Rumen health and the mammary immune system

A common symptom of SARA is lower milk fat (Zebeli and Ametaj, 2009). Dairy cattle scientists have long recognized the effect of rumen fermentation disorders (i.e. SARA) on mammary gland metabolism. New data suggestthat endogenous LPS derived from the gastrointestinal tract can invade the mammary gland after breaking the milk-blood barrier (Kim et al., 2013), thereby eliciting a local immune response (Dong et al., 2011). Higher amounts of LBP in milk (Khafipour et al., 2009) and pro-inflammatory cytokines in mammary blood (Zhou et al.,

  • 2014), in cows experiencing SARA episodes, have also been reported in the literature. These results are similar to the effects caused by exogenous LPS- induced mastitis in cows, which also results in higher milk-LBP(Bannerman etal.,
  • 2003) and pro-inflammatory cytokines (Lee et al., 2003; Wellnitz et al., 2011). It is likely that endogenous LPS (deriving from the gastrointestinal bacteria) as well as exogenous LPS (deriving from the environment) are able to destroy the blood-milk barrier (Wall et al., 2016; Zhang et al., 2016). Humer et al. (2018b) found that cows experiencing SARA had higher concentrations of milk amyloid A (MAA) compared with non-SARA cows when they were intramammarily challenged with exogenous LPS (Fig. 4). It is likely that SARA episodes amplify
The concentration of milk amyloid A (MAA) in cows receiving LPS infusion subjected SARA (SARA-LPS) and non-SARA (CON-LPS) conditions

Figure 4 The concentration of milk amyloid A (MAA) in cows receiving LPS infusion subjected SARA (SARA-LPS) and non-SARA (CON-LPS) conditions.

the inflammatory response to infectious external stimuli like exogenous LPS (Aditya et al„ 2017).

Contrasting effects were observed in a study by Gott et al. (2015). They found higher MAA concentrations and somatic cell counts in cows fed a control diet compared to a high starch diet (formulated to induce chronic ruminal pH depression) after an intramammary LPS challenge, thus suggesting a certain LPS tolerance. One explanation for the observed differences might be a stronger SARA and thus a chronic exposure to higher LPS loads in the study conducted by Gott et al. (2015). One possible explanation for the stronger response in SARA cows in the study by Humer et al. (2018b) might be the assumed long-term exposure to low dosages of LPS related to mild SARA and generally low concentrations of APP, for example, LBP. Studies in humans have reported that low doses of LPS induce a state of tolerance to subsequent toxic doses of LPS, while very low doses can even have an opposite effect (Morris and Li, 2012). However, as no information regarding ruminal pH dynamics and LPS or LBP concentrations has been reported by Gott et al. (2015), this explanation remains hypothetical. There is clearly a need for further research to elucidate the responsiveness of dairy cows to external infectious agents after experiencing rumen fermentation disorders.

It has been recently reported that LPS is able to disrupt the blood-milk barrier by modifying claudins in the alveolar tight junctions (TJ) of mammary epithelial cells (Kobayashi et al., 2013). Claudins are the most important proteins in the control of the TJ barrier function (Beeman et al., 2012; Schlingmann et al., 2016). Alterations of their composition might enable LPS to destroy the blood-milk barrier. Interestingly, the activation of NF-кВ pathways via LPS/TLR-4 signaling has been assumed to induce changes in TJ permeability (Kobayashi et al., 2013). Once LPS breaks this barrier, bovine mammary epithelial cells would be the further line of defense (Strandberg et al., 2005; Zbinden et al., 2014).

Most of the defense mechanisms of the mammary gland act as nonspecific immune responses via leukocytes and soluble immune components such as inflammatory markers and antimicrobial factors (Schmitz et al., 2004). Antimicrobial defense proteins in milk, such as lactoferrin and lysozyme, are typically augmented during acute mastitis (Carlsson et al., 1989). Jin et al. (2016) observed an enhanced expression of defensins, such as lingual antimicrobial peptide, in the mammary epithelial cells of dairy cows experiencing SARA. These authors hypothesized the activation of the NF-кВ signaling pathway as one of the underlying mechanisms. The activities of other bactericidal proteins reflecting inflammation and oxidative stress (i.e. p-N-acetyl glucosaminidase and myeloperoxidase) have been upregulated in cows experiencing SARA, indicating infection in the bovine mammary glands.

When LPS invades the mammary gland, excessive pro-inflammatory cytokines such as IL-1(3, IL-6 and TNF-a are produced, inducing local inflammatory events via LPS/TLR4 signaling pathways (Akira et al., 2006; Ingman et al., 2014). In general, bovine mammary epithelial cells contribute to the innate immune response to intramammary infections by recognizing pathogens through specialized pattern recognition receptors, such as TLR4, which binds and is activated by the LPS-LBP complex (Ibeagha-Awemu et al., 2008). Overall, about 10 bovine TLRs have been identified, each recognizing specific ligands or pathogen-associated molecular patterns (McGuire et al., 2006). However, some pathogens have been reported to be able to activate more than one TLR (Swanson et al., 2004). In this regard, TLR4 mainly recognizes LPS, whereas TLR2 is commonly triggered by other cell wall components including those found on Gram-positive bacteria (GPB), such as peptidoglycan and lipoteichoic acid (Eckel and Ametaj, 2016). Incubation of bovine mammary epithelial cells with increasing LPS-concentrations has been shown to upregulate the expression of TLR4 as well as TLR2 as a result of downstream TLR4 signaling molecules and increased surface expression of specific antibodies against those receptors (Ibeagha-Awemu et al., 2008). The upregulation of TLR2 is likely due to some cross-talk among TLR2 and TLR4 receptors, as it is secondary to TLR4 activation and NF-кВ production (Faure et al., 2001; Fan et al., 2003).

TLR4-dependent upregulation of TLR2 seems to depend on the presence of NF-кВ sites on TLR2 (Ibeagha-Awemu et al., 2008). However, as several studies found no TLR2 involvement in LPS signaling (Heine et al., 1999; Takeuchi et al., 1999), the mammary epithelial cells may respond differently to the presence of some pathogenic compounds compared to other cell types (Ibeagha-Awemu et al., 2008). Goldammer et al. (2004) observed a coordinated upregulation of TLR2 as well asTLR4 in experimentally-induced Staphylococcus aureus mastitis in dairy cows, although Staphylococcus aureus is generally expected only to upregulate TLR2. Mammary epithelial cells appear not only to possess the required immune repertoires to mount a robust defense against Escherichia coli, but also to adapt toward an effective response to different types of mastitis pathogens (Ibeagha-Awemu et al., 2008).

It is important to note that excessive production of pro-inflammatory cytokines following infection may lead to injury of mammary epithelial cells and can also induce serious systemic disorders such as chronic enterocolitis and atherosclerosis or even septic shock (Takeda and Akira, 2005). The study by Kobayashi et al. (2013) clearly demonstrated negative relationships between the concentration of inflammatory cytokines (i.e. IL-1(3 and IL-8) in mammary blood and milk production parameters. Impaired milk production in dairy cows experiencing SARA might be partly attributable to local inflammatory processes, which decrease the available nutrients or milk component precursors for milk component synthesis.

LPS that enter the mammary tissue might also activate neutrophils which, in turn, can produce large amounts of bactericidal molecules, including proteins, peptides and reactive oxygen species (ROS; Dong et al., 2011). Since ROS are unstable oxygen-containing molecules which respond to other molecules (ranging from proteins to lipids to DNA and RNA in cells), they promote oxidation which causes tissue damage (Abuelo et al., 2015; Zebeli et al., 2015). Production of ROS exceeding the antioxidative potential results in oxidative stress. This causes dysfunctional inflammation which can then cause metabolic stress, thereby increasing cows' susceptibility to health disorders (Sordillo and Aitken, 2009). It has been reported that the secretory tissue of the mammary gland is highly sensitive to LPS (Schmitz et al., 2004; Blum et al., 2000), due to high levels of oxygen free radicals and metabolites of lipid peroxidation in the mammary gland, especially in high-producing cows (Shi et al., 2016). SARA can thus be a risk factor for udder health.

Prolonged SARA episodes impair the antioxidant mechanism in the liver and mammary gland of lactating cows (Abaker et al., 2017; Memon et al., 2019). This mechanism involves an increased concentration of malondialdehyde (MDA) and mitogen-activated protein kinase (МАРК) pro-inflammatory genes. It also involves a decreased level of nuclear factor erythroid 2-related factor 2 (Nrf2) which is associated with protein expression and antioxidant genes in the mammary gland tissue of dairy cows experiencing SARA (Memon et al., 2019). The Nrf2 protein plays a key role in the expression of antioxidant defenses against ROS triggered by inflammation (Kansanen et al., 2013). A reduced expression of Nrf2 indicates suppression of antioxidant status which subsequently induces oxidative stress in mammary gland tissue.

The local immune response in the mammary gland caused by the translocation of LPS or other immunogenic compounds into the mammary gland might also impair the immune defense mechanisms of the teat and even destroy its barrier function (Pareek et al., 2005; Dong et al., 2011). Cows experiencing SARA might also be more vulnerable to bacterial invasion and colonization in the mammary tissue compared to healthy cows (Sordillo and Streicher, 2002). After bacteria overcome the teat and streak canal barriers - as the first line of anatomical defenses - they might evade the mammary gland's cellular and humoral defense mechanisms (Sordillo and Streicher, 2002; Zhao and Lacasse, 2008). Besides the well-known shifts in the rumen microbiome due to SARA, high-grain feeding may also affect the composition of milk microbiota. A recent study revealed a higher proportion of several mastitis-causing pathogens, such as Stenotrophomonas maltophilia, Streptococcus parauberis and Brevundimonas diminuta, in dairy cows experiencing SARA (Zhang et al., 2015). Cows suffering from SARA showed a higher abundance of several psychrotrophic bacteria, such as Brevundimonas, Sphingobacterium, Alcaligenes, Enterobacter and Lactobacillus in milk compared to healthy cows. High-grain feeding may therefore enhance the risk of dairy cows suffering from gram-negative mastitis and also decrease raw milk quality and safety and limit the shelf life of processed milk (Zhang et al., 2015).

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