Heat stress disrupts gut microbiota to increase LPS levels and enhance arginine catabolism, amplifying MyD88-dependent inflammatory responses, while exogenous arginine suppresses inflammation by activating MyD88 ubiquitination and weakening the MyD88-TLR4 interaction.
Key Findings
Results
Heat stress disrupted gut microbiota, characterized by increased LPS levels and enhanced arginine catabolism in HS mice.
Gut microbiota composition was significantly altered in heat stress (HS) mice compared to controls
HS led to elevated lipopolysaccharide (LPS) levels, indicative of increased gut barrier permeability and gram-negative bacterial products entering circulation
Enhanced arginine catabolism was identified as a key microbial metabolic change associated with HS
These findings established a dual disruption: increased pro-inflammatory LPS and decreased anti-inflammatory arginine availability
Results
Fecal microbiota transplant from HS mice aggravated inflammatory responses in recipient mice following heat stress.
Recipient mice that received fecal microbiota transplantation (FMT) from HS mice showed worsened inflammatory responses after being subjected to HS themselves
This experiment demonstrated that the gut microbial alterations induced by HS are sufficient to amplify HS-associated inflammation
The FMT model provided causal evidence that gut microbiota changes drive, rather than merely correlate with, enhanced inflammatory responses
Results
Exogenous arginine pretreatment notably suppressed inflammation in the liver and cortex of HS mice.
Arginine pretreatment reduced inflammatory markers in both hepatic and cortical tissues of HS-exposed mice
The protective effect was observed in two distinct organ systems, suggesting a systemic anti-inflammatory mechanism
This finding identified arginine as a key mediator whose depletion by gut microbiota contributes to HS-associated multi-organ inflammation
Results
Arginine mechanistically reduced MyD88 protein levels by activating its ubiquitination and weakening the MyD88-TLR4 interaction, thereby inhibiting nuclear translocation of p65 and expression of pro-inflammatory genes.
Arginine promoted ubiquitination-mediated degradation of the MyD88 adaptor protein, reducing its availability for downstream signaling
The MyD88-TLR4 protein-protein interaction was weakened in the presence of arginine, disrupting assembly of the pro-inflammatory signaling complex
Reduced MyD88 activity resulted in decreased nuclear translocation of p65 (NF-κB subunit), a master transcriptional regulator of inflammation
Downstream expression of pro-inflammatory genes was inhibited as a consequence of this signaling disruption
This identified a MyD88-dependent pathway as the mechanistic link between arginine depletion and amplified HS inflammatory responses
Results
Lower serum arginine levels were detected in heat stress patients and positively correlated with liver injury and inflammatory indicators.
Clinical samples from HS patients showed reduced circulating arginine compared to non-HS controls
Serum arginine levels were positively correlated with markers of liver injury in HS patients
Arginine levels were also positively associated with inflammatory indicators in the patient cohort
These clinical findings validated the translational relevance of the mouse model findings to human heat stress pathology
Results
An arginine-enriched oral inulin hydrogel was developed that prevented HS-associated inflammatory responses by maintaining gut microbiota homeostasis, reducing LPS, and providing sustained arginine supply.
The novel delivery system combined inulin (a prebiotic fiber) as the hydrogel matrix with arginine as the active therapeutic payload
The formulation was designed for oral delivery to target the gut microbiota directly
The inulin component helped maintain gut microbiota homeostasis and reduce LPS levels
The hydrogel format provided sustained release of arginine, as opposed to a bolus dose
This dual-action approach addressed both components of the LPS-arginine imbalance identified as driving HS-associated inflammation
What This Means
This research suggests that when people or animals are exposed to dangerous levels of heat, the bacteria living in their gut undergo significant changes that make the body's inflammatory response much worse. Specifically, heat stress causes gut bacteria to break down more arginine (an amino acid) while simultaneously releasing more LPS (a bacterial toxin that triggers immune responses). This double shift — less arginine, more LPS — creates conditions that amplify inflammation throughout the body, including in the liver and brain. The researchers showed this gut microbiota connection is causal, not just coincidental, by transplanting gut bacteria from heat-stressed mice into healthy mice and observing that those recipients also showed worse inflammation when heat-stressed.
The molecular explanation involves a protein called MyD88, which acts as a key relay station linking bacterial toxin signals (from LPS via the TLR4 receptor) to inflammatory gene activation. This research suggests that arginine normally keeps this relay station in check by tagging MyD88 for degradation and weakening its interaction with TLR4, thereby reducing the activation of NF-κB and pro-inflammatory genes. When heat stress depletes arginine through enhanced gut microbial catabolism, this brake on inflammation is lost, worsening outcomes. Importantly, the researchers confirmed that heat stroke patients also have lower blood arginine levels, and these levels correlated with how much liver damage and inflammation the patients experienced.
To address this, the research team developed an oral hydrogel made from inulin fiber loaded with arginine. This formulation worked on two fronts simultaneously: the inulin helped restore healthy gut bacteria and reduce LPS, while the hydrogel slowly released arginine to replenish what the gut microbiota had depleted. This research suggests that maintaining arginine levels and gut microbiota balance could be a promising strategy for preventing or reducing the serious inflammatory organ damage associated with heat stress, which is increasingly relevant as global temperatures rise.
Ye X, Cai Q, Pan Y, Xu M, Li Y, You M, et al.. (2026). Heat stress enhances gut microbial arginine catabolism to amplify MyD88-dependent inflammatory responses.. Microbiome. https://doi.org/10.1186/s40168-026-02514-6