For over a decade, the role of short-chain fatty acids (SCFAs) as mediators of the microbiota-host communication in the regulation of pain has been explored. Particularly, butyrate has been described as an analgesic and anti-hyperalgesic mediator of microbiota-host communication [1]. This narrative, however, is incomplete. Although most studies exploring this issue point to an anti-inflammatory and analgesic role of butyrate, other studies reveal contradictory conclusions: the same microbial metabolites, butyrate in this example, might also exacerbate hyperalgesia [2]. Similarly, evidence shows that propionate predominantly exerts anti-nociceptive effects, reducing hyperalgesia in inflammatory, trigeminal/migraine, and visceral pain models through anti-inflammatory, antioxidant, and neuroprotective mechanisms [3]. However, when present as part of a sustained, elevated SCFA milieu (rather than administered alone), it can contribute to microglia-driven pain sensitisation in neuropathic contexts [4]. Acetate displays a more ambivalent and context-dependent profile: at high systemic or local concentrations, it can be clearly pronociceptive (e.g., headache models and chemical irritation-induced visceral pain), whereas under conditions of microbiota-mediated physiological modulation, moderate acetate levels have been associated with reduced visceral hypersensitivity. In neuropathic settings, sustained increases in acetate as part of a combined SCFA pool can also participate in the maintenance of chronic pain [4].

This controversy persists because research has treated SCFAs as isolated mediators rather than as components of an integrated signalling system. Since many SCFA receptors might bind the same ligands, but with different affinities (see Table 1), and are expressed in different cell types involved in regulatory circuits of pain (immune cells, nociceptive neurons, epithelial cells, and others), we propose here an integrative model for the role of these bacterial mediators in the regulation of pain. We hypothesize that SCFAs operate within a competitive triad of receptors whose internal balance determines pain outcomes. This triad consists of three context-dependent axes: i. A pro-inflammatory immune axis, ii. a resolution-promoting metabolic axis, and iii. a direct neuronal sensing axis. Their dynamic interplay, which we refer to as triad competition, functions across multiple biological levels. At the ligand level, SCFAs with overlapping receptor affinities compete for binding. At the cellular level, distinct cell populations differentially sequester and metabolise these ligands.

Finally, at the network level, their downstream transcriptional and metabolic programmes exert reciprocal regulation, whereby activation of one axis can suppress or enhance signalling through the others. In this framework, pain does not result simply from the presence or absence of SCFAs, but from a disruption in the balance among the axes of the triad. Understanding how this competition is regulated enables movement beyond correlative associations towards a predictive, mechanistic understanding of how microbial metabolism shapes nociception.

Distinct pain disorders exhibit characteristic microbial signatures that move beyond mere correlation and increasingly suggest causality. Chronic visceral pain conditions, particularly irritable bowel syndrome (IBS), are consistently associated with fermentative dysbiosis, characterised by increased abundance of Prevotella and Bacteroides species. These bacteria generate high levels of propionate and acetate, a profile that correlates with symptom severity [14]. Conversely, chronic neuropathic pain states frequently display a depletive dysbiosis marked by reduced microbial diversity and lower abundance of butyrate-producing genera such as Roseburia [15]. In inflammatory and post-surgical pain models, broad-spectrum antibiotics have been shown to either attenuate or exacerbate pain, directly implicating microbial communities in both the initiation and resolution of pain [16]. Together, these clinical and experimental patterns provide a critical conceptual bridge between the microbial ecosystem and the pain phenotype, underscoring the need for mechanistic explanations linking microbiota dynamics to nociceptive regulation.

This “receptor triad” model reaches its full potential when conceptualised as a dynamic signalling balance system. Chronic pain does not arise from the simple presence or absence of SCFAs, but from pathological imbalances among three interdependent axes: a pro-inflammatory immune axis, a resolution-promoting metabolic axis, and a direct neuronal sensing axis, each shaped by distinct dysbiosis profiles. Within this framework, the adaptive immune component, particularly colonic T-cells, emerges as a pivotal mediator that translates microbial metabolism into long-term neuroimmune outcomes.

Butyrate produced by Roseburia intestinalis has been shown to activate the vagus nerve via GPR41 and to modulate brain circuits that suppress pain in mouse models of neuropathic pain induced either by oxaliplatin or by spared nerve injury [1]. Propionate has also been reported to alleviate neuropathic pain by inhibiting the inflammatory RIG-I–NF-κB signalling pathway in a mouse model of sciatic nerve transection [34].

Regarding inflammatory pain, butyrate has been shown to reverse the hyperexcitability of trigeminal ganglion neurons induced by inflammation in a rat model of orofacial inflammation triggered by complete Freund’s adjuvant [35]. Furthermore, in a mouse model of nitroglycerin-induced migraine, both propionate and butyrate reduce pain and promote the restoration of the intestinal epithelial barrier [36].

In the context of visceral pain, however, results concerning butyrate remain controversial. Using a rat model of colorectal distension, one study reported that butyrate promotes pain. Mechanistic analyses indicated that butyrate acts on mast cells via GPR43, thereby promoting the sensitisation of dorsal root ganglion neurons [18]. Therefore, the triad model appears to be limited to neuropathic and inflammatory pain and does not seem to adequately account for visceral pain.

The SCFA receptor triad model resolves the longstanding paradox by reconceptualising SCFA signalling as a competitive balance system. Chronic pain arises from specific axis imbalances shaped by underlying dysbiosis. This framework provides more than mechanistic insight; it offers a precision medicine roadmap in which identifying dysbiosis profiles and dominant axes can guide targeted therapeutic interventions. By moving beyond correlation towards mechanistic prediction, it opens new avenues for treating pain through the strategic rebalancing of microbial-host communication.