Study overview

The PubMed search results yielded 378 studies; ultimately 32 met criteria to be included in narrative review. Studies were published from 2003 to 2024, utilized murine models (50%), in-vitro models (22%), or a combination (28%); with investigational scope which covered molecular mechanisms, immunologic pathways, and therapeutic strategies. Reported tissue types included pulmonary, cardiac, renal, lymphatic, gastrointestinal, nervous (brain), adipose, osseous, urologic, dental, hepatic, pancreatic, and uterine. Common inflammatory cells and markers included, M1 macrophage counts, nitric oxide (NO)/inducible nitric oxide synthase (iNOS), TNF-α, IL-6, IL-1β, MyD88, and NF-κB. In animal models, metabolic endotoxemia was induced via direct LPS injection, antibiotic courses or fatty diets to trigger gut dysbiosis, or cecal ligation and puncture. The methodological landscape included transcriptomics, cytokine profiling, and disease progression models (Fig. 1, Table 1).

Fig. 1

PRISMA flow diagram for study selection process

Table 1 Summary of studies included in review, organized by organ/system investigated by each author groupM1 Macrophage polarization mechanism

The core mechanism underlying LPS-mediated macrophage polarization and tissue dysfunction is conserved across diverse organ systems, including pulmonary [22,23,24,25,26,27], cardiac [28,29,30,31,32], renal [33], lymphatic [34], gastrointestinal [35, 36], nervous (brain) [14, 37, 38], adipose [39, 40], osseous [41], urologic [42], dental [43], hepatic [44], uterine [45, 46], pancreatic [47], and global/systemic [48,49,50,51,52] (Table 1).

In the studies evaluated, LPS originated from endogenous gut sources or exogenous injection; regardless of endotoxin origin, similar innate immune pathways were triggered. Across tissue types, the M1 macrophage polarization mechanism begins with the recognition of the LPS bioactive lipid A domain. This moiety binds either soluble or membrane-bound lipopolysaccharide-binding protein (LBP), forming an LPS-LBP complex that is transferred to CD14. The CD14 protein acts as a co-receptor, presenting the LPS ligand to the transmembrane pattern recognition receptor, Toll-like receptor 4 (TLR4), which is universally expressed on macrophage membranes throughout the body.

Toll-like receptor 4’s affinity for LPS is enhanced by its non-covalently associated co-receptor MD-2, which forms a hydrophobic binding pocket for lipid A. After ligand engagement, the TLR4/MD-2 complex dimerizes, triggering downstream signaling via both MyD88-dependent (early-phase NF-κB and MAPK activation) and TRIF-dependent (late-phase IRF3/7 activation and Type I interferon production) pathways. Lipopolysaccharide is demonstrated to be one of the only ligands which concurrently triggers both MyD88 and TRIF pathways.

Throughout the body, activation of the NF-κB pathway results in macrophage polarization to the classically activated, pro-inflammatory (M1) phenotype, which includes the upregulation of pro-inflammatory cytokines TNF-α, IL-6, IL-1β, as well as iNOS, and reactive oxygen species (ROS). This inflammation is shown to cause pathophysiologic systemic changes, as well acute disruption of tissues throughout the body. The inflammatory-immune-tissue injury cascade, beginning with the proximate step of LPS from the gut, is shown in Fig. 2.

Fig. 2

Gut dysbiosis leads to the weakening of tight junctions between epithelial cells in the large intestine. A compromised gut barrier allows for the translocation of LPS into the bloodstream. Across tissue types, circulating LPS binds to TLR4 on the surface of macrophages, triggering NF-κB pathways. This molecular cascade promotes macrophage polarization to a pro-inflammatory (M1-like) phenotype, and upregulates TNF-α, IL-6, IL-12, IL-1β cytokine production. Chronic innate immune activation is associated with dysfunction across diverse tissue types. This mechanism is conserved throughout the body (original figure created using BioRender software (Toronto, ON, Canada))

Mechanistic chain completeness evaluation

The author-proposed mechanism linking gut dysbiosis to peripheral neuropathy mirrors pathways previously demonstrated across multiple organ systems. To quantify this mechanistic conservation across heterogeneous models, we constructed an evidence map for in-vivo studies capturing direct measurement of the following key pathway steps:

(1) Gut perturbation→(2) gut barrier disruption→(3) circulating LPS→(4) systemic inflammatory response→(5) tissue interface disruption→(6) tissue innate immune activation→(7) M1-like macrophage skew→(8) tissue dysfunction.

If a pathway step was explicitly evaluated in a study and exhibited positive findings, it was scored as “1”; if a step was explicitly evaluated in a study and exhibited null or negative findings it was scored as “0”. To mitigate the risk of false positive or negative bias in mechanistic concordance or completeness, no evidentiary contribution was assigned to mechanistic steps not evaluated in the included literature. Therefore, if a step from the proposed pathway was not examined in an included study, it was marked as “not evaluated” and removed from concordance or completeness calculation. For studies using gut dysbiotic models as a source of endogenous LPS, scoring began at gut perturbation; for studies using injected exogenous LPS, scoring began at the most proximal assessable step (either circulating LPS or tissue innate immune activation, depending on study design). A study was considered to exhibit full downstream chain completeness only if all steps from proximal LPS introduction through tissue dysfunction were individually evaluated and positive.

Twenty-three in-vivo studies were eligible for mechanistic mapping. Eleven studies explicitly evaluated all downstream mechanistic steps from LPS introduction to tissue dysfunction; all 11 (100%) exhibited full downstream chain completeness. Across all in-vivo studies, we additionally calculated conditional concordance (number of positive steps divided by number of steps assessed). Mean conditional concordance was high among the included studies (0.984 ± 0.053; range 0.80–1.00), indicating strong alignment of assessed findings with the proposed pathway.

Among downstream steps, the most frequently evaluated were M1 macrophage skew (20/23, 87.0%), tissue innate immune activation (20/23, 87.0%), and circulating LPS (19/23, 82.6%). Direct evidence of tissue interface disruption associated with LPS was assessed in 15 studies, all of which reported positive findings (100%).

Together, this evidence map indicates that, following systemic LPS introduction, the downstream inflammatory-immune-tissue injury cascade demonstrates conservation across diverse models, organ systems evaluated, and irrespective of whether LPS exposure was endogenous or exogenous.

Tissue-specific nuances

While the core molecular cascade by which LPS polarizes macrophages toward an M1-like phenotype demonstrates conservation regardless of tissue type, the expression of this polarization may be further modulated by tissue-specific microenvironments, macrophage ontogeny, and local immunologic signaling. As such, some tissues exhibit a modified M1 response correspondent with either increased sensitivity or tolerogenic demands.

Alveolar macrophages

Alveolar macrophages (AMs), located throughout the alveolar epithelial layer at the air-tissue interface, are chronically exposed to airborne pathogens, allergens, and particulates. To prevent excessive inflammation and preserve the integrity of the alveolar gas-exchange barrier, AMs exhibit a tightly regulated pro-inflammatory polarization response.

The immune restraint of AMs is maintained, in part, through cross-talk with alveolar epithelial cells, particularly type II pneumocytes, which secrete immunomodulatory signals including granulocyte–macrophage colony-stimulating factor, transforming growth factor-beta, and surfactant proteins A and D. These factors work in concert to preserve AM homeostasis and suppress inappropriate TLR activation. However, with LPS exposure, regulatory control mechanisms become overwhelmed, driving AMs largely toward a pro-inflammatory, M1-like phenotype.

The resultant pro-inflammatory environment can disrupt epithelial integrity and promote alveolar-capillary barrier breakdown. This pathophysiology is a hallmark of acute lung injury and acute respiratory distress syndrome, both of which are frequently observed in septic patient populations.

Adipose macrophages

Adipose tissue, particularly in the context of clinical obesity, is actively inflammatory. As such, infiltrating macrophages within adipose tissue are exposed to a pro-inflammatory microenvironment conducive to M1 phenotyping.

Adipocytes and macrophages can synergistically trigger pro-inflammatory cascades in one another, which often results in a feed-forward inflammatory loop, especially in the presence of LPS. For instance, LPS can intensify adipocyte release of monocyte chemoattractant protein-1 and serum amyloid A. Both of these factors act as chemoattractants, recruiting more monocytes and promoting M1 polarization, which increases localized levels of pro-inflammatory cytokines. Additionally, LPS itself triggers lipolysis in adipocytes, increasing levels of free fatty acids (FFA). Like LPS, the FFA molecule is a ligand which activates TLR4 pathways. Lipopolysaccharide-liberated FFAs therefore increase M1 macrophage polarization alongside LPS, further amplifying pro-inflammatory cytokine production, accelerating lipolysis, and sustaining a self-perpetuating inflammatory loop. It is this inflammatory microenvironment in adipose tissue that also contributes significantly to systemic low-grade inflammation and metabolic dysfunction in obesity [39, 40].

Microglia

The CNS maintains an immune-privileged, anti-inflammatory microenvironment, tightly regulated by cross-talk among astrocytes, neurons, and microglia. Homeostasis is maintained by immunomodulatory cytokines such as TGF-β, interleukin-10 (IL-10), and CX3CL1 (fractalkine).

Unlike peripheral macrophages, microglia are long-lived, yolk-sac derived cells with tightly restricted activation profiles under baseline conditions. Upon systemic exposure to LPS, the resultant elevated levels of circulating cytokines act in concert with LPS to disrupt the integrity of the blood-brain barrier (BBB) by degrading tight junction proteins (e.g., ZO-1, occludin, claudins) and upregulating leukocyte adhesion molecules (ICAM-1, VCAM-1). This barrier compromise permits the infiltration of peripheral immune cells, plasma proteins, and microbial products into the CNS parenchyma.

Upon BBB disruption, microglia, alongside astrocytes, produce ROS, NO, and pro-inflammatory cytokines (e.g., IL-1β, TNF-α), amplifying neuroinflammation. This self-sustaining immune activation loop contributes to further BBB dysfunction, synaptic damage, and neuronal injury. Chronic dysregulation of this axis has been implicated in the progression of neurodegenerative and neuropathic disorders. Notably, these mechanisms underscore the vulnerability of glial-regulated, barrier-protected tissues to systemic immune disruptions, parallels that will be further explored in the context of peripheral nerve tissue.

Proposed LPS-driven peripheral neuropathy

The BNB is dual-layered, composed of the endothelial tissue of intrinsic nerve microvasculature and the multilayered perineurium which encases nerve fascicles. This selectively permeable barrier provides structural protection and maintains an immune-privileged endoneurial microenvironment surrounding peripheral nerve axons and their associated glial support cells.

A stepwise pathophysiologic link between gut dysbiosis and BNB compromise has been increasingly delineated in the literature. Mechanisms have been described for the disruption of gut epithelial tight junctions [53], which allows translocation of bacterial LPS into the bloodstream [54]. Circulating LPS induces systemic inflammation through activation of TLR4 on monocytes and macrophages, driving secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [55]. These cytokines, alongside LPS itself, are known to degrade endothelial tight junctions and upregulate leukocyte adhesion molecules [56], including within the vasculature of the BNB [57]. As such, it is biologically plausible that systemic inflammation may result in increased permeability of the peripheral nerve barrier, facilitating infiltration of circulating immune cells, cytokines, and microbial products into the otherwise immune-restricted nerve tissue.

This stepwise progression from epithelial gut barrier dysfunction to neurovascular compromise outlines a feasible mechanistic pathway from gut dysbiosis to BNB disruption. This is effectively, a “leaky gut to leaky nerve” cascade.

Given the conserved nature of LPS-induced M1-like macrophage polarization across diverse tissue types, and the parallels between the CNS and peripheral nerve in terms of barrier regulation, glial support, and immune privilege, the authors propose the following mechanism linking chronic gut dysbiosis to downstream peripheral neuropathy (Fig. 3):

(1)

Gut dysbiosis – characterized by metabolite imbalance, increased pathogenic bacterial endotoxins (i.e., LPS), thinning of the protective mucus layer, and marked increase in pro-inflammatory cytokines – impairs the integrity of tight junctions between intestinal epithelial cells.

(2)

Weakened tight junctions and damaged gut epithelial cells allow for increased translocation of LPS into the bloodstream.

(3)

LPS activates TLR4 on the surface of monocytes and macrophages, triggering NF-κB pathways and upregulating the release of pro-inflammatory cytokines (TNF-α, IL-6, IL-1 β) in circulation.

(4)

Increased levels of LPS and pro-inflammatory cytokines access and act upon the intrinsic microvasculature of peripheral nerves and begin to weaken the tight junctions of the endothelial cells of the blood-nerve barrier.

(5)

The blood-nerve barrier becomes structurally compromised and immune cells, pro-inflammatory cytokines, and LPS infiltrate the immune privileged endoneurial environment surrounding nerve axons.

(6)

Infiltrating LPS and pro-inflammatory cytokines begin to polarize resident endoneurial macrophages to an M1 or pro-inflammatory phenotype. LPS exposure also changes the functionality of Schwann cells, further inducing pro-inflammatory pathways and amplifying neuroimmune dysregulation. Disruption of homeostatic mechanisms leads to myelin destruction, axonal damage, and neuropathic dysfunction.

Fig. 3

Proposed pathway linking gut dysbiosis to downstream peripheral neuropathy. Original figure created using BioRender software (Toronto, ON, Canada)

It is important to note that Schwann cells play a central role in peripheral nerve immune modulation. Somewhat analogous to glial cells in the CNS, Schwann cells support axonal function and contribute to the maintenance of the BNB. Under homeostatic conditions, Schwann cells help preserve the immune-privileged endoneurial environment through expression of anti-inflammatory mediators and tight junction proteins. However, in the presence of systemic inflammation and LPS infiltration, Schwann cells become reactive, upregulating TLR4, producing pro-inflammatory cytokines themselves (e.g., TNF-α, IL-6), and initiating complement cascade activation [58, 59]. These changes, in concert with M1 macrophage infiltration, can drive a pathologic neuroimmune feedback loop that disrupts axonal support, promotes demyelination, and accelerates neuropathic degeneration.

This reactive profile may mirror glial dysregulation in the CNS, highlighting the shared vulnerability of glial-governed, barrier-protected tissues to systemic immunologic perturbation. The parallels between microglial and Schwann cell response pathways further support the plausibility of LPS-driven neuropathy within peripheral nerve tissue under chronic inflammatory conditions.