Peripheral nerve injury (PNI) resulting from limb trauma (Noble et al., 1998; Simske et al., 2019), or entrapment syndromes (Bowley and Doughty, 2019; Neal and Fields, 2010; Porter et al., 2002) like carpal and cubital tunnel syndromes in the upper extremities, and peroneal and tarsal tunnel syndromes in the lower extremities, can lead to substantial disability. Besides traumatic PNI and nerve entrapment syndromes, metabolic or autoimmune neuropathies can cause axonal damage to peripheral nerves (Dong and Ubogu, 2022). However, current therapeutic options, including surgical intervention and noninvasive management, do not always achieve satisfactory recovery of sensorimotor nerve functions, particularly among elderly patients (Porter et al., 2002). The age of patient is an important factor in nerve recovery after PNI (Black and Lasek, 1979; Navarro et al., 1988; Painter et al., 2014; Scheib and Hoke, 2016). As the average life expectancy continues to climb, the issue of suboptimal nerve recovery associated with aging will become increasingly prevalent.

In case of peripheral nerve injury, the endoneurial inflammatory response plays a vital role in the process of nerve repair. Abnormal local and systemic immune responses contribute to both tissue damage and impaired recovery (Forbes and Rosenthal, 2014). In this context, a timely orchestration of damage-associated macrophage influx and differentiation is vital to achieve nerve recovery. Typically occurring within the first 7–10 days after nerve injury, infiltration of blood-derived macrophages into the damaged nerve, along with their pro-inflammatory M1 response, ensures the clearance of neural debris. Subsequently, there is a shift towards an anti-inflammatory state mediated by interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1), promoting a pro-regenerative M2 macrophage response that facilitates neurite outgrowth and nerve recovery (David and Kroner, 2011; Liu et al., 2019).

The regenerative capacity of peripheral nerves diminishes with age, which could be associated with chronically elevated systemic and tissue-specific inflammation (Buttner et al., 2018; Scheib and Hoke, 2013), often referred to as inflammaging (Navarrete-Reyes and Montana-Alvarez, 2009). This age-related decline is likely associated with an impaired transition from the M1 to the pro-regenerative M2 macrophage polarization state (Buttner et al., 2018; Liu et al., 2019; Zhao et al., 2023). After sciatic nerve crush injury, inflammaging is reflected by a delayed endoneurial macrophage response, followed by a prolonged macrophage-induced hyperinflammation and thus less efficient nerve recovery (Buttner et al., 2018). Therefore, discovering immunomodulatory strategies to mitigate tissue damage and promote axonal regeneration is highly desirable.

Inflammaging has been linked to imbalances in the gut microbiota, also known as gut dysbiosis (imbalance in beneficial versus detrimental bacteria), and reduced production of short-chain fatty acids (SCFAs) (Lee et al., 2020b). The gut microbiome functions as a balanced homeostatic ecosystem that plays a significant role in sustaining a gut-immune equilibrium. SCFAs, produced primarily by beneficial gut bacteria, are important signaling molecules and stabilize the gut epithelial barrier by moderating inflammation (Thorburn et al., 2014). Under certain circumstances, the gut microbiome balance is disrupted, leading to persistent inflammation and immunity alterations with links to various autoimmune disorders (Lee et al., 2020b; Zhang et al., 2020). Thus, understanding the impact of commensal gut microbiota on PNI and axonal recovery represents an essential novel research area.

It is well documented that gut dysbiosis occurs with aging in both human and animal models (Biagi et al., 2010; Claesson et al., 2011; Lee et al., 2020a). Our previous studies have demonstrated that aged mice exhibit gut dysbiosis compared to younger counterparts, and that these dysbiotic changes contribute to heightened inflammation associated with aging (Lee et al., 2020b). We propose that age-related changes in the gut microbiota among aged individuals lead to impaired gut mucosal barrier integrity and dysfunctional local and systemic immune responses, potentially mediated by a reduction in beneficial microbial metabolites. This cascade of events ultimately contributes to impaired peripheral nerve recovery following PNI in the elderly. In the current study, our investigation focused on assessing the impact of manipulating the gut microbiome through fecal microbiota transplant (FMT) on peripheral nerve repair in aged mice. To achieve this, we employed the sciatic nerve crush model, a well-established mouse model (Lehmann et al., 2007) for studying PNI and the subsequent nerve repair mechanisms. The sciatic nerve crush animal model clinically and pathologically resembles Sunderland Grade IV injuries where the epineurium remains intact and nerve fibers are transected (Sunderland, 1951). Additionally, we assessed the impact of rejuvenating FMT on endoneurial immune responses in aged recipient mice. A visual summary of the experimental design and key findings is presented in the graphical abstract. Understanding the interactions between the gut microbiome and nerve repair mechanisms opens up exciting avenues for future research and potential therapeutic interventions in the context of PNI.