Metals in the gut: microbial strategies to overcome nutritional immunity in the intestinal tract

Abstract

Trace metals are indispensable nutritional factors for all living organisms. During host-pathogen interactions, they serve as crucial resources that dictate infection outcomes. Accordingly, the host uses a defense strategy known as nutritional immunity, which relies on coordinated metal chelation to mitigate bacterial advances. In response, pathogens employ complex strategies to secure these resources at sites of infection. In the gastrointestinal (GI) tract, the microbiota must also acquire metals for survival, making metals a central line of competition in this complex ecosystem. In this minireview, we outline how bacteria secure iron, zinc, and manganese from the host with a focus on the GI tract. We also reflect on how host dietary changes impact disease outcomes and discuss therapeutic opportunities to target bacterial metal uptake systems. Ultimately, we find that recent discoveries on the dynamics of transition metals at the host-pathogen-microbiota interface have reshaped our understanding of enteric infections and provided insights into virulence strategies, microbial cooperation, and antibacterial strategies.

Graphical Abstract

Graphical Abstract.

Introduction

Transition metals are essential nutrients for survival across the tree of life, including multicellular organisms, like humans, to single-celled organisms, like bacteria. These trace metals function within biological systems, serving as cofactors for enzymes and structural components in other noncatalytic proteins [1]. In this minireview, we focus on several important metals that have been shown to be central to host-pathogen interactions in the gut: iron, manganese, and zinc. Iron and manganese are redox-active metals and function as vital cofactors involved in numerous cellular processes [2]. Zinc is a redox-inert metal that predominantly resides within enzymes [2]. Zinc assumes a dual role, acting as both an enzyme cofactor and a structural component in proteins [2]. A major paradox that all living organisms must overcome is the fact that these metals are essential, yet excess levels of these micronutrients can lead to cytotoxic effects, so their concentrations must be tightly controlled.

In the context of host-pathogen interactions, transition metals are central to infection outcomes. While the host can acquire trace metals through diet for metabolic needs, bacterial pathogens must obtain these nutrients from the host environment for survival [3,4]. The competition for metal acquisition thus emerges between the host and the pathogen. Mammalian hosts are among the most free-metal restricted environments on earth, as they employ numerous strategies to modulate access to metals and starve or intoxicate the invading pathogen [3,4]. Broadly, this is referred to as nutritional immunity and represents a potent host defense strategy to counter infections [3,4]. Successful bacterial pathogens have developed tactics to evade or exploit nutritional immunity through dedicated metal acquisition, storage, and detoxification systems [3,4]. These pathogens also coordinate the expression of their systems through regulators that sense and respond to metal levels, including metal-binding transcription factors and even regulatory small RNAs [3,4]. Importantly, recent advances have also demonstrated that the gut microbiota plays a critical role in modulating metal bioavailability in the gastrointestinal (GI) tract, subsequently shaping ecological niches during infection.

In this minireview, we provide an overview of recent literature focused on how bacteria acquire and store nutrient metals in the mammalian host, with a specific emphasis on iron, manganese, and zinc (Fig. 1). We outline how bacteria rely on polymicrobial interactions, dedicated organelles, toxin production, and other variable strategies for survival during metal starvation in the host. We specifically focus on the GI tract, where exciting new studies have begun to shed light on mechanisms by which Gram-negative and Gram-positive bacteria circumvent nutritional immunity and thrive in this complex and dynamic ecosystem.

Figure 1.

The tug-of-war for transition metals at the host-microbe interface. Iron, zinc, and manganese are fundamental transition metals required for many life forms. These critical nutrients dictate dynamics at the host-pathogen-microbiota interface. As the host limits these resources in an effort to control bacterial growth and colonization, microbes must employ strategies to scavenge for transition metals in host tissues and regulate the storage of these acquired nutrients. Created with BioRender.com.

Bacterial strategies to scavenge and store iron during infection

Iron is a micronutrient that is indispensable for many forms of life; however, excess iron can be toxic to certain organisms. In the host, the biologically relevant forms of iron exist in two oxidation states: ferrous iron (Fe²⁺) and ferric iron (Fe³⁺) [2]. Due to the importance of iron for the survival of invading pathogens, the host has evolved mechanisms to limit access to free iron in the body. Within the body, iron is stored in complexes like ferritin molecules, heme, metalloproteins, and iron-sulfur proteins [5]. This strategy allows for deployment of the functional capacity of iron while also protecting the host from toxicity and preventing bacterial poaching of this nutrient [5]. For example, transferrin was the first documented iron-binding protein in human blood plasma [3,6]. In addition, lactoferrin is a member of the transferrin superfamily and acts as a multifunctional iron-binding protein found at high concentrations in secretory fluids, including milk and saliva [7]. These proteins represent key antimicrobial strategies for the host, as they serve to deprive pathogens of host iron [3,6,7]. To counteract these host defense tactics, bacterial pathogens use dedicated strategies to procure iron from host tissues and carry out necessary metabolic functions, detailed below.

Bacterial siderophores for iron capture

Siderophores are high-affinity iron chelators secreted by bacteria to scavenge iron in iron-depleted niches [8]. They bind ferric iron with a higher affinity than some host iron-binding proteins; thus, siderophores can effectively strip iron from host proteins, such as transferrin and lactoferrin [9–11]. Upon binding iron, siderophores produce a ferric-siderophore complex that is then imported by the bacteria [8]. Siderophore biosynthesis is a tightly regulated process, orchestrated by major regulators including the ferric uptake regulator (Fur) [12]. This global transcription factor controls iron homeostasis in bacteria and binds ferrous iron as a corepressor [12]. Under iron starvation conditions, binding of Fur is alleviated, allowing for coordinated production of siderophores [12]. Both Gram-positive and Gram-negative pathogens involve siderophores in their virulence strategies [8]. As a countermeasure, the mammalian host produces proteins like lipocalin-2, also known as neutrophil gelatinase-associated lipocalin or siderocalin, to sequester siderophores and interrupt bacterial iron acquisition [13–15]. In response, some pathogens, including members of the Enterobacteriaceae family, have evolved “stealth siderophores” that are unrecognizable by lipocalin-2 due to structural modifications [16]. This evasion strategy allows pathogens to acquire iron even during inflammatory conditions, during which lipocalin-2 is highly expressed [16–18]. For example, the enteric Gram-negative pathogen Salmonella produces salmochelins, which are stealth siderophores that evade sequestration by lipocalin-2 through glucosylation [16] (Fig. 2A). Salmochelins promote the survival of Salmonella in the inflamed gut, helping the pathogen thrive despite nutritional immunity and competition with resident microbiota [17,18]. Still, the extent of siderophore use in complex microbial communities remains unknown, motivating future studies that clarify the impact of siderophores on pathogen colonization and infection outcomes.

Figure 2.

Bacterial siderophores for transition metal capture. Bacteria utilize high-affinity metal chelators known as siderophores to scavenge transition metals in restrictive host tissues. (A) Salmonella produces the iron-chelating siderophore salmochelin, which is considered to be a “stealth siderophore,” for it evades sequestration by the host protein lipocalin-2. (B) Salmonella secretes the iron-chelating siderophore enterobactin, which is susceptible to lipocalin-2 sequestration. However, the commensal organism Bacteroides thetaiotaomicron produces a siderophore-binding lipoprotein, XusB, that shields enterobactin from lipocalin-2 sequestration. In turn, Bacteroides and Salmonella can utilize enterobactin to scavenge iron. (C) The commensal organism E. coli Nissle produces siderophores to outcompete pathogens like Salmonella. E. coli Nissle uses the siderophore yersiniabactin to scavenge zinc and lipocalin-resistant stealth siderophores to scavenge iron to thrive in the inflamed gut. Created with BioRender.com.

Siderophores are utilized by nonpathogenic commensals and pathogens alike. In fact, some commensals obtain siderophores produced by other microbes, known as xenosiderophores. For example, a member of the human gut microbiota, Bacteroides thetaiotaomicron, capitalizes on siderophore cross-feeding to survive in the inflamed gut, utilizing siderophores produced by commensal and pathogenic Enterobacteriaceae [19]. Recent work revealed that this commensal secretes a siderophore-binding lipoprotein (XusB) to utilize enterobactin, a siderophore produced by Salmonella [20] (Fig. 2B). Thus, XusB allows B. thetaiotaomicron to subsist despite the metal starvation induced by intestinal inflammation during Salmonella infection. Notably, when enterobactin is bound to XusB, the siderophore is protected from lipocalin-2 sequestration, thereby also helping Salmonella evade nutritional immunity [20] (Fig. 2B). However, commensals can also compete with pathogens for iron in the inflamed gut. The probiotic strain E. coli Nissle outcompetes Salmonella in mouse models through iron uptake mechanisms, including the use of stealth siderophores [21] (Fig. 2C). In fact, E. coli Nissle requires these systems to limit Salmonella colonization [21] (Fig. 2C). Future studies are needed to further elucidate the contributions of commensals in defining host microbial niches via iron availability.

Heme as an iron source for bacteria

In vertebrates, the majority of iron is complexed to heme, which associates with hemoglobin in circulating erythrocytes [22]. As an iron reservoir, heme contributes to nutritional immunity by limiting iron availability to bacteria [22]. Still, bacterial pathogens can exploit host heme to acquire iron. While some bacteria are able to synthesize heme de novo, others must acquire it from the host. Several pathogens have developed strategies to use heme as an iron source in the GI tract through hemolysins, heme transporters, among other heme uptake systems. Vibrio cholerae, the causative agent of cholera, induces secretory diarrhea through cholera toxin. In neonatal rabbit models of infection, cholera toxin leads to iron-scarcity in the gut, yet this iron depletion is independent of intestinal inflammation [23]. To overcome this limitation, V. cholerae increases expression of its heme uptake systems and the siderophore vibriobactin during infection, which ultimately confers a fitness advantage for the pathogen [23]. These findings demonstrate that V. cholerae may exploit host heme as a survival tactic in the iron-scarce intestinal niche. Campylobacter jejuni serves as another example of a Gram-negative enteric pathogen that utilizes heme to successfully colonize the mammalian host. This bacterium encodes genes dedicated to heme utilization and regulation, including the heme uptake regulator, heuR [24]. In fact, C. jejuni requires HeuR to colonize the GI tract of chickens and to utilize heme as an iron source [24].

Additionally, the Gram-positive organism Enterococcus faecalis colonizes the human intestinal tract as a commensal and an opportunistic pathogen. E. faecalis cannot synthesize its own heme, but encodes several heme-requiring enzymes, thus this bacterium must scavenge for heme from the environment [25,26]. A recent study found that E. faecalis can internalize and extract iron from heme [27]. In fact, under iron-depleted conditions, heme supplementation restores the growth and virulence of an E. faecalis mutant that lacks iron transport systems [27]. Thus, heme is an important source of iron for E. faecalis. The impact of polymicrobial communities on heme availability in the gut is also important to consider. In a collaborative study, our team recently demonstrated that Enterococcus blooms during Clostridioides difficile infection (CDI) and enhances the virulence of C. difficile [28]. Toxin production by C. difficile damages the colonic epithelium, liberating host heme that can be subsequently leveraged by E. faecalis to perform aerobic respiration and thrive in dysanaerobiosis during CDI [29]. Additional studies have demonstrated that E. faecalis can acquire heme from other bacteria, like Staphylococcus aureus and E. coli, through cross-feeding in vitro [30,31]. These findings further underscore the importance of microbe-microbe interactions on heme acquisition for pathogens like E. faecalis. Notably, C. difficile also contends with host heme through machinery that senses and detoxifies excess heme, including the HatRT and HsmRA systems [32,33]. The HsmRA system even protects C. difficile from oxidative stress by co-opting exogenous heme [33]. Altogether, these studies reflect the importance of bacterial strategies to acquire and repurpose host heme in the inflamed gut for survival.

Ferrosomes: bacterial iron storage organelles

Once iron has been acquired, storage strategies are essential to mitigate toxicity; however, until lately, very little has been known about metal chaperones and storage strategies in bacteria. Recent studies discovered that the Gram-negative environmental anaerobes Desulfovibrio magneticus, Rhodopseudomonas palustris, and Shewanella putrefaciens harbor iron storage organelles known as ferrosomes [34]. Whether Gram-positive pathogens also generate ferrosomes remained unclear, until a recent finding identified the iron storage system in C. difficile [35]. Importantly, this study uncovered the relevance of ferrosomes in vivo, as these iron granules allow C. difficile to overcome nutritional immunity mediated by the host metal-chelating protein calprotectin [35] (Fig. 3A). Thus, ferrosomes enable the pathogen to survive and persist in the inflamed gut [35]. Future studies are needed to investigate whether ferrosomes and other related bacterial organelles play pivotal roles in the pathogenesis of other enteric bacteria.

Figure 3.

Bacterial strategies to overcome calprotectin-mediated metal starvation. Calprotectin is a host metal-chelating protein that facilitates nutritional immunity. To overcome this host defense tactic, bacterial pathogens have evolved strategies to import and store nutrient metals despite calprotectin-mediated sequestration. (A) Clostridioides difficile utilizes transport systems like ZupT to import zinc; this pathogen also harbors dedicated iron-storage organelles known as ferrosomes. (B) To import zinc, Acinetobacter baumannii uses the ZnuABCD transport system; to maintain zinc homeostasis, the opportunistic pathogen relies on the metallosensor Zur, which regulates expression of zrlA, coding for a zinc-binding peptidase. (C) Salmonella harbors several metal transport systems, including ZupT for zinc import and SitABCD and MntH for manganese import; this pathogen also uses the manganese superoxide dismutase SodA to detoxify reactive oxygen species (ROS). Created with BioRender.com.

Targeting bacterial iron uptake machinery for therapeutic options

Owing to the importance of iron uptake machinery for pathogen survival in the host, new developments have focused on targeting these systems for therapeutic purposes. In particular, siderophores offer a unique therapeutic opportunity to deliver antibiotics by exploiting siderophore transport machinery. Most recently, a synthetic enterobactin mimetic conjugated to the β-lactam antibiotic ampicillin yielded selective transport of the drug to multiple Gram-negative bacterial pathogens and subsequently enhanced killing of the bacteria [36,37]. Hijacking siderophores as antibiotic delivery vectors represents a promising approach for targeted drug delivery and increased antimicrobial activity [36,37]. Moreover, siderophore-based vaccines offer a compelling approach to target Enterobacteriaceae [38–40]. Recent work revealed that enterobactin immunization protected mice from colonization with adherent-invasive E. coli (AIEC) during colitis [40]. Since AIEC is prevalent in patients suffering from Crohn's disease, this immunization strategy could prove to be a viable alternative to antibiotic use. Ultimately, due to the rise of antimicrobial resistance, future work exploring antibacterial applications of targeting bacterial iron transport systems will be of great interest and importance to the field.

The impact of zinc and manganese on infection outcomes

In addition to iron, bacterial survival hinges on acquiring other micronutrients from the host during infection. These include, but are not limited to, zinc and manganese. To survive oxidative stress as well as iron-deprivation, many bacterial species rely on manganese in critical metalloproteins, including redox-active enzymes [41]. In fact, several pathogens encode manganese-dependent superoxide dismutase (SodA) to detoxify reactive oxygen species (ROS) or leverage free manganese as an ROS detoxification strategy [42–45]. Zinc is the most common enzyme-associated transition metal and serves as an essential cofactor and/or structure component in numerous bacterial proteins, including metalloproteases [2]. To restrict pathogen colonization, the host withholds zinc and manganese using metal transporters and metal chelators [3,4]. As mentioned previously, calprotectin is an antimicrobial protein that binds and sequesters different transition metals, including iron, zinc, and manganese [46–50]. While calprotectin is a secreted protein and acts extracellularly, other host proteins restrict access to transition metal within cellular compartments to combat intracellular pathogens. In macrophages, the natural resistance-associated macrophage protein 1 transports divalent cations, including iron, manganese, cobalt, and magnesium, out of phagosomes in an attempt to starve vacuolar pathogens like Salmonella [51–55]. To combat these host defense maneuvers, bacteria use coordinated responses to acquire manganese and zinc from the host while also avoiding metal intoxication.

Manganese transport systems promote bacterial survival

Though Gram-negative bacteria often have iron-centric metabolisms, they still can rely heavily on manganese, especially in the face of antimicrobials in the host. Salmonella harbors high-affinity manganese transporters, including MntH and SitABCD, and these systems are required for the pathogen to withstand nitrosative stress in vitro [56]. Importantly, these manganese transporters along with a manganese SodA support the growth of Salmonella in vivo [57]. Upon Salmonella infection in mice, manganese is scarce in the gut, a hallmark of nutritional immunity [57]. However, manganese transporters enable Salmonella to withstand inflammatory defenses, including ROS generation and calprotectin-mediated metal sequestration [57] (Fig. 3C). In fact, these transporters help Salmonella outcompete commensal E. coli to gain a competitive advantage, suggesting that manganese is a critical resource that influences host-pathogen-microbiota interactions in the inflamed gut [57]. Gram-positive bacteria also employ high-affinity manganese transporters to secure the nutrient under restrictive host conditions. A recent study revealed the primary manganese acquisition systems in E. faecalis, namely the EfaCBA, MntH1, and MntH2 systems [58]. These transporters promote the growth of E. faecalis in vitro during manganese restriction and augment the virulence of E. faecalis in several animal models of infection [58]. Overall, these studies suggest that manganese uptake is an important component of the virulence strategies for both Gram-negative and Gram-positive pathogens.

Zinc transport systems promote bacterial survival

Bacteria also harbor high-affinity zinc transport systems to capture zinc from the host environment and survive metal starvation. Members of the Enterobacteriaceae family, including Salmonella, express transport machinery to import zinc, including ZnuABCD and ZupT [46,59–62]. These uptake systems protect Salmonella from oxidative stress in vitro and support the virulence of Salmonella in vivo [59,60,63,64]. Recently, it was observed that E. coli Nissle is more resistant to zinc starvation induced by calprotectin than Salmonella due to an additional zinc-acquisition method [65]. E. coli Nissle uses the metallophore yersiniabactin to scavenge zinc and thrive in the inflamed gut [65] (Fig. 2C). While this siderophore is absent in Salmonella, it is present in other pathogenic Enterobacteriaceae, including Yersinia [65]. Notably, yersiniabactin is one example of a siderophore that can bind metals other than iron. The opportunistic Gram-negative pathogen Acinetobacter baumannii most commonly infects the lung, urinary tract, and blood, where it must overcome zinc restriction. Interestingly, emerging data suggests A. baumannii can colonize and persist in the GI tract [66]. A. baumannii utilizes the ZnuABCD transport system to import zinc and relies on the regulator Zur to maintain zinc homeostasis, for this transcription factor promotes bacterial survival during both zinc-deficient and zinc-replete conditions [49,67,68]. The relevance of Zur was also observed in vivo, as this metallosensor supports the dissemination of A. baumannii during calprotectin-mediated metal sequestration in mouse models of lung infection [49,67,69] (Fig. 3B). Recent work characterized the structure of Zur from A. baumannii while also elucidating its zinc binding affinity and dynamics [70]. The Zur regulon in A. baumannii includes zrlA, which encodes a zinc-binding peptidase that maintains cell envelope integrity [67,71] (Fig. 3B). Although the majority of studies in A. baumannii have focused on the role of metals in lung infection, the emergence of evidence of a potential gut reservoir makes these findings important to consider in the context of the GI tract [66].

Zinc acquisition is similarly critical for Gram-positive bacteria. A recent study demonstrated the ability of the opportunistic Gram-positive pathogen methicillin-resistant Staphylococcus aureus (MRSA) to colonize the GI tract of germ-free mice [72]. Furthermore, intestinal colonization is commonly observed in hospitalized human patients [72]. S. aureus relies on metal-responsive regulators to overcome metal limitation imposed by calprotectin, including Zur and Fur, as well as the ATP-dependent Clp protease [73]. Although much of this work has focused on nasal, skin, and systemic colonization and infection, there is likely an unexplored role for metals in the gut niche of S. aureus. Streptococcus agalactiae (Group B Streptococcus), which colonizes the GI and female reproductive tracts, requires three zinc binding proteins, adcA, adcAII, and lmb, to overcome zinc limitation by calprotectin [74]. The role of these proteins in gut colonization and systemic invasion remains unclear but is a key area of investigation [75]. C. difficile employs the high-affinity metal importer, ZupT, to import zinc during calprotectin-mediated metal starvation, thereby overcoming nutritional immunity during infection [76] (Fig. 3A). In addition, E. faecalis relies on the AdcACB/AdcAII system to maintain zinc homeostasis, particularly during zinc-depletion [77]. This system even contributes to the virulence of E. faecalis, further underscoring the importance of zinc import for bacterial pathogenesis [77]. Notably, common members of the healthy gut microbiota, like Lactobacillaceae, also encounter changes in metal availability. A recent study discovered that Lactobacillaceae harbor genes encoding predicted zinc transporters, motivating future work to uncover the roles of these systems in zinc uptake and homeostasis [78].

However, excess zinc can be toxic to certain bacteria, which the host exploits to limit bacterial invasion. For instance, human macrophages deliver zinc-containing vesicles to intracellular bacteria, such as Salmonella and even nonpathogenic E. coli, to induce zinc toxicity and promote bacterial clearance [79]. A recent study found that zinc overload inhibits iron-sulfur cluster biogenesis in E. coli, suggesting a possible mechanism underlying zinc toxicity in bacteria [80]. Moreover, excess zinc can also impact the gut microbiota, as high zinc levels reduce the growth of Lactobacillus species during in vitro conditions [78]. Additional studies are needed to understand the impact of zinc intoxication on bacteria, particularly in the context of the host and gut ecology.

Dietary zinc and dietary manganese modulate infection outcomes

Since the host typically secures transition metals through diet, a growing body of literature suggests that host dietary changes in metal homeostasis impact susceptibility to infection as well as disease outcomes. In particular, host diet can alter the diversity and structure of the gut microbiota. Dietary iron has lasting impacts on host and microbial metabolites in murine fecal content [81]. Moreover, it was recently observed that excess dietary zinc shifts the gut microbiota in mice [82]. This microbial community often protects the host through colonization resistance, thereby opposing the invasion and expansion of exogenous enteric pathogens. Thus, disruptions of the gut microbiota can prove detrimental to the host. For example, antibiotic use perturbs the gut microbiota and, thus, profoundly increases susceptibility to invading pathogens, like C. difficile. In the context of CDI, alterations to the gut microbiota mediated by excess dietary zinc lower the threshold of antibiotics required to confer susceptibility to C. difficile and worsen infection in mice [82]. Ultimately, excess dietary zinc helps C. difficile overcome calprotectin-mediated host sequestration of zinc, suggesting that dietary considerations may be useful in mitigating CDI [82].

For other pathogens, zinc deficiency is associated with altered susceptibility to infection. Zinc deficiency promotes the virulence of the enteric pathogen enteroaggregative E. coli in mice, while also remodeling the host immune response, resulting in enhanced disease [83,84]. Zinc even impairs the virulence of a related pathogen, enteropathogenic E. coli (EPEC). By damaging the cell membranes of EPEC, zinc induces the RpoE stress response pathway and consequently inhibits the virulence of EPEC in vitro [85,86]. These observations are especially intriguing, given that oral rehydration salts are often given with dietary zinc supplements to treat acute diarrheal infections across the globe. Altogether, this suggests that zinc supplementation can impair the virulence of certain bacterial pathogens while also promoting protective host responses in certain infectious contexts. Beyond dietary zinc, dietary manganese also regulates host-pathogen interactions. For example, high dietary manganese exacerbates S. aureus infection of the heart in mice [87]. Still, the dietary impact of manganese among other transition metals on host-microbe interactions remains understudied and represents a promising area for future research.

Conclusions and perspectives

Transition metals act as coveted resources at the host-pathogen-microbiota interface. The GI tract serves as a dynamic stage that showcases the tug-of-war between the host and microbes over these micronutrients. While the host strives to limit bacterial expansion by controlling metal availability, bacteria have developed strategies to extract these commodities from host tissues and survive in the face of nutritional immunity. In this minireview, we have highlighted a select few recent studies that illustrate how both Gram-negative and Gram-positive bacteria secure iron, zinc, and manganese from the host, employing strategies that hinge on polymicrobial interactions, dedicated storage organelles, and versatile transport systems. These tactics are finely tuned by bacterial regulators and downstream factors that sense and respond to metal concentrations. Altogether, these findings motivate future work aimed at deciphering the complexities of bacterial metal acquisition in the gut. For example, it remains unknown how transition metals shape the early life gut ecosystem and little is known about the role that metal competition plays in succession of the microbiome early in life. Furthermore, it is unclear how microbe-microbe competition for metals in the GI tract influences the health of the host, microbial community composition, colonization resistance, and ultimately infection outcomes. Recent observations also suggest that there are compelling opportunities to target bacterial metal uptake pathways for therapeutic purposes, including novel antibiotics and vaccine strategies. Further investigations exploring the potential of exploiting the machinery that enteric pathogens dedicate to overcoming nutritional immunity could prove useful to combatting GI infections. In conclusion, nutrient metals shape infection dynamics, impacting microbial ecosystems, host responses, and even bacterial gene regulation and physiology. Understanding how individual microbes, pathogens, and commensals alike, confront metal starvation in the host is critical to our understanding of human health and disease. Future studies that continue to define bacterial maneuvers to endure nutritional immunity will yield critical insights that could eventually be leveraged to treat enteric infections and improve disease outcomes.

Data availability

No new data were generated or analyzed in support of this research.