Gut microbiota in chronic inflammation: the interplay with lipid mediators

ABSTRACT

The gut microbiota plays a fundamental role in maintaining host health by regulating immune function, epithelial barrier integrity, and metabolic homeostasis. Disruption of microbial community structure (also known as dysbiosis) and altered host–microbiota interactions can shift microbial composition and metabolite production, promote immune dysregulation, and contribute to the initiation and persistence of chronic inflammation. Eicosanoids, a class of signaling lipid mediators derived from arachidonic acid , are essential modulators of acute and chronic inflammatory responses. Emerging evidence highlights a bidirectional interplay between the microbiota and eicosanoid pathways as a hallmark of chronic inflammation. Microbial taxa and their metabolites regulate arachidonic acid availability, eicosanoid biosynthesis, and receptor signaling in host cells. In turn, host-derived eicosanoids shape the gut environment, influencing the gut microbiota and host health state. This self-reinforcing loop drives key features of chronic inflammatory diseases, including a shift toward pro-inflammatory eicosanoid profiles, a relative deficiency of anti-inflammatory or pro-resolving lipid mediators, and microbiota dysbiosis. In this review, we summarize recent advances in the mechanisms underpinning microbiota-eicosanoid crosstalk, outline its contribution to chronic inflammatory diseases, and discuss the therapeutic potential of targeting this bidirectional axis.

1. Introduction

The gut microbiota forms a vast and complex ecosystem of microorganisms that resides within the human gastrointestinal tract. It plays a fundamental role in aiding digestion, regulating immune function, maintaining gut epithelial homeostasis, and supporting whole-body health.^1-5 In this context, an imbalance in the microbiota, known as dysbiosis, including an increase in the abundance of harmful taxa and a reduction of beneficial taxa, is associated with impaired gut barrier integrity and systemic inflammation, driving the development and progression of various diseases. Gut microbiota dysbiosis can profoundly influence disease induction through the altered production of microbial molecules and metabolites.³ Mechanistically, dysbiosis often leads to an increase in pro-inflammatory bacterial components such as lipopolysaccharide (LPS), which can translocate across a compromised intestinal barrier, often termed “leaky gut”, and trigger systemic inflammation.^6,7 Additionally, imbalances in microbial metabolites can disrupt host metabolic and immune homeostasis.⁸ These alterations collectively contribute to the onset and progression of metabolic, inflammatory, and autoimmune diseases. Thus, microbial-derived metabolites serve as critical mediators linking gut dysbiosis to host pathophysiology.

Chronic inflammation often arises from persistent, low-grade immune activation, which can be triggered by metabolic stress, microbial dysbiosis, and tissue damage.^9-11 These inflammatory programs are shaped by downstream effector systems, such as the key eicosanoid networks.^12,13 Eicosanoids are bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Their biosynthetic pathways and major signaling receptors are outlined in Figure 1. In the gut, they regulate immune responses, epithelial barrier function, and tissue remodeling. Their biological effects are shaped by (i) the spectrum of eicosanoids generated by distinct enzymatic pathways, (ii) the receptor landscape of local target cells, (iii) the state of tissue (homeostasis versus disease), which positions them as key mediators of microbiota-host inflammatory crosstalk, and (iv) the timing of lipid signaling across immune activation and tissue injury, inflammation, and repair. In this context, microbial dysbiosis and eicosanoid dysregulation can amplify each other, creating a self-perpetuating loop to sustain inflammation. Shifts in the gut microbial community can directly and indirectly influence host eicosanoid pathways. For instance, gut microbiota can metabolize dietary fats, including PUFAs, oxidizing them into precursors of lipid mediators and thereby reprogramming the balance of eicosanoids.^14,15 Reciprocally, changes in the host eicosanoid signaling can modify the intestinal microenvironment, which in turn reshapes microbiota community structure and function.^16,17 Collectively, microbiota–host eicosanoid crosstalk represents a critical mechanism that drives the pathogenesis of chronic inflammatory diseases, acting both locally within the gut and at systemic sites.

Figure 1.

Eicosanoid biosynthesis and their receptors. Arachidonic acid (AA) is released from membrane phospholipids by cytosolic phospholipase A₂ (cPLA₂) and is subsequently oxidized by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP450) enzymes, respectively, to generate intermediate products. These intermediates are then converted into eicosanoids, including prostaglandins (PGs, e.g., PGD₂, PGE₂, PGF_2α, and PGI₂), thromboxane A₂ (TXA₂), leukotrienes (e.g., LTB₄ and LTC₄), lipoxins (e.g., LXA₄), hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), and DHETs, by specific terminal synthases, such as prostaglandin synthases, LTA₄ hydrolase (LTA4H), LTC₄ synthase (LTC4S), lipoxygenases (LOXs), and soluble epoxide hydrolase (sEH), respectively. Bioactive eicosanoids signal primarily via cognate cell surface G protein-coupled receptors, although some can also act through nuclear receptors such as the aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptors (PPARs).

In this review, we examine bidirectional crosstalk between the gut microbiota and eicosanoid pathways in the context of chronic inflammation. We summarize current evidence for how microbiota community shifts contribute to eicosanoid imbalance and, in turn, how dysregulated eicosanoid signaling reshapes the microbiota composition and function, collectively influencing host homeostasis and the development of chronic inflammatory diseases. We then detail the specific roles of these pathways in a range of chronic inflammatory diseases, including inflammatory bowel disease (IBD), metabolic disorders, and arthritis. Furthermore, we examine emerging evidence supporting the therapeutic potential of targeting these pathways for disease modulation.

2. Microbiota regulation of host eicosanoid pathways

The gut microbiota plays a critical role in shaping host lipid mediator profiles by controlling both substrate availability and the host enzymatic programs that mobilize these substrates and generate bioactive mediators.^18-20 Microbial community members and their metabolites influence the intestinal handling of dietary components, including fibres, medium-chain fatty acids (MCFAs) and long-chain fatty acids (LCFAs, including PUFAs), by affecting their absorption and incorporation into cell membrane phospholipid pools, and by modulating phospholipase-dependent release of AA, a major precursor for host eicosanoids. In parallel, the microbiota can also regulate lipid mediator metabolism by tuning eicosanoid synthase expression and activity, for example via activation of pattern recognition receptors (PRRs) on host cells (Figure 2A). Together, these mechanisms reprogram the intestinal eicosanoid profile and provide a mechanistic link between microbial dysbiosis and chronic inflammatory conditions.

Figure 2.

Microbiota-eicosanoid directional interactions. (A) Diet-derived microbial metabolites (e.g., SCFAs, HYA) and dysbiosis-associated microbial products (e.g., LPS and related Lipid A) influence PUFA handling, cPLA₂-mediated AA mobilization, and the activity of key eicosanoid-biosynthetic enzymes (COX, LOX, CYP450). These signals reprogramme intestinal eicosanoid profiles, shaping epithelial barrier function, immune responses, and inflammatory outcomes. (B) Dietary fatty acids influence membrane lipid composition and the supply of substrates for cPLA2-mediated release of arachidonic acid (AA). Steroids suppress cPLA₂ activity, whereas NSAIDs inhibit COX-dependent PG biosynthesis and can reciprocally enhance LOX- and CYP450-mediated eicosanoid pathways. The resulting host-derived eicosanoids regulate the gut epithelial barrier niche, shape mucosal immune programs, and in some instances, affect microbial growth. Together, these actions alter microbiota diversity and metabolic output, with consequences for intestinal and systemic health.

2.1. Microbial shaping of eicosanoid precursor pool

Upon entering the digestive tract, dietary fats are predominantly hydrolyzed and absorbed by host cells (primarily enterocytes) in the small intestine, supplying LCFAs that are incorporated into cellular membrane lipid pools. While the gut microbiota has a limited direct role in LCFA digestion, it can aid the metabolism of unabsorbed lipids and shape lipid uptake by influencing host cell emulsification processes.²¹ LCFAs comprise saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and PUFAs, such as AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

PUFAs are key structural components of cellular membranes and serve as precursors for bioactive lipid mediators, such as eicosanoids. The eicosanoid precursors are primarily obtained from dietary fat intake, with AA arising from dietary linoleic acid (ω-6 PUFA) and EPA/DHA from α-linolenic acid (ω-3 PUFAs). Following intake, these fatty acids are incorporated into the host cell membrane, released into the cellular plasma by the actions of phospholipases, and then converted into downstream lipid mediators.²² Dietary ω-6 versus ω-3 PUFA balance can bias the overall eicosanoid profile. While high ω-6 PUFA intake favors AA-derived pro-inflammatory mediators, ω-3 PUFA supplementation generally increases anti-inflammatory and/or pro-resolving eicosanoids.^23,24

The microbiota can further skew the process by biotransforming dietary PUFAs, thereby shifting the availability and balance of different eicosanoid precursors.²¹ For example, gut microbes can directly generate oxylipins from dietary EPA and DHA.¹⁴ Notably, Lactobacillus species convert dietary linoleic acid into 10-hydroxy-cis-12-octadecenoic acid (HYA), which limits the pool of AA available for proinflammatory eicosanoid synthesis.²⁵ Furthermore, gut microbes directly metabolize PUFA-derived epoxides into diols, shifting the colonic eicosanoid profile by reducing colonic levels of epoxide-type eicosanoids and increasing downstream diol metabolites.²⁰ Beyond these specific biotransformations, the gut microbiota can also convert some dietary PUFAs into conjugated and more saturated products via isomerization and hydrogenation,²⁶ lipolysis of complex lipids, and actively convert linoleic acid into bioactive intermediates, thus increasing the availability of precursors and intermediates for downstream eicosanoid production.^27,28

Although the gut microbiota is not generally considered a direct source of LCFAs, certain bacterial strains can be enriched in specific LCFA species. For example, Escherichia coli Nissle 1917 contains higher levels of the anti-inflammatory LCFA 3-hydroxyoctadecaenoic acid (C18-3OH) than other E. coli strains.²⁹ More broadly, the gut microbiota can significantly promote intestinal LCFA utilization and absorption,³⁰ improve intestinal lipid sensing,³¹ and facilitate lipid storage and metabolism,³² therefore shaping the substrate landscape for host lipid mediator generation.

2.2. Microbiota control of eicosanoid precursor mobilization

Besides substrate availability, eicosanoid output also depends on the mobilization of membrane fatty acids, particularly AA release driven by phospholipase activation. The microbiota can prime and potentiate phospholipase activity to drive the release of AA from membrane phospholipids and subsequently expand the substrate pool availability for eicosanoid biosynthesis.^20,22,33 In inflammatory settings, microbial dysbiosis further promotes AA release by triggering pro-inflammatory factors that activate the innate sensing pathway. Collectively, microbiota-dependent control of phospholipase activation provides a critical mechanistic link between dysbiosis and AA monilisation, thereby enabling tuning of downstream eicosanoid biosynthetic enzymes and pathways.

2.3. Microbiota regulation of eicosanoid biosynthesis

Once AA is released, eicosanoid biosynthesis proceeds through three major enzymatic branches (Figure 1). The cyclooxygenase (COX) pathway generates prostaglandins (PGs) and thromboxane via downstream PG synthases.^12,13 The lipoxygenase (LOX) pathway produces leukotrienes (LTs), lipoxins, and some hydroxyeicosatetraenoic acids (HETEs), with key downstream enzymes including LTA₄ hydrolase (LTAH) and LTC₄ synthase (LTC4S). The cytochrome P450 (CYP450) pathway generates additional HETEs and epoxyeicosatrienoic acids (EETs), which are further converted to DHETs by soluble and microsomal epoxide hydrolases (sEH and mEH).²⁰ COX and LOX enzymes can also oxidize ω-3 PUFAs such as DHA and EPA, further expanding the spectrum of bioactive lipid mediators. The final mediator profile is dictated by cell type, anatomical niche, and inflammatory context, which together determine the expression and activity of terminal synthases that convert intermediates into distinct eicosanoid species. Consistent with pathway-specific regulation, microbiota-dependent metabolites can activate CYP450-mediated protective eicosanoids (e.g., DHETs and EETs), with reported hepatoprotective effects in liver injury and fibrosis models.³⁴

2.3.1. Innate sensing pathways control eicosanoid enzymes

Microbiota-driven regulation of eicosanoid biosynthesis is frequently initiated by recognition of microbial components and stimulation by microbial metabolites. PRR activation by bacterial molecules can upregulate key eicosanoid-generating enzymes, including cytosolic phospholipase A₂ (cPLA₂) and downstream COX and LOX enzymes. Mononuclear phagocytes (macrophages, monocytes, and dendritic cells) are major intestinal sources of eicosanoids and respond robustly to bacterial and fungal stimulation by inducing cPLA₂ and COX-2, subsequently increasing eicosanoid output.^16,35 Consistently, Clostridium difficile infection induces COX-2 overexpression in human colonocytes via toxin A-induced reactive oxygen species and p38 MAPK signaling, whereas the probiotic Lactobacillus rhamnosus GG increases COX-2 expression in colonic myofibroblasts through TLR4-MyD88 signaling.^36,37 Infections can trigger an “eicosanoid storm” characterized by COX-2 and 5-LOX upregulation and excessive production of inflammatory eicosanoids such as PGE₂, PGD₂, and cysteinyl leukotrienes.^13,38 Staphylococcus aureus infection similarly increases COX-2- and mPGES1-mediated inflammatory eicosanoids while repressing 15-LOX-mediated specialized pro-resolving mediators in macrophages.³⁹ By contrast, probiotic Lactobacillus and Bifidobacterium reduce COX-2 expression and pro-inflammatory eicosanoid production (e.g., PGE₂) in macrophages.⁴⁰

2.3.2. Microbial metabolites tune eicosanoid enzymes

Microbiota-derived metabolites fine-tune eicosanoid enzyme expression and activity. Among the best-characterized microbial metabolites are short-chain fatty acids (SCFAs), C2–C5 fatty acids primarily generated from the fermentation of dietary fiber. Major SCFAs (acetic, propionic, butyric, and valeric acid) exert diverse physiological effects on immune regulation, metabolic control, tissue regeneration, and cancer biology.⁴¹ In the gut, SCFAs promote the induction of intestinal regulatory T cells,^42-44 stimulate the release of enteroendocrine hormones,⁴⁵ and support intestinal epithelial integrity.⁴⁶

SCFAs also directly modulate eicosanoid synthases, but their effects are cell type- and context-dependent. In subepithelial myofibroblasts, SCFAs shift prostaglandin profiles by enhancing PGE₁ while reducing PGE₂. Through the greater potency of PGE₁, this promotes epithelial MUC2 expression and reinforces mucosal barrier integrity.⁴⁷ In human mononuclear cells (including monocytes), SCFAs, particularly n-butyrate, can synergize with TLR agonists to upregulate COX-2 and, via a G protein-coupled receptor-dependent mechanism, amplify PGE₂ secretion.^48,49 Conversely, SFCAs can epigenetically suppress key eicosanoid-synthesizing enzymes (including COX-2 and mPTGES) through histone deacetylase inhibition in the contexts of colorectal carcinogenesis and vascular smooth muscle cell function.^50,51 In addition, receptor-dependent SCFA signaling (e.g., via GPR43 and GPR41) in enterocytes can promote intestinal inflammatory responses in chemical- or infection-induced colitis models.⁵² Beyond these direct effects, SCFAs can indirectly reshape mucosal immune tone and thereby alter the gut microbiota composition, creating feedback loops that ultimately influence the host intestinal eicosanoid landscape.

Beyond SCFAs, the microbiota intersects with other fatty acid classes that can influence the intestinal inflammatory milieu and microbial ecology. Medium-chain fatty acids (MCFAs), including caproic, caprylic, capric, and lauric acid, are mainly derived from dietary medium-chain triglycerides and are absorbed by intestinal epithelial cells. Although MCFAs are not direct eicosanoid precursors, they can indirectly influence lipid mediator outputs by modulating epithelial integrity and immune tone. MCFAs support energy expenditure and lipid oxidation in various tissues such as the liver and brain^53-55 and promote epithelial renewal, barrier repair, and reduced mucosal inflammation.^56,57 They can also exert antimicrobial activity that reshapes microbiota community structure by reducing pathogenic loads and potentially contribute to host resistance to infection.^58,59 MCFA levels are reduced in patients with IBD,⁶⁰ although immune associations can be context-dependent, for example, caproic acid has been positively associated with inflammatory interferon (IFN)-γ-producing CD4⁺ type 1 T helper (Th1) cells in multiple sclerosis.⁶¹ Age-associated microbiota shifts, especially expansion of Parabacteroides goldsteinii, has also been linked to increased MCFA production (notably 3-hydroxyoctanoic acid), engaging GPR84-expressing peripheral myeloid cells, impairing vagal afferent interoceptive signaling, and thereby reducing hippocampal activation and memory in aged mice.⁶²

2.4. Dysbiosis-driven pathophysiological eicosanoid skewing

During dysbiosis, changes in microbial product composition can amplify innate sensing pathways, reinforce AA mobilization, and promote eicosanoid-dependent inflammatory milieu. Dysbiosis contributes to chronic inflammatory conditions such as IBD, metabolic diseases, and arthritis. In IBD, dysbiosis is often marked by expansion of Proteobacteria, a feature associated with epithelial stress and inflammation.^63-65 Beyond taxonomic changes, dysbiosis can increase the inflammatory potency of microbial products. For example, it can drive remodeling of lipid A, the bioactive portion of LPS, through enhanced activity of bacterial modifying enzymes (e.g., PagP, LpxR, and LpxP), augmenting acylation and reducing phosphorylation levels, and then enhancing lipid A affinity for the toll-like receptor 4 (TLR4)-MD-2 complex.^66,67 Functionally, hypo-acylated lipid A antagonizes TLR4-mediated pro-inflammatory interleukin (IL)-8 production in Crohn's disease (CD), whereas hyper-acylated lipid A activates TLR4 to potentiate IL-8 secretion in ulcerative colitis (UC).⁶⁸ Therefore, lipid A remodeling represents a key mechanism linking microbial imbalance to pro-inflammatory eicosanoid signaling. In turn, TLR4 engagement activates MyD88- and TRIF-dependent MAPK signaling that phosphorylates and activates cPLA₂ and COX-2, facilitating AA release and subsequent eicosanoid production.⁶⁹ Collectively, dysbiosis-driven rewiring of microbial immunogenicity sustains AA mobilization and heightens eicosanoid output during inflammation.

Overall, the gut microbiota modulates host lipid mediator metabolism and signaling through complementary mechanisms that act on eicosanoid precursor pools (PUFAs), precursor mobilization (AA release), and enzymatic programming (COX/LOX/CYP pathways and terminal enzymes, e.g., PTGES, PTGDS, PTGIS, PTGFS, TBXAS), with additional contributions from metabolite signaling and local environmental cues. By reshaping the pool of eicosanoid precursors, dietary fat composition and microbial lipid handling influence downstream eicosanoid biosynthesis. Concurrently, microbiota-derived metabolites (e.g., SCFAs) and microbial products (e.g., LPS) differently tune key enzymatic checkpoints that determine precursor availability and/or eicosanoid biosynthetic processes, recalibrating eicosanoid output and balance. Together, these mechanisms provide a high-level framework for microbiota-driven reprogramming of lipid mediator pathways across homeostatic and inflammatory settings in a context-dependent manner.

3. Eicosanoid regulation of the gut microbiota

Eicosanoids exert their biological effects mainly through cell membrane G protein-coupled receptors, with distinct eicosanoid classes engaging different receptor families and downstream signaling pathways. For example, prostaglandin E₂ (PGE₂) signals via EP1–EP4 receptors, leukotrienes (e.g., LTB₄, LTC₄) bind to BLT1/2 and CysLT1/2 receptors, and lipoxins (e.g., LXA₄) activate FPR2 (formyl peptide receptor 2) and other receptors (Figure 1). In addition, eicosanoids, their precursors, and downstream metabolites can signal through nuclear receptors. Lipoxins and CYP450-generated eicosanoids are ligands for the arylhydrocarbon receptor (AHR),^70,71 while several oxidized eicosanoids (e.g., 15d-PGJ₂, 15-keto-PGE₂) and HETEs can activate peroxisome proliferator-activated receptors (PPARs).^72,73 Through these receptor- and context-dependent pathways, eicosanoids can reshape the gut microbiota by altering gut epithelial barrier and mucus niches, modulating mucosal immune responses and antimicrobial programs, and in some cases directly influencing microbial growth. Upstream dietary and pharmacological interventions further perturb this axis by changing lipid input and membrane composition, AA availability and mobilization, and COXL/LOX/CYP450 pathway output, with downstream consequences for microbial diversity, composition, and function (Figure 2B).

3.1. Eicosanoid–immune interaction reshaping of the microbiota

3.1.1. PGE₂-driven microbiota shifts

PGE₂ is a key regulator of intestinal homeostasis, supporting immune function, epithelial integrity, and containment of bacterial translocation, primarily through EP4 signaling in epithelial cells, innate lymphoid cells, and macrophages.^74,75 Emerging evidence also indicates that PGE₂-EP4 signaling can feed back onto the microbiota, but the direction and functional consequences of these effects are highly context dependent. At steady state, PGE₂-EP4 signaling in myeloid cells reshapes the gut microbiota by reducing SCFA-producing bacteria and dampening myeloid interferon production, which in turn lowers colonic regulatory T cells (Tregs), especially RORγt-expressing Tregs with enhanced regulatory capacity.¹⁷ In contrast, during T cell-mediated intestinal inflammation, myeloid-specific EP4 signaling facilitates a dysbiotic shift characterized by expansion of pro-inflammatory taxa (notably Proteobacteria, especially Escherichia) and loss of segmented filamentous bacteria (SFB) adhesion to the epithelium. This microbial dysbiosis amplifies pathogenic T cell responses and exacerbates inflammation.¹⁶ Together, these studies illustrate that the same eicosanoid receptor pathway can drive microbiota outcomes depending on tissue state.

Consistent with eicosanoid-mediated control of microbial ecology, the PGE₁ analog misoprostol leaves baseline microbiota largely unchanged but restores microbial diversity and community structure after antibiotic perturbation. In particular, misoprostol enriches beneficial taxa such as Porphyromonadaceae and Akkermansia while reducing Bacteroides overgrowth, thereby reducing tissue damage and protecting mice against Clostridioides difficile infection.⁷⁶

3.1.2. Impact of the intestinal barrier

By modulating key physiological functions, eicosanoids also maintain intestinal barrier integrity and limit translocation of bacteria and their products, therefore altering microbial persistence and community stability. Through EP4, PGE₂ stimulates epithelial cell mucin secretion and enhances epithelial junctional protein expression by promoting IL-22 production from group 3 innate lymphoid cells (ILC3s).⁷⁷ However, eicosanoid effects on the barrier can be context-dependent and may become disruptive under inflammatory conditions. In epithelial models, PGE₂ increases intracellular calcium and activates myosin light chain kinase through EP1- and EP4-associated PLC-IP₃ and cAMP-IP₃-Ca²⁺ signaling, thereby redistributing tight junction proteins and increasing paracellular permeability.⁷⁸ In parallel, inflammation-associated fibroblasts can disrupt epithelial architecture through paracrine PGE₂-EP4 signaling that activates a PKA-CFTR axis, driving transepithelial fluid secretion and epithelial cell dysfunction.⁷⁹ Furthermore, inflammatory stimuli [such as tumor necrosis factor (TNF)-α] increase the expression of PG transporters in epithelial cells, promoting vectorial transport of PGE₂ (generated by myeloid cells in the lamina propria) from the basolateral (interstitial) compartment to the apical (luminal) surface. Because EP4 is typically expressed on the apical surface of epithelial cells, the resulting rise in luminal PGE₂ preferentially activates apical EP4 signaling, ultimately disrupting colonic epithelial barrier integrity.⁸⁰ Together, these mechanisms indicate that eicosanoids can either reinforce or undermine epithelial niches, regulating microbial access to the mucosa and shaping the microbial community.

3.1.3. Direct effects on microbes

Eicosanoids may also influence microbes more directly, although the underlying mechanisms remain incompletely defined and require further investigation. For example, PGE₂ has been reported to promote E. coli growth through direct and indirect host-mediated mechanisms, including immunosuppression of lymphocyte activity. Consistent with this, elevated PGE₂ levels correlate with increased bacterial colonization and disease progression.⁸¹ Conversely, PGE₂ has also been reported to synergize with antibiotics to enhance killing of Staphylococcus aureus.⁸² However, as there is currently no evidence that S. aureus synthesizes PGE₂ or expresses cognate PGE₂ receptors, the mechanistic basis of this observation remains unclear.

3.2. Reshaping microbiota via perturbations of eicosanoid tone

3.2.1. Impact of dietary fats and eicosanoid precursors

Dietary fats, including eicosanoid precursors, can reshape gut microbiota diversity and composition with important consequences for intestinal inflammation. Supplementation with 20:4 ω-6 AA, which increases the dietary ω-6/ω-3 ratio, is associated with increased abundance of the Escherichia-Shigella genus and reduced Bifidobacterium pseudolongum in the colonic microbiota.⁸³ These microbial shifts coincide with altered eicosanoid profiles and increased expression of inflammatory genes, including IL-1β and CD40.⁸³

By contrast, supplementation with ω-3 PUFAs such as EPA and DHA generally enhances microbial diversity and enriches beneficial genera such as Veillonella and Dialister.⁸⁴ Multiple studies further report a shift toward SCFA-producing taxa, including Lactobacillus, Bifidobacterium, and Akkermansia, with accompanying increases in SCFA production.^85,86 EPA supplementation has also been reported to reduce LPS-producing bacteria within Bacteroidetes while increasing butyrate-producing Firmicutes, and to enrich beneficial taxa (e.g., Akkermansia muciniphila and Bacteroidetes), increase SCFA production, and reduce Proteobacteria.^87,88 Similarly, dicosapentaenoic acid increases microbial diversity and selectively enriches genera such as Akkermansia, Alistipes, Butyricicoccus, and Lactobacillus, consistent with enhanced production of anti-inflammatory and barrier-protective metabolites.⁸⁹

3.2.2. Impact of pharmacological modulation of eicosanoid biosynthesis

Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX enzymes and thereby reduce prostaglandin synthesis, are associated with disruption of the gut microbial community and NSAID enteropathy. Indomethacin, a non-selective COX inhibitor, significantly alters small intestinal microbiota composition and community structure in association with epithelial injury.^17,77,90,91 A time-course study further showed disruption of the mucosal biofilm, indicating broader changes in microbiota architecture.⁹² NSAID-associated microbiota changes, including enrichment of Bacteroides, Akkermansia, and Parasutterella and reduction of Turicibacter, can contribute to exacerbation of Clostridioides difficile infection and related intestinal inflammation.⁹³ Another NSAID, Ketorolac, similarly increases small intestinal Proteobacteria despite limited effects on overt intestinal mucosal damage.⁹⁴ In humans, aspirin, ibuprofen, and celecoxib have also been reported to significantly shape the gut microbiota, although effects on specific bacterial taxa vary across drugs.⁹⁵ Use of standard dose of aspirin (325 mg) has been suggested to increase the relative abundance of taxa linked to SCFA-associated community structure, including Akkermansia, Ruminococcaceae and Prevotella and relatively decrease Parabacteroides, Bacteroides and Dorea in healthy volunteers.⁹⁶ Overall, while direct NSAID-microbe interactions remain incompletely resolved, pharmacological perturbations of eicosanoid pathways can reshape microbial communities largely through host-mediated effects on barrier and immune tone.

3.3. Impact of other eicosanoid pathways

Different eicosanoid receptor pathways can have distinct, and often opposing, biological functions. For example, LTB₄-BLT1/2 and cysteinyl leukotriene-CysLT1/2 pathways induce neutrophilic and asthmatic inflammatory responses, respectively.^97-100 In a colorectal cancer model (Apc^Min/+ mice), loss of LTB₄-BLT1 signaling was associated with increased Verrucomicrobia (Akkermansia muciniphila) and Firmicutes and decreased Bacteroidetes.¹⁰¹ Interestingly, BLT1-deficiency-driven microbiota changes were MyD88-independent, and BLT1 and MyD88 might act synergistically to control Akkermansia.¹⁰¹

Other eicosanoids also influence barrier function and permeability. PGD₂ and its metabolite 15d-PGJ₂ decrease intestinal permeability.^102-104 While LTB₄-BLT1 signaling maintains intestinal barrier integrity by preserving tight junction proteins,¹⁰¹ other 5-LOX metabolites, such as LTC₄, LTD₄ and 5-HETE, can increase intestinal paracellular permeability by disrupting tight junctions, potentially via PLC/PKC activation.^105,106 Finally, although many eicosanoids are unlikely to directly bind nuclear receptors, some (like PGE₂) can modulate nuclear receptor transcriptional activities in various cell types,^107-109 providing an additional layer of context-dependent regulation.

Overall, eicosanoid-microbiota interactions are highly context dependent, reflecting differences in ligand availability, receptor expression, and the local tissue environment. Challenges remain to identify the dominant eicosanoid pathways that control microbiota in specific physiological or disease settings. Another warrant is to determine to what extent microbiota shifts are driven by host immunity and barrier programs. Establishing these mechanisms is essential to explaining how disease-specific outcomes occur.

4. Microbiota-eicosanoid crosstalk in chronic inflammatory diseases

4.1. IBD

IBD is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract, primarily including CD and UC. Its pathogenesis arises from a complex interplay between genetic susceptibility, dysregulated immune functions, alterations in the gut microbiota, and environmental triggers. In IBD, microbiota-driven innate sensing together with dysregulated PUFA metabolism skews COX/LOX-dependent eicosanoid production. In turn, these lipid mediators reshape microbiota communities by affecting epithelial barrier function and mucosal immune tone, establishing positive feedback loops that fuel ongoing inflammation. Consistent with this, microbial dysbiosis is linked to disturbed intestinal eicosanoid metabolism, especially during inflammation. Conversely, eicosanoid-driven changes in the mucosal environment can further remodel the microbiota and influence disease course. While immune dysregulation and epithelial barrier dysfunction have long been recognized as central features of IBD, emerging evidence suggests that profound metabolic reprogramming, particularly within microbiota-eicosanoid crosstalk, plays a key role in sustaining and amplifying intestinal inflammation (Figure 3).

Figure 3.

Microbiota–eicosanoid interactions in IBD. (A) Under physiological conditions, basal PGE₂ supports epithelial integrity and confers immune protective effects through EP4-mediated actions on epithelial cells, ILC3s (and possibly Th17 cells), and gut-resident macrophages. This helps maintain a stable commensal community. PGE₂ also restrains intestinal Treg responses, contributing to the steady-state balance of mucosal immunity. (B) Pathogenic stress and dysbiotic microbial cues drive increased production of PGE₂ and other inflammatory eicosanoids such as LTB₄ by fibroblasts and myeloid cells. Elevated eicosanoid signaling promotes epithelial injury and fuels mucosal inflammation by enhancing pathogenic Th1 and/or Th17 responses, activating inflammatory macrophages and monocytes, and recruiting neutrophils. These effects may be further amplified via suppression of Tregs. These host inflammatory responses reinforce dysbiosis, including expansion of Escherichia species, loss of beneficial SCFA-producing taxa, and reduced SFB adhesion, leading to sustained barrier breakdown and chronic inflammation.

4.1.1. The COX pathway

Beyond serving as substrates for eicosanoid biosynthesis, dietary fatty acids can also modulate intestinal inflammation through receptor-mediated pathways. For example, PUFAs associated with Western-style diets can promote Crohn’s-like inflammation by inducing epithelial RXR activities.¹¹⁰ In addition, the ω-3/ω-6 PUFA balance helps maintain intestinal barrier function and mucosal homeostasis, and disruption of this balance has been linked to IBD and metabolic disease.^111,112 In both murine models and human intestinal inflammation, the expression of key eicosanoid-synthesizing enzymes, such as COX-1/2 and mPGES, is markedly upregulated, resulting in increased production of PGE₂ and other lipids capable of activating the EP4 receptor. For example, in dextran sodium sulfate- and 2,4,6-trinitrobenzenesulfonic acid-induced experimental models for UC, PGE synthase gene expression and associated PGE₂ production are significantly increased in intestinal and mesenteric lymphatic tissues.¹¹³ Similar upregulation of PGE₂ synthases, elevated PGE₂ levels, and altered production of other eicosanoids have also been reported in T cell-driven animal models for CD.¹⁶ Consistently, increased upregulation of core PGE synthase genes and PGE₂ production were also seen in human UC and CD intestine and blood samples.^16,17,114 In the intestine, stromal fibroblasts and myeloid cells, especially monocytes and macrophages, are major producers of eicosanoids such as PGE₂.^16,37 In stromal cells, eicosanoid synthesis is typically driven by tissue-derived cues including cytokines,^115,116 whereas in myeloid cells it is strongly influenced by microbial stimuli from the intestinal lumen, encompassing both pathogens and commensals.³⁵ By contrast, epithelial cells and other non-myeloid populations generally contribute relatively little to the eicosanoid pool at steady state. However, under epithelial stress or inflammatory signaling, epithelial eicosanoid production can increase and act locally to influence epithelial repair and barrier function.

Under homeostatic conditions, the microbiota-COX-PGE₂-EP4 axis supports mucosal integrity and regulates immune responses (Figure 3A). This pathway can be initiated by specific commensal or probiotic strains, such as Lactobacillus rhamnosus GG, which stimulate MyD88-dependent, COX-2-driven PGE₂ production to promote epithelial restitution.³⁷ Acting on intestinal epithelial cells, PGE₂-EP4 signaling enhances survival and regeneration via the cAMP-PI3K-ERK pathways, thereby reducing apoptosis, promoting proliferation, and preserving goblet cell populations to restore barrier integrity.¹¹⁷ EP4 activation in epithelial cells also suppresses TNF-induced necroptosis by inhibiting the RIPK1–MLKL cascade¹¹⁸ and accelerates wound repair by inducing wound-associated epithelial cell differentiation through a non-canonical Wnt pathway involving GSK-3β inhibition and nuclear β-catenin accumulation.¹¹⁹

Beyond the epithelium, the PGE₂-EP4 pathway coordinates repair and immune regulation across stromal and immune compartments. In the stromal-lymphatic niche, EP4 promotes lymphangiogenesis via the VEGF-VEGFR3 signaling,¹²⁰ and gut microbial stimulation of lymphatic endothelial cells can recruit immature myeloid cells that secrete COX-2-derived PGE₂. This eicosanoid acts through EP4 to further enhance lymphangiogenesis and induce regenerative factors such as R-spondin 3, supporting intestinal epithelial repair and regeneration.¹²¹ In parallel, bacterial or inflammatory cues activate a TPL2-ERK-COX-2-PGE₂-EP4 cascade in intestinal myofibroblasts, reinforcing epithelial proliferation.¹²² Immunologically, EP4 signaling in ILC3s boosts the production of IL-22 and antimicrobial peptides (e.g., Reg3β and Reg3γ).⁷⁷ In T cells, PGE₂ promotes type 17 T helper (Th17) cell differentiation and expansion, and Th17-driven IL-17 plays protective roles similar to IL-22 in maintaining intestinal epithelial homeostasis.¹²³ PGE₂-EP4 signaling has also been implicated in shaping adaptive immunity, with enteroprotective effects linked to regulation of Treg function and suppression of Th1 cell activation.^124,125

In addition to effects in epithelial, stromal, and lymphoid cells, the PGE₂-EP4 axis is likely to be particularly important in myeloid cells, given that they are among the dominant intestinal sources of PGE₂ and express high levels of EP4, positioning them to both generate and respond to this signal within the gut. Selective deletion of mPGES1, the terminal enzyme for PGE₂ biosynthesis, in non-lymphoid cells reduced Treg abundances in both mesenteric lymph nodes and the colon, expanded inflammatory CD4⁺ T cells, and worsened T cell-driven colonic inflammation.¹²⁴ Mechanistically, PGE₂-EP4 signaling in macrophages/monocytes can limit gut injury and promote tissue repair, in part through regulating IL-10 and TGF-β signaling. For example, Na et al. showed that EP4 activation in CSF1R⁺ macrophages promoted CXCL1 production, which in turn drives epithelial differentiation and proliferation in regenerating crypts during dextran sulfate sodium (DSS)-induced colitis, thereby enhancing mucosal repair.⁷⁵ Consistent with a protective EP4 axis in macrophages, Nakatsuji et al. reported that macrophage-specific deficiency of EP4-associated protein (EPRAP), a cytoplasmic EP4-interacting molecule required for EP4-driven downstream cAMP signaling, increased multiple pro-inflammatory mediators (e.g., CXCL1, MCP-1, IL-6, and IL-1β) and worsened DSS-induced colitis and inflammation-associated colorectal cancer, whereas macrophage-specific EPRAP overexpression ameliorated DSS colitis.¹²⁶ In line with these findings, we and others have further observed that EP4 deletion in additional Cre-driven macrophage lineages (e.g., CD11c-Cre and CX₃CR1-cre) similarly exacerbated DSS-induced colitis (reference¹²⁷ and unpublished observations). These findings from animal models are consistent with recent genetic and single-cell network analyses showing that a PTGER4 (encoding EP4)-containing co-expression meta-module of UC risk genes in healthy macrophages may be linked to cAMP-related signaling pathways that could influence macrophage activation.^127,128

On the other hand, dysregulated or sustained COX-PGE₂-EP4 signaling can exacerbate intestinal inflammation by engaging immunological epithelial and microbial pathways (Figure 3B). PGE₂ can reinforce microbiota dysbiosis through EP4-dependent suppression of type I interferon production in mononuclear phagocytes and limitation of intestinal Treg expansion and accumulation, establishing a pathogenic feed-forward loop.¹⁷ In parallel, EP4 can also directly act on CD4⁺ T cells to bias differentiation toward inflammatory effector lineages. For example, PGE₂, signaling through EP2 and EP4 receptors, directly inhibits Treg differentiation and functions. Mice with a specific knockout of EP2 or EP4 in CD4⁺ T cells or Foxp3⁺ Tregs show higher Treg frequencies in the intestine and peripheral lymph nodes, and they experience less intestinal inflammation in different colitis models.^129-131 Within the tumor microenvironment, however, PGE₂-EP2/EP4 signaling has also been observed to encourage Treg induction and maintain Treg phenotype.^132,133 PGE₂-EP4 signaling has been shown to promote Th1 and Th17 polarization and effector function, increase their accumulation in the intestine, and amplify mucosal inflammatory responses.^{124,129,130,134} Consistent with a clinically relevant role for this pathway, host–microbe co-evolution analyses of IBD genetic risk loci identified PTGER4 among genes whose IBD-associated variation bears signatures of selective pressure linked to microbial exposure, supporting a role for altered EP4 signaling in shaping mucosal immune-microbial homeostasis.¹³⁵

At the barrier level, although PGE₂ is well-known to critically maintain intestinal integrity, but it can also impair intestinal integrity under certain conditions. Clinically, intestinal COX-2–PGE₂–EP4 pathway gene expression was elevated at baseline in IBD patients compared with non-IBD controls and was highest in IBD patients resistant to anti-TNF therapy relative to both anti-TNF responders and non-IBD patients. Following anti-TNF treatment, COX-2–PGE₂–EP4 signaling decreased in responders, whereas it failed to decline and remained persistently high in non-responders.¹⁶ These findings link enhanced and sustained activation of the COX-2–PGE₂ pathway in anti-TNF failure with heightened intestinal inflammation and impaired epithelial regeneration, potentially through suppression of stem cell function, providing a plausible mechanism for treatment resistance in ulcerative colitis.¹³⁶ Loss of IL-10 signaling in macrophages increased expression of PGE₂-EP4 pathway genes, elevated PGE₂ production, and impaired macrophage bacterial killing.¹³⁷ Collectively, these findings suggest that context-dependent modulation of PGE₂-EP4 signaling may help rebalance microbiota–eicosanoid interactions and control amplified inflammation in IBD. Therapeutically, targeting the COX- PGE₂-EP4 axis can mitigate intestinal inflammation in experimental settings. COX inhibitors reduce colitis severity in animal models, at least in part by limiting PGE₂ overproduction.¹³⁸ In addition, microbiota-derived factors (e.g., HM0539 from L. rhamnosus GG) and microbiota-modulating agents such as berberine have been reported to alleviate colitis by suppressing the COX-2–PGE₂ signaling.^139,140

4.1.2. The LOX pathway

Enhanced 5-LOX activity and increased LTB₄ production represent a major proinflammatory pathway that links microbial sensing to immune activation in IBD. Elevated 5-LOX activity and LTB₄ levels have been reported in inflamed colonic tissue and in leukocytes from IBD patients.^141-143 Microbial PRR signaling, particularly Dectin-1 activation in intestinal macrophages, upregulates 5-LOX and LTA₄ hydrolase and promotes LTB₄ biosynthesis and inflammasome-dependent IL-1β production, thereby exacerbating tissue injury.¹⁴⁴ In contrast, disruption of microbial recognition further perturbs bacterial community structure and ameliorates colitis severity.¹⁴⁵ LTB₄ can also amplify inflammation by reinforcing microbial dysbiosis. For example, BLT1 deficiency reshapes gut microbiota composition, including enrichment of Akkermansia muciniphila, but impairs antimicrobial responses, leading to MyD88-dependent pro-inflammatory cytokine production, COX-2 induction, and enhanced susceptibility to colitis and tumorigenesis.¹⁰¹ As a key neutrophil chemoattractant, the increased neutrophil chemotactic activity observed in IBD mucosa is largely attributable to LTB₄.¹⁴⁶ Beyond recruitment, LTB₄ also acts as a neutrophil-derived secondary amplifier that enhances the magnitude of neutrophil transepithelial migration initiated by epithelial hepoxilin A3.¹⁴⁷ Consistently, pharmacological blockade of LTB₄ signaling reduces neutrophil infiltration and oedema in experimental colitis, supporting a pathogenic role for this pathway.¹⁴⁸ Similarly, intestinal manipulation was shown to induce 5-LOX-dependent LTB₄ production and leukocyte infiltration in the muscularis externa, contributing to postoperative ileus, and these effects were ameliorated by 5-LOX-deficiency or antagonism.¹⁴⁹ Collectively, the 5-LOX-LTB₄-BLT1 axis emerges as a key microbiota-responsive amplifier of IBD pathology, representing a potential therapeutic target to control intestinal inflammatory responses.

4.2. Metabolic diseases

Metabolic diseases are characterized by impaired glucose and lipid homeostasis, chronic low-grade systemic inflammation, and insulin resistance. Diabetes mellitus features persistent hyperglycemia due to impaired insulin secretion and/or reduced insulin sensitivity, leading to widespread disturbances in whole-body energy metabolism. Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which is associated with hepatocellular damage, inflammation, and fibrosis. These interlinked conditions share key features, including abnormal lipid accumulation and reduced metabolic flexibility, underscoring an important role for gut microbiota–lipid interactions in metabolic dysfunction. In metabolic disease, gut dysbiosis and barrier dysfunction promote metabolic endotoxemia, linking microbial signals to systemic inflammation and insulin resistance. In parallel, metabolic stress and microbial cues reprogramme hepatic eicosanoid pathways, particularly the CYP450-EET-sEH axis, affecting steatohepatitis progression, fibrosis, and glucose homeostasis. Dietary fats shape these processes by supplying substrates for eicosanoid biosynthesis and modulating host-microbial energy metabolism, altering the intestinal milieu and downstream metabolic outcomes (Figure 4).

Figure 4.

Microbiota–eicosanoid interactions in metabolic diseases. (A) A diet with balanced fatty acids (low ω-6/ω-3 PUFA ratio) and high fiber helps maintain gut epithelial barrier integrity, microbial homeostasis, a balanced eicosanoid profile, normal endocrine hormone levels (e.g., GLP-1), and immune equilibrium. These coordinated effects support metabolic health, including efficient lipid and glucose metabolism and intact insulin signaling. (B) A high-fat diet, particularly when combined with an imbalanced fat composition such as an elevated ω-6/ω-3 PUFA ratio, disrupts gut barrier function, induces microbial dysbiosis, disturbs immune and eicosanoid balance, and reduces protective endocrine hormones. These changes impair lipid and glucose metabolism, promote hepatic inflammation, and contribute to the development of metabolic diseases, including NAFLD/NASH and insulin-resistant diabetes.

4.2.1. Gut microbiota dysbiosis and metabolic endotoxemia

One hallmark of metabolic dysfunction is gut microbial dysbiosis, which depletes SCFA producers and enriches pro-inflammatory LPS-linked taxa, promoting endotoxemia, inflammation, and insulin resistance. Patients with type 2 diabetes (T2D) mellitus commonly exhibit a decrease in butyrate-producing taxa (e.g., Faecalibacterium and Roseburia) alongside an expansion of opportunistic LPS-producing bacteria. These compositional changes are accompanied by reduced SCFA levels and increased systemic LPS levels, which together promote chronic, low-grade inflammation and insulin resistance.^150-153 Similarly, patients with NAFLD/NASH show an increased abundance of pro-inflammatory taxa (e.g., Bacteroides, Ruminococcus, Streptococcaceae, Enterobacteriaceae, and Veillonella) and reduced abundance of potentially beneficial taxa (e.g., Prevotella, Lactobacillaceae, and Bifidobacterium).¹⁵⁴ Importantly, microbial shifts in NAFLD/NASH correlate with histological severity, and the enrichment of certain genera (e.g., Bacteroides, Ruminococcus) has been associated with NASH and more advanced fibrosis.¹⁵⁵ Microbiota-derived SCFAs shape host metabolism by modulating enteroendocrine hormone secretion and attenuating inflammatory responses, thereby influencing both glucose and lipid homeostasis.^156,157 Accordingly, dysbiosis-associated SCFA depletion has been linked to impaired glucose regulation and augmented susceptibility to metabolic disorders.¹⁵⁸ In rodent models, interventions that restore SCFA-producing bacteria and subsequently SCFA levels can improve metabolic outcomes.¹⁵⁹

Metabolic endotoxemia is characterized by elevated circulating LPS, largely arising from increased intestinal permeability, and is strongly associated with high-fat diet consumption and microbial dysbiosis.^158,160 Following intestinal bacterial overgrowth and/or translocation, increased circulating LPS activates the TLR4/CD14 axis, promoting systemic, low-grade chronic inflammation and insulin resistance in T2D mellitus.^161-164 Consistently, fasting LPS levels are significantly increased in patients with T2D mellitus,¹⁶⁵ and endotoxemia predicts an increased risk of developing diabetes.¹⁶⁶ In NAFLD, endotoxemia similarly contributes to hepatic inflammation,^167,168 as reflected by elevated plasma endotoxin levels, which correlate positively with hepatic steatosis severity and disease progression.^169,170 Moreover, low-dose LPS also sustains low-grade activation of p38 MAPKs and neutrophil infiltration, exacerbating high-fat diet-induced steatohepatitis.¹⁷¹ Therapeutic modulation of the gut microbiota (e.g., with probiotics or antibiotics) can reduce endotoxemia, rebalance eicosanoid profiles, improve gut barrier function, and attenuate metabolic inflammation in both clinical and experimental settings.^20,172,173

4.2.2. Dysregulation of the CYP450-EET-sEH pathway

Hepatic eicosanoid metabolism is profoundly dysregulated in metabolic disease, particularly with alterations in the CYP450–EET–sEH axis. EETs exert beneficial effects on glucose homeostasis by supporting pancreatic islet cell function and enhancing peripheral insulin sensitivity.¹⁷⁴ In addition to host enzymes, the gut microbiota contributes to colonic lipid metabolism by converting EETs into their corresponding diols.²⁰ Specifically, commensal bacteria-derived dihydroxy fatty acids, the downstream sEH pathway products (e.g., 9,10-DiHOME), facilitate the differentiation of regulatory T cells.¹⁷⁵ In type 1 diabetes mellitus, EETs protect pancreatic β-cells from cytokine-induced apoptosis by inhibiting NF-κB activation and nitric oxide production.¹⁷⁶ Increasing EET biosynthesis, for example via CYP2J3 gene therapy, improves insulin sensitivity and reduces blood pressure in diabetic rodents, partly by enhancing insulin receptor signaling and activating AMPK in peripheral tissues.¹⁷⁷ Conversely, sEH promotes insulin resistance and reduces islet size in high-fat diet-induced T2D mellitus.¹⁷⁴ Furthermore, sEH inhibition has been shown to alleviate high-sucrose diet-induced colonic inflammation and bolster tight junction integrity, highlighting it as a potential therapeutic approach for gut barrier dysfunction.¹⁷⁸

Beyond diabetes, this pathway is also pivotal in NASH and NAFLD pathogenesis. In pediatric NAFLD, hepatic EET levels increase during steatosis (consistent with reduced sEH activity) but decline as fibrosis develops (reflecting diminished CYP450 epoxygenase expression), suggesting a stage-dependent protective role.¹⁷⁹ While high-fat diet-upregulated sEH facilitates disease progression,¹⁸⁰ sEH inhibition attenuates hepatic inflammation and steatosis.¹⁸¹ Specifically, sEH inhibition attenuates chronic ethanol-induced liver injury by increasing EpFA levels and reshaping the gut microbiota, but it fails to enrich Akkermansia in ethanol-fed mice.¹⁸² Moreover, sEH deficiency or pharmacological inhibition alleviates diet-induced endoplasmic reticulum stress in liver and adipose tissue, improves insulin signaling, and attenuates carbon tetrachloride-induced hepatic fibrosis, highlighting sEH as a promising therapeutic target in metabolic syndrome and liver fibrosis.^183,184

4.2.3. Therapeutic microbiota–eicosanoid interventions

Fecal microbiota transplantation (FMT) can restore microbial homeostasis and shows therapeutic promise in metabolic diseases. In NAFLD/NASH, FMT reduces hepatic fat accumulation and attenuates steatohepatitis by correcting gut microbiota dysbiosis, with clinical efficacy appearing more pronounced in lean than in obese phenotypes.^185-188 In T2D mellitus, FMT improves glycemic control, lipid profiles, and insulin resistance by reshaping the gut microbiota, alleviating the hyperglycemia, and reversing insulin resistance and reducing body mass index through enriching beneficial taxa, including Chlorobium phaeovibrioides, Bifidibacterium adolescentis, and Synechococcus sp.WH8103.^189-191 Repeated FMT in obese patients with T2D mellitus has been shown to promote sustained engraftment of lean donor microbiota, and combining FMT with lifestyle interventions further enriches beneficial probiotics and improves lipid profile and liver stiffness.¹⁹² Moreover, FMT may ameliorate T2D mellitus by remodeling the gut communities in ways that shift their serum metabolites, reinforce gut barrier function, and suppress systemic inflammatory immune responses.¹⁹³

These effects at least partially reflect FMT-driven changes in microbial metabolites and lipid signaling. Microbial metabolites such as SCFAs enhance insulin secretion and sensitivity, strengthen the intestinal barrier, and suppress chronic inflammation through their receptors including GPR41, GPR43 and GPR109A.^194-197 Accordingly, dietary SCFA supplementation and pharmacological strategies that increase SCFA availability can ameliorate insulin resistance, hepatic steatosis, and NASH progression through activating AMPK and GLP-1 signaling, and also enhance gut barrier function via the anti-inflammatory pathway.^197-200 Dietary PUFAs similarly intersect with the microbiota-eicosanoid axis. Supplementation with ω-3 PUFA increases pro-resolving lipid mediators,²⁰¹ modulates gut microbiota composition,^202,203 and alleviates NAFLD/NASH progression.²⁰⁴ In addition, gut microbiota-dependent PUFA metabolism (e.g., conversion of dietary linoleic acid to bioactive metabolites such as HYA) improves glucose homeostasis and promotes intestinal peristalsis, thereby reducing lipid absorption and adipose inflammation.²⁵ Consistently, high-fiber dietary intervention reduces liver steatosis, improves PUFAs profiles, and lowers PGE₂ levels in patients with NAFLD.²⁰⁵

Chronic low-grade inflammation can drive COX-2 upregulation and sustained PGE₂ production, aggravating metabolic dysfunction. Clinically, circulating PGE₂ metabolites correlate with T2D milieu status and therapeutic response.²⁰⁶ Pharmacological COX-2 inhibition ameliorates hepatic inflammation and improves insulin resistance in NASH by suppressing the non-canonical Wnt5a/JNK1 pathway.²⁰⁷ However, genetic deletion of mPGES-1 worsens NASH-associated liver inflammation and hepatocyte apoptosis by disrupting PGE₂-mediated suppression of macrophage TNF-α production, suggesting that blanket inhibition of PGE₂ biosynthesis may be context-dependent and that other PGs may also shape disease biology.²⁰⁸ Accordingly, targeting downstream PG receptors (e.g., IP or EP3) is likely to provide a more selective means to regulate liver inflammation, fibrosis, and pancreatic β-cell dysfunction.^209,210

4.3. Arthritis–RA, SpA

Arthritis, notably rheumatoid arthritis (RA) and spondyloarthritis (SpA), is an immune-mediated joint disorder driven by distinct yet partially overlapping immunopathological pathways. RA typically presents with symmetric polyarthritis and synovial hyperplasia, maintained by pro-inflammatory cytokine networks (e.g., TNF-α and IL-6) and autoantibody-associated immune responses. By contrast, SpA is marked by predominant axial and entheseal inflammation and is often accompanied by extra-articular manifestations. Despite these clinical differences, both conditions reflect a complex interplay of genetic susceptibility, environmental triggers, and mucosal immune dysregulation. In inflammatory arthritis, gut microbiota dysbiosis and alterations in microbial metabolites can drive mucosal immunity and promote systemic immune activation, contributing to joint inflammation. Within the joint, COX- and LOX-derived eicosanoid pathways help set the inflammatory tone, linking gut-driven immune perturbations to synovial inflammation, neutrophil recruitment, and bone remodeling (Figure 5). These observations together suggest that microbiota-eicosanoid crosstalk links intestinal mucosal dysregulation to the immune processes that drive joint pathology.

Figure 5.

Microbiota-eicosanoid interactions along the gut-joint axis in arthritis. Gut microbial dysbiosis activates inflammatory myeloid cells through altered bacterial products and metabolites, such as increased LPS and reduced SCFAs, driving the differentiation of pathogenic Th1 and Th17 cells and promoting their migration to the joint. Within the synovial niche, circulating microbial products stimulate local fibroblasts and myeloid cells to generate high levels of pro-inflammatory eicosanoids (including PGE₂, PGI₂, and LTB₄). These mediators amplify joint inflammation by expanding pathogenic T cells, activating inflammatory macrophages/monocytes, and recruiting neutrophils. Altogether, these signals promote synovial fibroblast activation and osteoclast differentiation, leading to bone erosion and chronic joint inflammation.

4.3.1. Gut microbial dysbiosis in arthritis

Beyond intestinal inflammation and metabolic inflammation (including liver diseases and diabetes mellitus), chronic inflammation in distal tissues, such as the joints, can also reciprocally influence the gut microbiota and promote dysbiosis. In RA and SpA, disease-associated gut microbial dysbiosis reshapes microbial taxa and metabolite profiles, thereby engaging mucosal and joint immune pathways that modulate inflammation.

In RA, expansion of Prevotella copri frequently coincides with depletion of Bacteroides and other beneficial taxa. Additional RA-associated microbes include Fusobacterium nucleatum, Eggerthella lenta, Escherichia coli, Collinsella, Lactobacillus, and Streptococcus.^211-215 Mechanistic evidence further supports a pathogenic role for specific taxa. For example, Fusobacterium nucleatum can aggravate disease via FadA-containing outer membrane vesicles,²¹⁶ and Subdoligranulum is targeted by autoantibodies in at-risk individuals.²¹⁷ Integrated microbiome-metabolome analyses have also revealed enrichment of Klebsiella and Escherichia and depletion of Fusicatenibacter, accompanied by disrupted tryptophan and glycerophospholipid metabolism.²¹⁸

In SpA, disease activity correlates with the abundance of Ruminococcus gnavus, Clostridium bolteae, Clostridium symbiosum, and Dialister.^215,219,220 Among HLA-B27⁺ ankylosing spondylitis patients, increased Faecalibacterium prausnitzii and Coprococcus and decreased Bacteroides fragilis, Ruminococcus, and Akkermansia muciniphila have been reported.²²¹ Similarly, reductions in Ruminococcus and Akkermansia distinguish psoriatic arthritis (PsA) from healthy controls and from psoriasis patients without arthritis.²²²

Across RA and SpA, a common functional signature is the loss of SCFA-producing bacteria and reduced butyrate availability. Butyrate-producing taxa such as Bifidobacterium in RA and Faecalibacterium prausnitzii in SpA are markedly decreased.^212,223,224 RA is additionally characterized by enrichment of butyrate-consuming species, which also contributes to lower butyrate levels and facilitates joint autoimmunity and bone erosion.²²⁵ In line with this, higher SCFAs levels correlate with non-progression to arthritis in at-risk of individuals, whereas declining butyrate appears to precede the clinical onset of RA and PsA.^226,227

These microbial and metabolic factors are linked to mucosal immune dysregulation, particularly Th17 polarization and dissemination, which connects intestinal inflammation to joint pathology. Expansion of pro-inflammatory Th17 cells strongly correlates with systemic disease activity in RA.²²⁸ Subdoligranulum didolesgii translocate across the intestinal epithelium and directly trigger Th17 cell responses,²¹⁷ while SFB potently induce small intestinal Th17 cells and facilitate their systemic dissemination.^229-231 Additionally, IgA-coated E. coli in CD-associated SpA promotes Th17-mediated inflammation, further supporting a gut-joint immune axis.²³²

Finally, functional studies and interventions support a causal contribution of SCFAs to disease modulation. SCFAs attenuate disease severity in HLA-B27 and β2-microglobulin transgenic models and in experimental arthritis,^233,234 increase bone volume, and suppress osteoclastogenesis in K/BxN and collagen-induced arthritis models.²³⁵ Consistent with these mechanisms, high-fiber dietary interventions increase systemic SCFAs, reduce pro-inflammatory mediators, and improve the functional outcomes in clinical settings.^236,237

4.3.2. The COX Pathway

Microbial dysbiosis and associated metabolic shifts can also influence eicosanoid pathways within the joint microenvironment. In RA, COX-2 is upregulated, and prostaglandin production, especially PGE₂ and PGI₂, is increased. These mediators stimulate IL-6 production from synovial fibroblasts and promote Th1/Th17 activation via the EP4, EP2, and IP receptors, thereby amplifying joint inflammation.^238,239 In SpA, PGE₂-EP4 signaling is linked to radiographic progression by enhancing pathogenic bone formation via interactions between CD14^highEP4⁺ cells and mesenchymal stem cells.²⁴⁰ Notably, EP4 signaling exerts context-dependent effects on bone remodeling, but in inflammatory settings, it can promote osteoclastogenesis and osteolysis by inducing RANKL (receptor activator of NF-κB ligand) expression in stromal/fibroblastic and osteoblastic cells, activating the RANKL-RANK axis.^241-243 In parallel, PGE₂ signaling via EP4/EP2-cAMP pathway can further drive bone resorption matrix degradation, in part through induction of matrix metalloproteinases.^244,245 Clinically, targeting this pathway remains highly relevant. COX-2 inhibition is a first-line treatment strategy for inflammatory joint symptoms, with celecoxib providing effective symptom control in RA and ankylosing spondylitis,^246,247 while EP4 antagonism suppresses inflammatory T-cell responses, alleviates pain, reduces disease severity,²⁴⁸ and attenuates RANKL-induced osteoclast differentiation and bone resorption.²⁴⁹ Collectively, dysbiosis-linked activation of the COX-2-PGE₂-EP4 axis provides a mechanistic bridge between altered microbial metabolism, joint inflammation, and bone remodeling, but it remains a tractable therapeutic target in inflammatory arthritis.

4.3.3. The LOX Pathway

LTB₄ biosynthesis is governed by the coordinated activity of 5-LOX and 5-LOX-activating protein. 5-LOX is predominantly expressed in RA synovial macrophages, neutrophils, and mast cells.²⁵⁰ Across inflammatory arthritis, LTB₄ signaling has been implicated in both RA and PsA. Elevated LTB₄ production and oxidative stress contribute to PsA progression²⁵¹ and may serve as a predictive biomarker for PsA development.²²⁶ Mechanistically, LTB₄ amplifies synovial inflammation by inducing inflammatory cytokines (e.g., TNF-α, IL-1β, IL-32, IFN-γ) and chemokines in synovial fibroblasts and immune cells, while also promoting synovial cell apoptosis.^252,253 In addition, IL-23-driven LTB₄ activates BLT1/BLT2 receptors on osteoclast precursors, triggering PLC-dependent calcium signaling and NFAT activation, thereby inducing osteoclastogenic gene expression and driving bone erosion.²⁵⁴ Consistent with these mechanisms, pharmacological inhibition of 5-LOX or 5-LOX-activating protein suppresses pro-inflammatory leukotriene production and exhibits anti-inflammatory efficacy, and targeting this pathway limits joint destruction in a murine model.^255,256 However, despite correlations between neutrophil LTB₄ release and disease activity, an LTB₄ antagonist, BIIL 284, showed limited efficacy in human RA trials, highlighting a complex and compensatory inflammatory landscape.^257,258 Overall, the 5-LOX-LTB₄ pathway provides a strong mechanistic link between synovial inflammation and bone erosion, but the clinical benefit of targeting this pathway requires further evaluation.

5. Conclusion

The bidirectional interplay between gut microbiota and eicosanoid signaling plays a critical role in the pathogenesis of chronic inflammatory diseases such as IBD, metabolic disorders, and arthritis. The dysregulation of this axis perpetuates inflammation and tissue damage. Current challenges include the context-dependent functions of key mediators like the EP4 receptor, the complexity of host-microbe interactions, and the risk of side effects from targeting broadly active pathways such as COX and LOX. A deeper understanding is needed of how microbiota dysbiosis, microbial products and metabolites, host bioactive lipid signaling pathways, and the host immune system are integrated across inter-kingdom and inter-organ networks in both homeostatic and chronic inflammatory conditions. It is also important to clarify how these interactions are shaped by external inputs, such as diets and medications. Future research should focus on elucidating cell-type and context-specific mechanisms, developing targeted therapies that selectively modulate pro-resolving pathways without disrupting homeostasis, and exploring personalized interventions guided by individual microbiota and lipid mediator profiles. Integrating multi-omics data with clinical outcomes will be essential to translate these insights into effective, safe, and precision-based anti-inflammatory strategies.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Data availability statement

Not applicable.