Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer's disease

Abstract

Background: The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at least in part by modulating neuroinflammation. Given the link between neuroinflammatory changes and neuronal activity, it is plausible that gut microbiota may affect neuronal functions indirectly by impacting microglia, a key player in neuroinflammation. Indeed, increasing evidence suggests that interplay between microglia and synaptic dysfunction may involve microbiota, among other factors. In addition to these indirect microglia-dependent actions of microbiota on neuronal activity, it has been recently recognized that microbiota could also affect neuronal activity directly by stimulation of the vagus nerve.

Main messages: The putative mechanisms of the indirect and direct impact of microbiota on neuronal activity are discussed by focusing on Alzheimer's disease, one of the most studied neurodegenerative disorders and the prime cause of dementia worldwide. More specifically, the mechanisms of microbiota-mediated microglial alterations are discussed in the context of the peripheral and central inflammation cross-talk. Next, we highlight the role of microbiota in the regulation of humoral mediators of peripheral immunity and their impact on vagus nerve stimulation. Finally, we address whether and how microbiota perturbations could affect synaptic neurotransmission and downstream cognitive dysfunction.

Conclusions: There is strong increasing evidence supporting a role for the gut microbiome in the pathogenesis of Alzheimer's disease, including effects on synaptic dysfunction and neuroinflammation, which contribute to cognitive decline. Putative early intervention strategies based on microbiota modulation appear therapeutically promising for Alzheimer's disease but still require further investigation.

Keywords: Alzheimer’s disease; Gut microbiota; Neuroinflammation; Peripheral immunomodulation; Synaptic dysfunction.

Fig. 1

Induction and expression of LTP in physiological and AD-related pathological conditions in animal models of AD-like pathology and its modulation by microbiota products. (A) In physiological conditions, optimal input to pre-synaptic hippocampal neurons triggers the release of glutamate into the synaptic cleft. This activates membrane AMPARs on the post-synaptic neurons and allows the entry of Na⁺ into the cell, yielding a excitatory postsynaptic potential (EPSP). When tetanic stimulation is given, a large amount of glutamate is released from presynaptic terminals, which increases the EPSP produced by postsynaptic membrane, resulting in the removal of Mg²⁺ blocked in NMDAR and its subsequent activation. NMDAR activation allows the influx of Ca²⁺ as well as Na⁺ ions into the cell, leading to the activation of Ca²⁺-calmodulin-dependent protein kinase-II, which phosphorylates AMPAR, increases its conductivity, promotes the transfer of AMPAR from the cytoplasm to the postsynaptic membrane and increases its density, resulting in LTP. (B) Early stages of AD-like pathology are likely associated with elevated glutamate release by pre-synaptic neurons and increased glutamate concentration in and around the synaptic cleft. Indeed, Aβ can stimulate glutamate release through α7nAchR activation on the pre-synaptic neuron and contribute to pre-synaptic facilitation. Pro-inflammatory cytokines, such as TNFα and IL-1β, produced by microglia in the presence of accumulating Aβ, can upregulate AMPAR expression on postsynaptic membrane, which allows higher ion influx and a greater depolarization. All of these changes at the synaptic level lead to a neuronal hyperactivation in the hippocampus and increased LTP in the early stages of AD. Microbiota metabolites such as SCFA, BA and TMAO have been identified in the brain (for details, see Impact of microbiota on neuroinflammation and AD and gut dysbiosis: link with neuroinflammation and involvement of microglia). The negative impact of TMAO on synaptic plasticity (i.e. LTP impairment) has been reported [76] but as the relevant experiments were carried on hippocampal slices ex-vivo which were incubated in the presence of TMAO, it is not clear presently whether TMAO exerts its effect directly on neurons, or indirectly by acting on microglia and subsequently affecting neuronal function via microglia-neuron cross-talk. In contrast, in the 5XFAD mouse model, sodium butyrate (one of the SCFAs) promoted synaptic plasticity as assessed by LTP electrophysiology recording in vivo [77]. The experimental set-up used in this study was unable to determine whether the observed impact on neuronal activity is direct or rather indirect (via microglia). There is currently no data on the putative impact of BA on neuronal activity. (C) Later stages of AD-like pathology are characterized by hypoactivity of the glutamatergic neurotransmission as a consequence of the paradox hyperactivity in earlier stages. Elevated Aβ levels yields reduced glutamate release by pre-synaptic neurons through inhibition of α7nAchRs, which reduces post-synaptic activation of NMDARs. Moreover, chronic stimulation of AMPARs during early stages of AD pathology leads to desensitization and internalization of these receptors. In addition, excessive production of pro-inflammatory cytokines (e. g. TNFα, IL-1β…) by microglia due to toxic conditions created by continued Aβ accumulation, can trigger neuronal death and release of glutamate from dying neurons, thus escalating neurotoxicity. Altogether, this results in reduced LTP and EPSP (and a mirror increase in LTD, not depicted in the figure for the sake of clarity) that are associated with cognitive deficits. Created with Biorender.com

Fig. 2

Hypothetical link between gut dysbiosis and mechanisms leading to the pathogenesis of AD. Alterations in the gut microbiota composition and function in AD patients increases permeability of the intestinal barrier and likely BBB, which creates a vicious cycle of enhancing inflammation at the gut and the CNS level. Early stages of AD (low concentrations of Aβ) are characterized by increased excitability of pyramidal neurons in the hippocampus subsequent to the increased glutamatergic neurotransmission, which in turn translates into presynaptic facilitation, enhanced fEPSP and LTP. Conversely, later stages of AD (high concentrations of Aβ) are associated with marked decrease in excitability and fEPSP, as well as reduced LTP and enhanced LTD, likely related to a decrease in the number of synaptic AMPA receptors and progressive memory loss. Created with Biorender.com

Fig. 3

Therapeutic potential of putative microbiota-based interventions. AD is associated with gut microbiota dysbiosis characterised by increased pro-inflammatory (red microorganisms) and decreased anti-inflammatory (green microorganisms) phyla and altered microbial metabolites amounts. Although significant differences exist according to the geographical and ethnical factors, an increase in Bacteroidetes and decrease in Firmicutes (pro- and anti-inflammatory phyla, respectively) have been reported in AD patients by most studies (see AD and gut dysbiosis: link with neuroinflammation and involvement of microglia). Prebiotics (non-digestible fiber components of the food) have the capacity to stimulate the growth of microbiota with beneficial actions, such as, for example, SCFA-producing microorganisms. Probiotics are live microorganisms (single strain or multi-strain cocktails) providing beneficial effects to the host as for instance, F. prausnitzii. Postbiotics are metabolites produced by microbiota, such, as for example, SCFA. FMT consists of transferring fecal matter from a healthy donor to restore microbiota composition and function of patient. All these approaches could represent protective therapeutic strategies to prevent the shift towards detrimental peripheral inflammation, neuroinflammation, synaptic dysfunction and subsequent neurodegeneration and thereby, slow disease progression (for details, see Restoring AD-associated neuronal function by targeting microbiota?). Created with Biorender.com.