CO₂ Holdup and Its Role in Ruminal Inflammation
Traditionally, subacute ruminal acidosis (SARA) has been associated with inflammation triggered by lipopolysaccharide (LPS) endotoxins (Zhao et al., 2018; Zhao et al., 2023). While this mechanism is well established (Khafipour et al., 2009b; Li et al., 2012), it does not always align with clinical observations, since SARA and LPS presence do not consistently coincide (Khafipour et al., 2009a).
Recent evidence suggests that dissolved carbon dioxide (dCO₂) may play a critical and previously underestimated role in exacerbating SARA (Laporte-Uribe, 2024).
The CO₂ Holdup Hypothesis
CO₂ holdup refers to the excessive accumulation of dCO₂ in the rumen, which can set off a cascade of pathological events:
Promotion of LPS and metabolite production
Elevated dCO₂ supports the growth of bacteria that produce LPS, lactate, and propionate (Prescott & Stutts, 1955; Wright, 1960; Dehority, 1971; Laporte-Uribe, 2016).
This helps explain why LPS is consistently detected in ruminal fluid during SARA, even when pH and microbial shifts alone cannot account for it.
Enhanced toxin translocation
CO₂ holdup increases ruminal blood flow (hyperaemia) (Dobson, 1984; Thorlacius, 1972), potentially facilitating the transport of microbial toxins into the bloodstream.
Disruption of epithelial nutrient absorption
Hyperosmolarity, induced by excess dCO₂, impairs ruminal epithelial absorption (Abdoun et al., 2010; Aschenbach et al., 2011; Rabbani et al., 2021).
This includes the depletion of intracellular bicarbonate (HCO₃⁻) due to impaired aquaporin function (Li et al., 2021).
Intracellular Consequences of HCO₃⁻ Depletion
The loss of intracellular HCO₃⁻ initiates two opposing cellular responses:
Restorative response via ketogenesis
Activation of AMPK and PDK (Cummins et al., 2020; Phelan et al., 2021; Can et al., 2022) stimulates ketogenesis.
This process generates CO₂ and H₂O, replenishing H⁺ and HCO₃⁻ pools to restore intracellular balance.
Inflammatory response via NLRP3 inflammasome activation
HCO₃⁻ depletion also activates the NLRP3 inflammasome (Rajamäki et al., 2013).
This leads to the release of pro-inflammatory cytokines (IL-1β, IL-18), amplifying the inflammatory cascade characteristic of SARA (Zhao et al., 2023).
Implications
In summary, CO₂ holdup contributes to SARA by:
Enhancing microbial production of LPS and other inflammatory mediators,
Disrupting epithelial integrity and nutrient absorption,
Triggering intracellular stress pathways, including NLRP3-driven inflammation.
Thus, monitoring and managing ruminal CO₂ levels is crucial for reducing SARA risk. Preventing CO₂ holdup not only helps mitigate acidosis but also reduces the prevalence of other nutrition-related disorders.
This approach — termed precision ruminal fermentation — has the potential to:
Improve ruminant health and welfare,
Enhance productivity,
Reduce the environmental impacts of intensive feeding systems.
Conclusion
CO₂ holdup represents a potentially central mechanism in ruminal inflammation that should not be overlooked. By unravelling the interplay between dCO₂, epithelial function, and inflammatory signalling, we can develop more effective strategies to prevent and manage SARA, ultimately supporting healthier and more sustainable ruminant farming systems.
Figure 1. The Effect of Ruminal CO₂ Holdup on Epithelial Function
CO₂ holdup can profoundly disrupt ruminal epithelial physiology. Excessive dCO₂ accumulation may stimulate LPS formation and induce ruminal hyperosmolarity.
Hyperosmolarity promotes hyperaemia (increased blood flow) and leads to epithelial dehydration.
This dehydration reduces water and CO₂ absorption through aquaporins, causing a decline in cytosolic HCO₃⁻ concentrations.
Intracellular HCO₃⁻ depletion triggers inflammatory pathways and may contribute to ketosis.
Meanwhile, hyperaemia can compromise epithelial barrier integrity, facilitating the translocation of toxins such as LPS, lactate, and histamine into the bloodstream.
