A network approach to investigating the key microbes and stability of gut microbial communities in a mouse neuropathic pain model

Abstract

Background Neuropathic pain is an abnormally increased sensitivity to pain, especially from mechanical or thermal stimuli. To date, the current pharmacological treatments for neuropathic pain are still unsatisfactory. The gut microbiota reportedly plays important roles in inducing neuropathic pain, so probiotics have also been used to treat it. However, the underlying questions around the interactions in and stability of the gut microbiota in a spared nerve injury-induced neuropathic pain model and the key microbes (i.e., the microbes that play critical roles) involved have not been answered. We collected 66 fecal samples over 2 weeks (three mice and 11 time points in spared nerve injury-induced neuropathic pain and Sham groups). The 16S rRNA gene was polymerase chain reaction amplified, sequenced on a MiSeq platform, and analyzed using a MOTHUR- UPARSE pipeline. Results Here we show that spared nerve injury-induced neuropathic pain alters gut microbial diversity in mice. We successfully constructed reliable microbial interaction networks using the Metagenomic Microbial Interaction Simulator (MetaMIS) and analyzed these networks based on 177,147 simulations. Interestingly, at a higher resolution, our results showed that spared nerve injury-induced neuropathic pain altered both the stability of the microbial community and the key microbes in a gut micro-ecosystem. Oscillospira, which was classified as a low-abundance and core microbe, was identified as the key microbe in the Sham group, whereas Staphylococcus, classified as a rare and non-core microbe, was identified as the key microbe in the spared nerve injury-induced neuropathic pain group. Conclusions In summary, our results provide novel experimental evidence that spared nerve injury-induced neuropathic pain reshapes gut microbial diversity, and alters the stability and key microbes in the gut.

The gut microbiota-neuroimmune crosstalk and neuropathic pain: a scoping review

“…Of the 48 full texts reviewed, only 15 articles met the set inclusion criteria (Figure 1). The reviewed articles encompassed 13 studies using various animal models (Sommer et al, 2001;Gwak et al, 2006; ("neuropath"):ti,ab,kw AND ("microbiota"):ti,ab,kw ("neuropathic pain"):ti,ab,kw AND ("bacteria"):ti,ab,kw ("nerve pain"):ti,ab,kw AND ("gut microbe"):ti,ab,kw ("neuralgi"):ti,ab,kw AND ("gut bacteria"):ti,ab,kw ("neuropathy"):ti,ab,kw AND ("gut microbiome"):ti,ab,kw ("neuropath"):ti,ab,kw AND ("probiotics"):ti,ab,kw ("neuropathy"):ti,ab,kw AND ("prebiotics"):ti,ab,kw ("neuropathic"):ti,ab,kw AND ("synbiotic"):ti,ab,kw ("neuropathic pain"):ti,ab,kw AND ("postbiotic"):ti,ab,kw ("neuralgia"):ti,ab,kw AND ("chemotherapy"):ti,ab,kw ("neuropathy"):ti,ab,kw AND ("chemo-induced"):ti,ab,kw ("neuropathic pain"):ti,ab,kw AND ("chronic constriction injury"):ti,ab,kw ("neuropathy"):ti,ab,kw AND ("nerve-CCI"):ti,ab,kw ("neuropathic pain"):ti,ab,kw AND ("chronic constriction nerve injury"):ti,ab,kw ("neuralgia"):ti,ab,kw AND ("spinal injury"):ti,ab,kw ("hyperalgesia"):ti,ab,kw AND ("spinal nerve injury"):ti,ab,kw ("neuropathic pain"):ti,ab,kw AND ("SNI"):ti,ab,kw: ("hyperlagesia"):ti,ab,kw AND ("spared nerve injury"):ti,ab,kw: (((1 OR 3) AND 3 AND 5) OR ( 5 Austin et al, 2012;Bráz et al, 2012;Wardill et al, 2016;Shen et al, 2017;Ramakrishna et al, 2019;Yang et al, 2019;Brandon-Mong et al, 2020;Chen et al, 2021;Cuozzo et al, 2021;Ding et al, 2021;Lian et al, 2021), a single in vitro study (Castelli et al, 2018), and a single randomised controlled trial (RCT) with 327 enrolled participants, Table 2 (Ellis et al, 2022).…”

Droplet microfluidics-based high-throughput bacterial cultivation for validation of taxon pairs in microbial co-occurrence networks

“…Co-occurrence network analyses based on metagenomic and amplicon sequences have been frequently used to infer microbial relations in environmental or host microbiomes, and further predict microbial interactions (positive or negative) in these environments 9 , 23 , 24 , 40 , 41 , which are informatic for discovering the true microbial interactions attributing to either microbial properties (such as metabolic coupling, nutrient competition, etc.) or from environmental filtration (such as responding similarly to environmental factors or due to physical separation) 42 , 43 .…”

“…Microbial co-occurrence networks are composed of nodes [operational taxon units (OTUs)] and edges (predicted relations among microbes) 9 , 23 , 24 . The more nodes and edges, the more complex the microbial co-occurrence networks 25 , 26 .…”

Brachial plexus avulsion induced changes in gut microbiota promotes pain related anxiety-like behavior in mice

“…It is well-studied that gut microbes influence many biological processes including immunity, metabolism, and central nervous system (CNS) ( 10 – 12 ). The effects of gut microbiota on NPP animal models have also been characterized ( 13 , 14 ). Extensive studies have shown that the microbiota can directly or indirectly influence brain homeostasis through affecting anxiety and the occurrence of neurological diseases were related to nerve conduction dysfunction in animal models ( 15 ).…”