Abstract
Objective: Toll-like receptors (TLRs) play a pivotal role in the homeostatic microflora-host crosstalk. TLR4-mediated modulation of both motility and enteric neuronal survival has been reported mainly for colon with limited information on the role of TLR4 in tuning structural and functional integrity of enteric nervous system (ENS) and in controlling small bowel motility.Methods: Male TLR4 knockout (TLR4-/-, 9 ± 1 weeks old) and sex- and age-matched wild-type (WT) C57BL/6J mice were used for the experiments. Alterations in ENS morphology and neurochemical code were assessed by immunohistochemistry whereas neuromuscular function was evaluated by isometric mechanical activity of ileal preparations following receptor and non-receptor-mediated stimuli and by gastrointestinal transit.Results: The absence of TLR4 induced gliosis and reduced the total number of neurons, mainly nNOS+ neurons, in ileal myenteric plexus. Furthermore, a lower cholinergic excitatory response with an increased inhibitory neurotransmission was found together with a delayed gastrointestinal transit. These changes were dependent on increased ileal non-adrenergic non-cholinergic (NANC) relaxations mediated by a complex neuronal-glia signaling constituted by P2X7 and P2Y1 receptors, and NO produced by nNOS and iNOS.Conclusion: We provide novel evidence that TLR4 signaling is involved in the fine-tuning of P2 receptors controlling ileal contractility, ENS cell distribution, and inhibitory NANC neurotransmission via the combined action of NO and adenosine-5′-triphosphate (ATP). For the first time, this study implicates TLR4 at regulating the crosstalk between glia and neurons in small intestine and helps to define its role in gastrointestinal motor abnormalities during dysbiosis.
Highlights
The functional link between endogenous gut microbes and their host regulates the balance between commensalism and parasitism on the microbial side, and between infection and resistance on the host side
Since TLR4 expression is required for normal growth of the small intestine (Riehl et al, 2015), we sought to determine whether the absence of TLR4 influences structural architecture by examining hematoxylin and eosinstained sections
Considering that TLR4 is expressed in enteric nervous system (ENS) (Rumio et al, 2006; Barajon et al, 2009), the impact of TLR4 absence on ENS integrity was evaluated by immunohistochemistry
Summary
The functional link between endogenous gut microbes and their host regulates the balance between commensalism and parasitism on the microbial side, and between infection and resistance on the host side. Commensal enteric microbiota efficiently influences innate defenses by preventing pathogenic bacteria from crossing the mucosal barrier (Kamada et al, 2013) This delicate balance can be perturbed by several factors (e.g., stress, drugs, and inflammation) leading to GFD as a result of a vicious cycle in which host dysfunctions affect microflora environment leading to dysbiosis and vice versa (Rakoff-Nahoum et al, 2004; Lee and Lee, 2014). These disorders are characterized by intestinal barrier breakdown, bacterial translocation and changes in motility (Bischoff et al, 2014), and appear to be driven by abnormal responses to microbiota-derived molecules via stimulation of Toll-like receptors (TLRs) (Rakoff-Nahoum et al, 2004; Barbara et al, 2016). Under steadystate conditions, TLR4 is generally absent or detected in very small amounts in intestinal epithelial cells and in immune cells located in the subepithelial lamina propria, in order to avoid inappropriate activation despite the omnipresent microbiota (Cario, 2010)
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