiota in maintaining intestinal homeostasis, which is altered in intestinal inflammatory and functional conditions (IBD and irritable bowel syndrome (IBS), respectively) [9,10,11,12,13]
Antibiotic Treatment Leads to Significant Alterations in Proteobacteria, Actinobacteria and Firmicutes Abundance and in Acetate Levels in Casp1 KO Mice

Summary

Introduction

The resident microbiota of the gut plays a critical role in regulating the physiology, metabolism, immune function, and nutrition of the host. Changes in microbiota composition are associated with functional and inflammatory gastrointestinal disorders, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) [1,2] These are multifactorial disorders with alterations in immune and nociceptive responses to several factors, including diet and antibiotics [3,4,5]. Inflammasomes are cytosolic multiprotein complexes of the innate immune system composed of a sensor protein, an adaptor protein, and an inflammatory caspase They are activated by pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs), leading to caspase-1 activation (and caspase 11 in mice), inducing the secretion of the mature forms of the pro-inflammatory cytokines Interleukin (IL)-1β and IL-18 [3,6]. Recent studies have implicated the inflammasome in regulating the gut–brain axis in conditions, such as anxiety, depression and migraine, disorders associated with the activation of central nociceptive responses and pain [15,16,17,18,19]

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Conclusion