Cardioimmunology is a field of study that focuses on the interactions between the cardiovascular system and the immune system (1–5). It explores how the immune system can impact various cardiovascular diseases, such as atherosclerosis, myocardial infarction, cardiomyopathies, arrhythmias and heart failure. Research in cardioimmunology aims to understand the complex mechanisms by which immune cells and molecules contribute to both the pathogenesis and resolution of cardiovascular diseases (CVD) (6). By uncovering these interactions, scientists hope to develop new strategies for preventing and treating cardiovascular conditions through targeted immunomodulatory therapies (7).

Cardioimmunology, indeed, is a relatively new and rapidly growing field that focuses on the intersection of CVD and the immune system (8). It explores the complex interactions between the immune system and the cardiovascular system, as well as the role of inflammation in the development and progression of various cardiovascular conditions (9, 10). In the last decade, the systemic dimension has emerged as a predictor of CVD, alongside cardiomyopathies and arrhythmias. Immunomodulation in the local microenvironment, metabolism and mitochondria of the cardiac tissue are highly responsive to the environment (10–15). Experiments involving factors such as gut microbial composition (e.g., considering the host-microbiome dyad as a “superorganism”), the circadian clock (16) or hypoxia (17) have been shown to impact tissue function, leading to conditions such as cardiometabolic disorders, myocarditis, arrhythmias along with tissue remodeling notably with occurrence of fibrosis. Similarly, systemic inflammation, immune cells and oxidative stress also contribute to the pathogenesis of hypertension, which is a significant risk factor for CVD, through vascular inflammation and microvascular remodeling (18).

Mapping cell destinies, depleting and regenerating immune cells in experimental models of heart disease, along with analyzing the human heart at a cellular level, significantly enhance our comprehension of the intricate communication between immune and non-immune cells within the heart (19, 20). Although the immediate immune reaction is crucial for triggering inflammation and repairing tissue after damage, prolonged activation leads to harmful effects, influencing negative changes in the heart’s structure and function. Identifying the precise roles of immune cells within the cardiac setting opens up novel avenues for adjusting immune responses to manage inflammation effectively in cases of heart diseases.

The heart incorporates immune cells as crucial cellular elements that engage in communication with resident cardiac cells in situations of homeostasis, cardiac injury, and remodeling (21, 22). These discoveries play a pivotal role in shaping and broadening the emerging domain of cardioimmunology. In this analysis, we examine the latest literature related to this subject and deliberate on the ongoing and prospective initiatives aimed at propelling this field ahead. Some of the crucial aspects of cardioimmunology are depicted in Figure 1 and listed below. (a)

Inflammation and cardiovascular disease: Chronic inflammation is now recognized as a key driver of CVD, including atherosclerosis, cardiomyopathies, arrhythmias, heart failure, and myocarditis. Immune cells and inflammatory mediators play a crucial role in the development of these conditions (12, 23).

Overall, cardioimmunology represents an exciting and promising area of research that has the potential to improve our understanding of CVD and lead to the development of innovative therapies to combat these conditions. In particular, some emerging areas of particular interest are represented by: (i)

The role of the gut microbiota and products thereof. The gut microbiota plays a pivotal role in educating and modulating the immune system, influencing the balance between pro-inflammatory and anti-inflammatory responses. On the one hand, dysbiosis of the gut microbiota, characterized by alterations in microbial composition and function, has been linked to immune dysregulation and chronic low-grade inflammation, which are key drivers of atherosclerosis, hypertension, and other cardiovascular conditions. Understanding the interconnections between the cardiovascular and the gut microbiota opens avenues for developing novel therapeutic strategies (37, 38). On the other hand, the intricate crosstalk between the gut microbiota and the cardiovascular system underscores the importance of considering the gut as a key player in cardioimmunology (39). By elucidating the mechanisms by which the gut microbiota influences immune responses, inflammation, and metabolism in the context of cardiovascular health, researchers may uncover novel therapeutic targets and strategies for the prevention and management of several pathologic conditions, including CVD (39, 40).

Both humans and gut microbiota feed on dietary Trp for proteogenesis and other functions that rely of the degradation of this essential amino acid. The phylogenesis of Trp catabolism across different organisms provides insights into the evolutionary advantages and diverse functions of this pathway (59). Trp catabolism is a highly conserved process that has evolved over time, and its existence across various organisms suggests its importance in adaptation and survival (60–62). Here are some key points regarding the phylogenesis of Trp catabolism: (a) Universal presence: Trp catabolism is found in a wide range of organisms, including bacteria, fungi, plants, and animals. This universality indicates that the pathway has been evolutionarily conserved and is fundamental to the biology of diverse life forms (60); (b) Metabolic regulation: The regulation of Trp catabolism has likely evolved as a mechanism for organisms to adapt to changing environmental conditions, nutrient availability, and immune responses (63). In many cases, the regulation of Trp catabolism is responsive to external stimuli, such as stress, infection, or inflammation, highlighting its role in the adaptive response to various challenges; (c) Host-pathogen dynamics: The evolutionary arms race between hosts and pathogens has likely shaped the development and diversification of Trp catabolism. Hosts may have evolved this pathway as a defense mechanism to limit nutrient availability for pathogens, while some pathogens have developed strategies to exploit or manipulate Trp metabolism for their benefit (64); (d) Immunomodulation and tolerance: The immunomodulatory effects of Trp catabolism, including the generation of metabolites with immunosuppressive properties, suggest that this pathway has evolved to play a role in regulating the immune response (65). Tolerance induction, mediated by Trp catabolism, could have provided an evolutionary advantage by preventing excessive inflammation and immunopathology, contributing to the host’s ability to coexist with commensal microorganisms; (e) Nutrient sensing and energy metabolism: Trp catabolism is not only involved in immune responses but is also linked to broader metabolic processes. The breakdown of Trp can provide precursors for the synthesis of other molecules, and its regulation may be tied to overall energy metabolism.

Therefore, as to the question of why an organism would want to destroy an essential amino acid like Trp, it is important to note that the goal is not necessarily the destruction of Trp but rather the modulation of its levels (63, 66–69). The evolutionary advantage lies in the ability to dynamically regulate Trp availability in response to specific environmental and physiological cues. By controlling Trp levels, organisms can influence their own metabolism, respond to stressors, and shape the host-microbe interaction in ways that promote survival and adaptation. It is interesting to note that bacteria that eat worms use NAD as a ‘food signal’ to open their mouths but, if NAD is unavailable, they stop reproducing and enter a developmental and reproductive arrest phase, mediated by serotonin, to survive (60, 70). In the context of host defense, limiting the availability of essential nutrients like Trp can be a strategic means of thwarting the growth and proliferation of pathogens (Figure 2).

Much like their hosts, bacteria can metabolize Trp along all three pathways, influencing the so-called “brain-gut-microbiota axis”. Bacteroides spp., Clostridium spp., Escherichia coli, Lactobacillus spp., Bifidobacterium spp., Akkermansia muciniphila, Faecalibacterium prausnitzii, Prevotella spp., Ruminococcus spp., all degrade Trp in the gut via the kynurenine pathway (71). There is some evidence that several of the same species may likewise induce serotonin in the gut. Escherichia coli, Clostridium Spp., Bacteroides spp., Akkermansia muciniphila, Clostridioides difficile, Enterococcus spp., Proteus spp., Citrobacter spp., and Klebsiella spp. will instead produce a preponderance of indole or derivatives thereof (72). It follows that—if host and gut bacteria—both metabolize Trp there must be competition for the substrate, yet flexible balance for local and systemic homeostasis (69).

Gut microbiota and microbiota-derived metabolites have been increasingly recognized for their potential impact on CVD, including hypertension, heart failure, myocardial infarction, arrhythmia, atherosclerosis, and myocarditis. Evidence from recent studies has shown that gut microbiota contributes to the development of myocarditis, an inflammatory disease that can result in myocardial damage and the emerging field of cardioimmunology (37, 73, 74). The metabolites produced by gut microbiota can affect the immune system and have an impact on cardiovascular health (10, 40). This is in line with the long-established notion that gut microbiota-dependent metabolites serve as a link connecting the dynamic balance between the host and the gut microbiota (75). In addition to microbial-derived SCFAs, BAs and TMAO, a number of host and microbial metabolites derived from the essential amino acid tryptophan (Trp) degradation has been implicated in cardiovascular diseases (10, 76).

The kynurenine pathway is a metabolic pathway that plays a crucial role in Trp degradation (77–82). This pathway is primarily associated with immune regulation and has been implicated in various physiological and pathological processes, including immune homeostasis and cardiovascular integrity (83). The pathway’s contributions to immune homeostasis include (a) Regulation of T-cell responses: The kynurenine pathway is a key player in the modulation of immune responses. One of its main functions is the regulation of T cell activity. Specifically, the production of kynurenine metabolites can influence T cell differentiation and function (84); (b) Immunosuppressive effects: Certain metabolites of the kynurenine pathway, such as kynurenine itself, have immunosuppressive properties. They can inhibit the proliferation of T cells and promote the generation of regulatory T cells, which are crucial for maintaining immune tolerance and preventing autoimmune reactions (82). As regards the cardiovascular system, additional functions are: (c) Regulation of vascular function: Components of the kynurenine pathway, including kynurenine and its derivatives, have been implicated in vascular function by affecting, for instance, endothelial function and blood vessel integrity (85); (d) Control of inflammation and atherosclerosis. The immunomodulatory effects of the kynurenine pathway may influence the inflammatory processes associated with cardiovascular conditions (86–88). As a matter of fact, dysregulation of the kynurenine pathway has been implicated in cardiovascular diseases in which the kynurenine and the [Kyn]/[Trp]-ratio were associated with an increased risk of developing cardiovascular disease (10, 76) while higher Trp levels were associated with a tendency toward lower incident risk of mortality (76).

The serotonin pathway also plays an important role in the degradation of Trp with effects that go beyond its role as neurotransmitter in the central nervous system to include, among others, the regulation the immune and cardiovascular functions. In the periphery, serotonin is a major regulator of vasoreactivity, by directly inducing vasoconstriction in large arteries and veins and exerting a vasodilatory effect in arterioles via nitric oxide release and vascular smooth muscle relaxation (89). Aggregating platelets release serotonin that may contribute to the etiology of spasm in cerebral, digital and coronary vessels, and in the maintenance of the elevated peripheral resistance in arterial hypertension (90). Increased concentrations of serotonin were indeed associated with an increased risk of cardiovascular damage and disease (76, 91).

Finally, the impact of indoles, produced by bacterial degradation of Trp, has gained attention for their dual influence at the pathogen-host interface (84, 92–94). In cardiology, metabolites in the indole pathway did not show consistent associations with cardiovascular outcomes, although higher concentrations of some end products of the indole pathway have been reported to be associated with a lower risk of atherosclerosis (76, 95). For instance, the indole-3-aldehyde (3-IAld) metabolite was found to be lower, different from others, in patients with myocardial infarction (96). The section below delves into the manifold influence of indole metabolites on the host metabolism and immunity, specifically examining their systemic effects from the standpoint of cardioimmunology.

Accumulated evidence substantiates the notion that a triad comprising microbiota, Trp, and AhR is a targeted axis in several cardiovascular conditions (Figure 3).

Presently, most treatments primarily address symptoms, focusing on enhancing compromised functionality. However, therapeutic options capable of influencing cellular degeneration or pathology remain elusive. Should a significant role of abnormal intestinal flora composition in specific phenotypes be confirmed, a promising therapeutic avenue could emerge by optimizing pharmacological therapy of CVD with Trp supplementation and/or medications altering the Trp metabolic pathways. Nevertheless, variations among individuals, coupled with the impact of comorbidities, dietary patterns, medications, infections, and lifestyle, can alter gut microbiota composition. Hence, future research demands meticulous investigation using a rigorous experimental framework, taking these factors into account (124). Indeed, despite the potential promise of precisely defined and tailored diets in influencing the microbiome and inflammation, their practical applicability in the general population remains questionable as it is the potential long-lasting benefits of fecal microbiota transplantation in CVD (125).

Additionally, the potential value of the measurement of Trp metabolites as screening and diagnostic tools for a broader population, indicate that mechanistic studies are required to understand the role of Trp metabolism in CVD with the goal to identify new diagnostic and therapeutic options.

Lastly, delving into research on microbiota, Trp catabolic pathways and AhR signaling has uncovered insights into the mechanisms of intestinal distress (126, 127). Despite being underappreciated, a role for the intestinal barrier dysfunction in CVD has become evident in light of its occurrence in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction (128). Thus, testing indole derivatives as intestinal barrier-targeted compounds may lead to their potential new class of CVD therapeutics.