Salmonella—Host–microbiota interactions: Immunity and metabolism

Salmonella establish a foundation for systemic infection through induced inflammation and immune evasion. Salmonella manipulates host metabolism to favor its own proliferation within the host. Salmonella infection can disrupt the balance of gut commensal bacteria and use microbial metabolites to fuel its own energy metabolism. Salmonella is a group of zoonotic pathogens that causes intestinal infections, primarily transmitted through contaminated food or water. Salmonella invasion can trigger intestinal inflammation and exploit the electron receptors produced by inflamed cells to promote its infectivity [1]. Moreover, Salmonella-containing vacuole (SCV) can form within infected macrophages, which enables Salmonella to effectively evade the host immune response. Infected macrophages undergo a reprogramming of cellular oxidative metabolism, producing metabolic byproducts that serve as an energy source for Salmonella and as virulence activation signals, thus promoting further infection [2]. The host defends against Salmonella infection primarily through two mechanisms. The innate immune system, critical in the early stages of Salmonella infection, involves various cells playing distinct roles. For example, neutrophils promote extensive interferon-gamma (IFN-γ) release during the acute early infection of Salmonella, which effectively prevents extensive Salmonella replication and mitigating further infection (Figure 1). The adaptive immune response also plays a significant role in Salmonella clearance. CD4+ T cells predominantly drive this response, while the absence of B cells or CD8+ T cells does not seem to significantly affect Salmonella clearance. Salmonella interacts with the host–microbiota through diverse mechanisms, including competing for nutrients, influencing host cell metabolism. This review delves into how Salmonella promotes its expansion and replication within the host through immunity and metabolism, provides a comprehensive overview of this pathogenic mechanism in relation to the host and gut microbiota, furthering our understanding of Salmonella infection. Salmonella invades the host by utilizing the Salmonella pathogenicity island (SPI) encoding the type III secretion system (T3SS). The SPI-1 encoded T3SS-1 transfers bacterial effector proteins into host intestinal epithelial cells and induces cytosis. T3SS effectors such as SopE, SopE2, SopB, and SipA can disrupt the tight junctions between intestinal epithelial cells by acting as Rho-GTPase agonists (Figure 1). Once invading the epithelium, Salmonella replicates in the cytoplasm to promote its expansion, and cause intestinal inflammation, which promotes Salmonella infection in host. On the one hand, inflammation can stimulate the release of compounds, like, tetrathionate and nitrates, which provide growth advantages as respiratory electron receptors, and encourage its utilization of derivatives, such as succinate [1] (Figure 1). On the other hand, inflammation disrupts the gut microbial balance and helps Salmonella to utilize various fermentation products derived from the gut microbiota, such as propionic acid [3]. In addition, Salmonella can also use immune evasion mechanisms to promote its infection. Salmonella can replicate within SCVs after endocytosis by macrophages and further inducing SCV acidification, by utilizing the CadC-YdiV axis, halting flagellar synthesis to evade host immunity [4]. Additionally, Salmonella also has a unique immune evasion mechanism against host autophagic defenses through SPI-1 effector SopB to mediate autophagy evasion [5]. In conclusion, Salmonella exhibits a unique mechanism to host-induced inflammation and immune defense, which lays the foundation for systemic infection. During systemic infection, infected macrophages exhibit the Warburg effect, characterized by increased glycolysis and suppression of tricarboxylic acid (TCA) cycle. The upregulation of glycolytic processes leads to the accumulation of glycolytic intermediates, such as 3-phosphoglycerate (3PG), pyruvates, and lactates. 3PG can serve as a carbon source for intracellular replication of Salmonella, rescuing the bacteria from low glucose conditions. While pyruvates and lactates via the macrophage-sensing two-component system carbon source responsive (CreBC) to activate the SPI-2 gene [2] (Figure 2). Previous studies have shown that Salmonella Typhimurium secreted effector K3, an SPI-2 effector, further contributes to the upregulation of glycolysis, induction of macrophage apoptosis, and concurrently suppresses the expression of inflammatory factors [6] (Figure 2). Notably, the upregulation of glycolysis was previously thought to be a protective effect induced by the host, through which adenosine triphosphate can be obtained more quickly to support biosynthesis and meet the metabolic demands of cell proliferation. However, studies on human macrophages have shown that inhibiting glycolysis within host cells can reduce the growth of intracellular Salmonella, which is related to increasing reactive oxygen species production [7]. In addition, the accumulated lactate is produced by glycolysis in both mouse and human macrophages, it appears to be only required for Salmonella SPI-2 in mice [8]. The specific role of lactate in human macrophages during Salmonella infection remains unclear, warranting further investigation. Inhibition of the TCA cycle reduces the levels of key intermediates like citrate, conversely, the levels of succinate, itaconate increase in response to Salmonella infection [9]. These metabolic changes are pathways by which host cells react to infection. Salmonella infection can decrease host citrate levels, potentially due to the transfer of citrate from the TCA cycle to lipid biosynthesis. Elevated itaconate induces alkylation of the transcription factor EB alkylation to induce lysosomal generation, aiding bacterial clearance [10] (Figure 2). Succinate can upregulate hypoxia-inducible factor-1 alpha (HIF-1α) expression, ultimately leading to increased interleukin-1β production. In addition, HIF-1α expression inhibition decreases Salmonella viability, potentially through the epidermal growth factor receptor–HIF-1α axis, since inhibiting this pathway can enhance proinflammatory cytokine IFN-γ, tumor necrosis factor-alpha, interleukin-17 (IL-17) production, while reducing anti-inflammatory IL-10 secretion [11] (Figure 2). Overall, Salmonella can reprogram infected macrophage glucose metabolism, inducing a sufficient accumulation of macrophage-derived carbon sources and signals, which were utilized as an energy source to support intracellular replication and virulence of Salmonella. When Salmonella infects the gut, the intestinal epithelium rapidly recognizes the pathogen through the neuronal apoptosis inhibitory protein/nod-like receptors-family CARD-containing protein 4 inflammasome. This recognition triggers a contraction of the epithelial layer, helpful in maintaining the epithelial barrier integrity and preventing further Salmonella invasion [12]. Macrophages can also clear Salmonella through extracellular traps release, referred to as ETosis [13]. Dendritic cells also produce B-cell activating factor to stimulate the expansion of mature B cells and Salmonella-specific immunoglobulin M production, which is necessary to prevent Salmonella infection [14] (Figure 1). The adaptive immune response to Salmonella infection involves CD4+ and CD8+ T-cell activation. CD4+ T cells play a key role in persistent Salmonella infection by producing IFN-γ to inhibit Salmonella reactivation in the intestine. Interestingly, the protective effects of CD4+ T cell may exhibit heterogeneity in different organs. In chronically infected mice, research has found that compared to the spleen and lymph nodes, the liver CD4+ T cells can also generate IL-10, hindering Salmonella clearance [15]. During Salmonella infection, CD8+ T cells have been shown to exhibit delayed expansion and contraction, while play a protective role in primary infection after administration of a live attenuated Salmonella vaccine. Escherichia coli can reduce Salmonella intestinal colonization by competing for iron, and carbon sources (Figure 1). Reduced carbon sources can induce caloric restriction, which has previously been shown to reduce Salmonella infection through nitric oxide (NO). Salmonella employs siderophores to compete for iron from the host. Blocking siderophores effectively reduce Salmonella colonization in the gut. Recent studies have shown that Bacteroides thetaiotaomicron secreted siderophore-binding lipoprotein XusB to utilizing siderophores, but the XusB-bound enterobactin are utilized by Salmonella, allowing pathogenic bacteria to evade host nutritional immunity [16]. E. coli can also compete with Salmonella for oxygen to produce colonization resistance to Salmonella [17] (Figure 1). E. coli acquires nitrate from epithelial sources, but Salmonella is limited by the chemotactic receptors methyl-accepting chemotaxis proteins, which prevent it from accessing the E. coli niche to obtain epithelial-derived nitrate. Meanwhile, commensal E. coli can enter Salmonella's niche to compete for macrophage-derived nitrate, thereby enhance resistance against Salmonella colonization [18]. Salmonella uses virulence factors to eliminate butyric acid-producing Clostridium from the gut microbiota, leading to increased epithelial oxygenation (Figure 1). This, in turn, drives the cytochrome bd II oxidase-dependent expansion of Salmonella within the intestinal lumen through aerobic and nitrate respiration [19]. Salmonella can facilitate its own colonization and infection by disrupting gut microbial homeostasis and promoting oxidative metabolism. The agonists of peroxisome proliferator-activated receptor gamma can decrease the production of lactate by host cells and synergize with regulatory T cells to maintain colonic hypoxia, which contributes to the production of short-chain fatty acids by gut microbes and helps maintain intestinal homeostasis [20] (Figure 1). This mechanism represents a potential metabolic pathway target for treating Salmonella infections. During Salmonella infection, the production of inflammation can initially serve as a protective mechanism for the host, but certain byproducts of the inflammatory response may facilitate the movement of Salmonella in vivo, which can contribute to the survival and virulence of Salmonella. While the host mounts an immune response against Salmonella infection, the bacteria possess their own mechanisms to evade or circumvent the host defenses. Salmonella infection offers valuable insights into how the bacterium manipulates host metabolism to favor its own proliferation within the host. Yet, additional research is needed to fully elucidate the molecular mechanisms involved. Salmonella infection can disrupt the balance of gut commensal bacteria by competing for nutrients, changing the structure of the microbial community, and using microbial metabolites to fuel its own energy metabolism. The current research sheds light on the intricate interactions between Salmonella, the host, and gut microbiota in terms of immunity and metabolism; however, further research is needed to fully elucidate the immune and metabolic mechanisms underlying these interactions. By gaining a better understanding of these processes, it has the potential to harness the host's metabolic regulation to enhance immunity and provide better defense against pathogenic bacterial infections. Bingxin Tang: Writing—original draft; writing—review and editing; conceptualization. Wenwen Cui: Writing—review and editing. Xiao Li: Writing—review and editing. Huan Yang: Conceptualization; writing—review and editing; funding acquisition. This research was supported by the National Natural Science Foundation of China (82102408), China Postdoctoral Science Foundation (2022M712681), Jiangsu Provincial Natural Science Foundation (BK20231170), and Xuzhou Medical University Excellent Talent Introduction Project (D2019030 and D2020060). The authors declare no conflict of interest. No animals or humans were involved in this study. This manuscript does not generate any code or data. Supporting Information materials (graphical abstract, slides, videos, Chinese translated version, and update materials) may be found in the online DOI or iMeta Science http://www.imeta.science/imetaomics/.