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Phosphate limitation in the gut during surgical stress can significantly impact various physiological processes and microbial dynamics [201]. Surgical stress triggers an inflammatory response that can elevate the body’s demand for phosphate. Phosphate is a crucial component of adenosine triphosphate (ATP), nucleic acids, and cell membranes. The physiologic stress associated with the process of surgery can lead to increased cellular activities that utilize phosphate, such as tissue repair and immune activation. Patients undergoing surgery may experience fluid shifts and changes in nutritional intake that can adversely affect their phosphate levels. These changes can limit the availability of dietary phosphate, especially if oral intake is restricted preoperatively or if there is inadequate nutrient absorption postoperatively [201]. Phosphate metabolism is closely related to iron metabolism in the gut [174]. Both nutrients have interconnected regulatory mechanisms that can influence each other. For instance, the presence of hepcidin, a key regulator of iron, can also affect phosphate transport and homeostasis [229]. Hormones like parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulate phosphate metabolism and may be altered during surgical stress. An increase in PTH can lead to changes in kidney function that impact phosphate excretion and homeostasis [230, 231].

Phosphate is essential for many microbial processes in the gut. Phosphate limitation can affect the growth and metabolic activity of gut bacteria. Some beneficial microbes may struggle to thrive under low phosphate conditions, leading to dysbiosis, a degree of microbial disruption that itself can promote the growth of pathogenic organisms [201]. Under conditions of phosphate limitation opportunistic pathogens may gain a competitive advantage. Some pathogens possess specialized mechanisms to obtain and utilize phosphate more efficiently, allowing them to thrive in the gut even when essential nutrients are scarce.

Many bacteria, especially pathogenic strains, have evolved various mechanisms to acquire phosphate from organic and inorganic sources in their environment. As mentioned, phosphate is an essential nutrient for many cellular processes, including energy metabolism, nucleic acid synthesis, and signaling pathways. Some bacteria can utilize organic compounds such as phosphonates that contain a carbon-phosphorus (C-P) bond to acquire phosphorus [232]. This is particularly important in environments where free inorganic phosphate is limited. Enzymatic hydrolysis is a process that typically involves enzymes such as phosphonatases that cleave the C-P bond, releasing inorganic phosphate (Pi) that can then be taken up by the bacterial cell [232]. One of the most effective mechanisms is expression of extracellular enzymes known as phosphatases belonging to the group of exto-nucleotidases that hydrolyze different specific substrates including organic phosphate esters, such as nucleotides (e.g., ATP, ADP) and phospholipids, releasing inorganic phosphate for its uptake [233]. Different types of phosphatases such as alkaline phosphatases, acid phosphatases, or specific enzymes for particular organic compounds target different substrates. Upon secretion, these phosphatases act on organic phosphate substrates, converting them into free phosphate ions that can then be assimilated by the bacterial cells. In some cases, certain bacteria prefer to consume organic phosphates, where they break them down with phosphatases.

Bacteria have also evolved several regulatory mechanisms that sense phosphate availability in their environment. Systems such as the PstS- dependent expression of Pho regulon upregulate the expression of genes involved in phosphate uptake and utilization when phosphate is scarce [174, 234] and are tightly connected to the global virulence activation [174, 235]. Some clinical strains of pathogens (i.e., P. aeruginosa) have been shown to develop systems for extra-scavenging environmental phosphate concentrations by developing PstS-containing appendages [236, 237].

Despite the tightly regulated and common response to phosphate limitation in the microbial world, there is significant variability in the timing and concentration at which the bacterial response to phosphate is activated. For example, some strains respond earlier due to higher threshold of recognition of decreasing extracellular phosphate. Generally, phosphate concentrations in the range of 0.5 to 1 mM are considered sufficient for many bacterial species to grow and survive under normal conditions. Within this range, bacteria can carry out normal metabolic functions, including growth, replication, and biosynthesis. However, for P. aeruginosa, even at these physiologic levels, PstS expression is already induced. While optimal phosphate concentrations generally range from 0.5 to 1 mM, levels below 0.1 mM are often recognized as low by many bacterial species, triggering adaptive responses to enhance phosphate acquisition. Some bacteria can experience significant stress or metabolic slowdown when phosphate concentrations fall to the level of 4 mkM [238]. The ability to “sense and respond” to phosphate levels is vital for bacterial survival, especially in environments where this nutrient is limited. Variability in the threshold at which phosphate responses are triggered among bacterial species can significantly influence their ability to expand when present in the gut during stress. For example, in response to phosphate limitation, opportunistic pathogens such as P. aeruginosa express their global virulence machinery including to acquire organic phosphate, siderophores, quorum sensing MvfR-PQS, and efflux pumps [174]. This ability to thrive under phosphate limitation allows these pathogens to exploit available resources that commensal bacteria cannot utilize effectively; this situation inhibits growth of the commensal microflora via secreted virulence factors by pathogenic strains that include the precursors of PQS and that can directly suppress the immune response (Figure 1) [174].

ummarized effect of host stress derived signals on virulence activation in P. aeruginosa. This figure is created based on the findings described in Refs. Wu et al. [171], Zaborina et al. [172], Patel et al. [173], and Zaborin et al. [174]. During tissue injury/inflammation the released IFN-gamma binds to P. aeruginosa receptor protein OprF that leads to the activation of RhlRI pathway of quorum sensing system followed by the expression of virulence factors such as PA-I lectin that disrupts the tight junctions (i.e., loss of occludin) in epithelial cells and modulating innate immunity via DAF-16/FoxO pathway. Opioid dynorphin through MvfR-dependent Pseudomonas quinolone signaling activation induces overproduction of PQS and 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) leading to increased production of PA-I lectin and rhamnolipids causing apoptosis of epithelial cells, while HQNO is involved in the killing of intestine epithelium-protective Lactobacilli. Adenosine release during hypoxia to protect intestinal epithelium is converted to inosine by P. aeruginosa adenosine deaminase. Phosphate limitation in environment of gut in stressed host induces a global virulence in P. aeruginosa via PstS-PhoB system and activation of MvfR-PQS pathway of quorum sensing.

In summary, situations in which prolonged illness and its treatment involve surgical stress or inflammatory conditions, can lead to the diminished availability of key nutrients that some bacteria use for growth and survival, while other use to express virulence with the goal of obtaining phosphate in deeper tissues. This process involves systemic phosphate regulatory mechanisms such as the release of phosphatonins, which shift the availability of phosphate away from the gut to more vital organs of survival such as the heart and brain. Opportunistic pathogens can better exploit these changing conditions due to their adaptive mechanisms and metabolic versatility. The regulation of virulence factors in response to these stressors can also affect phosphate levels such that circumstances favor opportunistic pathogens with a greater probability of survival and pathogenicity. Differences in threshold phosphate levels can benefit opportunistic pathogens by enhancing their ability to acquire iron, utilize organic phosphates, and adapt their gene expression in response to changing environments. Their capacity to outcompete commensal bacteria and form protective biofilms allows them to expand their niche colonization in the gut resulting in enhanced survival and pathogenicity, especially during stress conditions when the disease state and its treatment are intensified.