Ruminal inflammation

Traditionally, ruminal acidosis (SARA) has been associated with inflammation triggered by lipopolysaccharide (LPS) endotoxins (Zhao et al., 2018, Zhao et al., 2023). While this is a well-established mechanism (Khafipour et al., 2009b, Li et al., 2012), often SARA and LPS seems not coincide (Khafipour et al., 2009a), recent evidence suggests that dissolved carbon dioxide (dCO2) may also play a significant role in exacerbating SARA (Laporte-Uribe, 2023).

CO2 holdup, a condition characterized by excessive dCO2 accumulation in the rumen, can lead to a cascade of events that contribute to inflammation. This accumulation can directly promote the growth of bacteria that produce LPS, lactate, and propionate (Prescott and Stutts, 1955, Wright, 1960, Dehority, 1971, Laporte-Uribe, 2016), all of which can explain why LPS is present in the rumen fluid always during SARA.

Additionally, CO2 holdup can increase ruminal blood flow (Dobson, 1984; Thorlacius, 1972), potentially enhancing the transport of these toxins into the bloodstream. Moreover, hyperosmolarity induced by CO2 holdup can impair the absorption of nutrients by the ruminal epithelium (Abdoun et al., 2010, Aschenbach et al., 2011, Rabbani et al., 2021), for instance leading to a depletion of intracellular bicarbonate (HCO3-) due to aquaporins impaired function (Li et al., 2021).

This depletion of HCO3- can trigger two opposing responses. On the one hand, it can stimulate ketogenesis via AMPK and PDK activation (Cummins et al., 2020; Phelan et al., 2021; Can et al., 2022), a metabolic process that generates both carbon dioxide and water, helping to replenish both H+ and HCO3- and restore intracellular balance.

On the other hand, the depletion of HCO3- can activate the NLRP3 inflammasome (Rajamäki et al., 2013), a complex that plays a central role in the inflammatory response. This activation contributes to the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which further exacerbate SARA (Zhao et al., 2023).

In summary, CO2 holdup can contribute to SARA by promoting the production of LPS and other inflammatory mediators, disrupting the integrity of the ruminal epithelium, and triggering the NLRP3 inflammasome. Therefore, monitoring and managing CO2 levels is crucial for reducing the risk of SARA and associated inflammation.

Furthermore, preventing CO2 holdup can help to mitigate other nutritional diseases in ruminants and reduce the negative impacts of modern diets. This approach, known as "precision ruminal fermentation," holds promise for improving animal health and productivity while minimizing environmental impacts.

In conclusion, while LPS-induced inflammation is a well-established contributor to SARA, CO2 holdup represents an emerging threat that should not be overlooked. By understanding the mechanisms by which CO2 can trigger inflammation, we can develop effective strategies to prevent and manage SARA and improve the overall health and welfare of ruminants.

The effect of ruminal CO2 holdup on ruminal epithelial function. CO2 holdup might leads to ruminal LPS formation and Hyperosmolarity. Hyperosmolarity produces hyperaemia, and dehydration of the ruminal epithelium. The reducing water and CO2 absorption through aquaporins due to hyperosmolarity depletes cytosolic HCO3- concentrations triggering inflammation, ketosis. Hyperaemia might lead to lost of epithelial integrity and toxins traslocation.