Bovine respiratory disease (BRD) is a significant endemic disease that has had a considerable impact on morbidity and mortality rates in feedlots in the United States (1, 2). The complexity of BRD in the feedlot industry arises from various environmental and physiological stress factors that cattle encounter during the critical receiving period (3, 4). These stressors include weaning, dietary changes, mixing of unfamiliar animals, transportation, and exposure to pathogenic agents (4). During the feedlot receiving period, cattle often experience reduced DMI, leading to impaired nutrient metabolism and compromised immune function (5, 6). The combination of these factors creates an environment conducive to the development and progression of BRD.

Vaccination and antibiotic treatments have been integral in the prevention and mitigation of BRD in beef cattle (7–9). These interventions have proven effective in reducing the severity of BRD (10, 11). However, it is essential to address the public concern surrounding the use of antibiotics in food animals, as this issue is likely to persist (1, 13). Therefore, in addition to vaccination and antibiotic treatments, it becomes necessary to implement other management strategies to mitigate the negative impact of BRD on beef cattle health and immune function (14, 15). In recent times, the application of metabolomics has provided a blueprint for the comprehensive analysis of metabolites in biofluids, which has emerged as a powerful tool for understanding disease processes and identifying metabolic alterations associated with various conditions (16–18). By exploring the impact of BRD on overall metabolism, effective strategies for managing and implementing nutritional interventions can be utilized to mitigate the detrimental effects of BRD infection on the nutritional status and performance of beef cattle. Indeed, a recent study (19) demonstrated that dairy calves deliberately infected with BRD causal agents exhibited altered metabolism. However, the metabolism of beef cattle infected with BRD during the receiving period has not been fully described. Therefore, the objective of this study was to determine the effects of BRD infection on the plasma metabolome of beef steers during a 35-d receiving period. We hypothesized that BRD infection would induce alterations in the plasma metabolome of beef steers during this critical period.

At the end of the experiment, 31 beef steers were diagnosed with BRD at any time during the 35-day period (Sick group) and 46 beef steers did not exhibit any signs of BRD throughout the 35-day period (Healthy group). The results of the growth performance of the healthy and sick beef steers are shown in Table 1. Sick beef steers had lower (p = 0.01) ADG compared to healthy steers (1.44 vs. 1.64 kg/d). However, DMI was similar for the two groups. Consequently, the sick beef steers had greater (p = 0.01) feed:gain ratio compared to healthy ones (3.57 vs. 3.13).

A total of 50 metabolites were detected and quantified in the plasma samples of all the beef steers (Supplementary Table S2). The PLS-DA scores plot showed an overlap but with a slight separation of the entire plasma metabolome between the sick and healthy steers. Thus, suggesting that the plasma metabolome was altered by BRD infection (Figure 1). Plasma concentrations of four metabolites (sarcosine, methionine, dimethyl sulfone and L-histidine) were greater (FDR ≤ 0.05) in the healthy steers compared to the sick steers (Table 2). Out of the four differentially abundant metabolites, only two metabolites (sarcosine and methionine) had AUC values >0.70 (Figure 2). The results of the ROC analysis of the two metabolites revealed an AUC value of 0.773, suggesting that plasma concentrations of methionine and sarcosine could be used as a plasma biomarker panel associated with BRD infection in beef steers (Figure 3). The results of the quantitative enrichment analysis revealed cysteine and methionine metabolism (p = 0.05) was enriched in healthy, compared to the sick steers (Figure 4). The enriched metabolites associated with this pathway were methionine, cysteine, and pyruvic acid.

The performance parameters of the sick and healthy steers during the receiving period were compared, revealing differences in ADG and feed:gain ratio. Sick steers exhibited lower ADG and higher feed:gain ratio compared to the Healthy steers, indicating that BRD may disrupt the metabolic processes involved in growth and nutrient utilization. Furthermore, though not statistically different, slightly lower DMI in sick steers suggests that BRD may affect satiety and feed intake. Similar effects of BRD on the performance of beef cattle have been reported in previous studies (25–27), suggesting that BRD negatively impacts nutrient absorption and utilization, alters metabolism, and increases energy expenditure due to the immune response and inflammation (28).

Bovine respiratory disease has a profound impact on the overall metabolic homeostasis, causing notable alterations in metabolite levels that reflect the body’s response to the infection and its defense mechanisms against the invading pathogens (29). The manifestation of BRD infection in beef cattle can have a significant impact on their metabolism, depending on the degree of pathological condition development (29). The disease disrupts various biological systems within the animal, particularly immune activation and nutrient metabolism (30, 31). The disruptions experienced as a result of these events lead to various biological alterations. One notable change is the upregulation of protein turnover, which is initiated by the production of cytokines in response to the pathogen. This heightened protein turnover necessitates an increased demand for amino acids to facilitate the synthesis of acute-phase proteins in the liver (29).

Metabolomics assessment revealed altered cysteine and methionine metabolism and identified specific plasma metabolites that differed between healthy and sick steers, including sarcosine, methionine, dimethyl sulfone, and L-histidine. These metabolites play crucial roles in biological and metabolic processes related to growth, production, and reproduction in farm animals (32). The decreased plasma concentration of sarcosine and methionine in sick steers suggests potential implications for the growth and energy substrate levels in the blood. Dysregulation in the metabolism of these amino acids may affect protein synthesis, muscle development, energy availability, and utilization, thereby impacting overall growth and body weight gain. Methionine, being an essential amino acid, is involved in various metabolic processes crucial for growth and muscle development. In the context of BRD, decreased methionine levels may compromise protein synthesis, utilization of other amino acids, dietary nutrient utilization, and immune defense mechanisms. Methionine deficiency has been associated with poor growth performance in growing beef cattle fed high forage diet such as the one fed in this study (33). Additionally, decreased methionine availability can compromise antioxidant defense mechanisms, leading to increased oxidative damage, inflammation, and impaired growth. Sarcosine is an intermediate product in the metabolism of glycine and methionine, thus, the reduced plasma concentration of sarcosine in sick beef steers may signify dysregulation in the metabolic pathways of these amino acids, which can have a significant impact on essential processes such as protein synthesis and muscle development which are critical for optimal growth in beef cattle. Furthermore, sarcosine is involved in the one-carbon metabolism pathway, which is crucial for the synthesis of important molecules such as DNA, RNA, and proteins. Disruptions in sarcosine and methionine metabolism can lead to reduced availability of metabolites involved in energy production, which may explain the reduced ADG of the sick steers observed in this study.

Our findings demonstrate that BRD infection reduced the ADG and increased gain:feed ratio, and altered the plasma metabolome of the beef steers toward reduced concentrations of sarcosine, methionine, dimethyl sulfone and L-histidine. Additionally, quantitative enrichment analysis revealed that cysteine and methionine metabolism was enriched in healthy steers compared to sick steers. Further research is warranted to elucidate the underlying mechanisms and explore targeted interventions, such as nutritional supplementation of methionine, sarcosine, or cysteine, for mitigating the metabolic consequences of BRD in cattle.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The animal study was reviewed and approved by West Virginia University (Protocol #2014-0194).

IO designed the experiment. FE, GT, MI, IO, TS, ET, DO, and YL conducted the experiment and analyzed the data. FE drafted the manuscript. IO reviewed the final manuscript together with FE, GT, MI, IO, TS, ET, DO, and YL. All authors contributed to the article and approved the submitted version.

This work was funded by West Virginia University Experimental Station in support of U.S. Department of Agriculture hatch multi-state regional project W-3010 Scientific Article Number 3463.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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