Table 2.
Major characteristics and results of the included studies
| Study Country |
Study type | Study intervention | Microbiota involvement |
|---|---|---|---|
| Nerve injury and neuropathic pain | |||
| Chen et al. (2021) China |
Pre-clinical study (animal model) | 16S rDNA amplicon sequencing and serum and spinal cord metabolomics were used to identify microbiota and metabolite changes in sham (control) and CCI (Chronic Constriction injury) model rats | The gut microbiota composition differed between CCI-induced neuropathic pain rats and sham controls There was an increase in Helicobacter, Phascolarctobacterium, Christensenella, Blautia, Streptococcus, Rothia, and Lactobacillus In contrast, a decrease in the abundance of Ignatzschineria, Butyricinomonas, Escherichia, AF12, and Corynebacterium Additionally, 72 serum metabolites and 17 spinal cord metabolites differed significantly between CCI and sham rats |
| Brandon-Mong et al. (2020) Taiwan |
Pre-clinical study (animal model) | Sixty-six faecal samples from three mice and at 11-time points in the spared nerve injury-induced neuropathic pain (SNI-NP) and Sham groups were analysed The 16S rRNA gene was PCR amplified and sequenced on a MiSeq platform |
SNI-NP changes gut microbial diversity; the microbial community in the gut micro-ecosystem was affected by SNIP-NP In the Sham group, Oscillospira, which was classified as a low-abundance and core microbe, was identified as the primary microbe In contrast, in the SNI-NP group, Staphylococcus – classified as a rare and non-core microbe, was identified as the primary microbe |
| Yang et al. (2019) China |
Pre-clinical study (animal model) | Comparing the gut microbiota makeup of the three groups (sham, anhedonia susceptible, and resilient rats) using 16S rRNA gene sequencing | The anhedonia-vulnerable gut microbiota differed from the sham-operated and resilient gut microbiota There was pain, depression, and anhedonia in antibiotic-treated rats, suggesting that the gut microbiota is responsible for these atypical behaviours Transplanting anhedonia-prone rat faeces into antibiotic-treated pseudo-germ-free mice increased pain and depression-like characteristics, including anhedonia However, transplanting resilient rat faeces into antibiotics-treated pseudo-germ-free mice improved pain and depression-like behaviours, including anhedonia |
| Drug-induced neuropathic pain | |||
| Ellis et al. (2022) United States |
Clinical study (Human) | Comparing gut microbial diversity and dysbiosis in people with HIV (PWH) and people without HIV (PWoH) with distal neuropathic pain (DNP). The gut microbiome was characterised using 16S rRNA sequencing, and diversity was assessed using phylogenetic tree construction | In contrast to PWoH in PWH, more severe DNP was related to reduced alpha diversity measured by Faith’s phylogenetic diversity Gut dysbiosis, specifically reductions in diversity and relative increases in Blautia and Clostridium to Lachnospira ratios plays a role in the prevalence of DNP in PWH |
| Ramakrishna et al. (2019) United States |
Pre-clinical study (animal model) | 129SvEv and C57BL/6 mice are sensitive and resistant to Paclitaxel-induced discomfort, respectively Reciprocal gut microbiota transfers and antibiotic depletion in B6 and 129 mice with changes in Paclitaxel-induced pain sensitivity |
Microglia increased in the spinal cords of Paclitaxel-treated mice with the pain-sensitive B6 microbiota but not the pain-resistant 129 microbiota, which had no immune cells invading Microglia are causally engaged in Chemotherapy-induced peripheral neuropathy (CIPN), and gut bacteria are the drivers of this phenotype |
| Shen et al. (2017) United States |
Pre-clinical study (animal model) | Mechanical hyperalgesia in germ-free (GF) and specific pathogen-free (SPF) mice treated with oxaliplatin | Oxaliplatin-induced neuropathic pain was reduced in GF mice and antibiotic-treated mice Restoring the microbiota of GF mice abolished the effects |
| Gut-neuroimmune crosstalk in neuropathic pain | |||
| Wardill et al. (2016) Australia |
Pre-clinical study (animal model) | The gut microbiome profile of control animals was determined through bacterial faecal sample sequencing TLR4 deletion reduces chemotherapy-induced gastrointestinal damage, and the pain was assessed in an animal model |
Chemo-drug-Irinotecan-induced gastrointestinal toxicity and pain were reduced in TLR4-deficient mice |
| Costigan et al. (2009) United Kingdom |
Pre-clinical study (animal model) | In response to the sparing nerve injury (SNI) model of peripheral neuropathic pain, compared the gene expression profiles in the spinal dorsal horn of adult and newborn rats | Compared to neonatal, in adult rats, spinal cords indicate a greater microglial and T-cell response Following peripheral nerve injury in the dorsal horn of the spinal cord, T-cell infiltration and activation promote the evolution of neuropathic pain-like hypersensitivity in adult rats than neonatal rats |
| Potential therapeutic targets of neuropathic pain | |||
| Cuozzo et al. (2021) Italy |
Pre-clinical study (animal model) | Each of the four experimental groups utilised ten animals (40 animals) in total: G1: Vehicle-treated Sham Mice (n = 10) G2: Probiotic-treated sham mice (n = 10) G3: Paclitaxel + Vehicle (n = 10) G4: Paclitaxel + probiotics (n = 10) |
In an ex vivo analysis, probiotic administration boosted the expression of opioid and cannabinoid receptors in the spinal cord, avoided nerve fibre injury in the paws, and altered serum pro-inflammatory cytokines concentration in CIPN-mice Probiotic administration maintained gut integrity and function. Also, probiotics reduced mechanical and cold hypersensitivity in paclitaxel mice |
| Lian et al. (2021) China |
Pre-clinical study (animal model) | All C57BL/6J mice were sorted into four groups: G1: Regular water and Saline (H2O + Saline) G2: Regular water and oxaliplatin (H2O + OXA) G3: Hydrogen-rich water and saline injections (HW + Saline) G4: Hydrogen-rich water plus oxaliplatin (HW + OXA) |
Hydrogen-rich water may diminish oxaliplatin-induced hyperalgesia, modify gut microbiota diversity and structure, reverse inflammatory cytokines and oxidative stress, and lower LPS and TLR4 expression |
| Ding et al. (2021) United States |
Pre-clinical study (animal model) | Broad-spectrum antibiotics/water were given to perturbed gut microbiota in mice, CCI in the intervention group, and water in the control mice The spinal cord infiltrating T cells was characterised by examining interferon (IFN)-γ, interleukin (IL)-17, and Foxp3, depleting regulatory T cells |
Oral antibiotics altered gut microbiota and slowed CCI neuropathic pain development Changes in gut microbiota skew immune profiles from pro-inflammatory to anti-inflammatory Foxp3+ regulatory T cells were protective against neuropathic pain mediated by gut microbiota changes, but their depletion increased IFN-producing Th1 cell infiltration in the spinal cord |
| Castelli et al. (2018) Italy |
In vitro study | Multistrain Probiotic Product (De Simone Formulation)-DSF probiotic formulation in an in vitro model of a sensitive neuron, the F11 cells | A probiotic formulation reduced Paclitaxel-induced neuropathic pain |
| Austin et al. (2012) Australia |
Pre-clinical study (animal model) | In two neuropathy models, sciatic nerve chronic constriction injury and experimental autoimmune neuritis (EAN) in rats, the effects of increasing regulatory T cells (Tregs) on pain hypersensitivity and neuroinflammation were investigated | Tregs play a key role in endogenous recovery from neuropathy-induced pain In nerve-injured and EAN-affected rats, boosting nTregs with CD28SupA lowers neuroinflammation and pain hypersensitivity, but lowering nTregs with an anti-CD25- depleting antibody enhances pain hypersensitivity in nerve-injured mice |
| Bráz et al. (2012) United States |
Pre-clinical study (animal model) | Immature telencephalic GABAergic interneurons from the mouse medial ganglionic eminence (MGE) were transplanted into the adult mouse spinal cord |
The MGE-derived GABAergic interneurons can reverse the mechanical hypersensitivity caused by peripheral nerve injury. Thus, they can be used to alleviate spinal cord hyperexcitability in neuropathic pain |
| Sommer et al. (2001) Germany |
Pre-clinical study (animal model) | Mice were given etanercept or sham treatment by local nerve injection to the injured nerve or by systemic application to study whether the etanercept can reduce neuropathic pain in chronic constriction injury of sciatic nerve animals model | Etanercept competitively inhibits tumour necrosis factor-alpha (TNF) Etanercept significantly reduced mechanical allodynia and thermal hyperalgesia in both application methods, suggesting a therapeutic option for neuropathic pain |