Introduction

Inflammatory bowel disease (IBD) is a multifactorial inflammation of the intestine driven by exogenous (environmental) and endogenous factors. It is characterized by a dysregulated immune response in genetically susceptible individuals. The global burden of IBD is on the rise, emphasizing the need for a better understanding of the disease and immediate action to implement this knowledge into new treatment strategies and preventive activities [1].

In the last 25 years, we have learned a lot of the pathophysiology of IBD from the study of experimental models. At least 50 different experimental models are described [2, 3] including spontaneous models, gene knockout and transgenic, chemically induced, and immune dysregulated models. The induction of colitis in mice with similar genetic modification differs from one mouse strain to the other due to the variation in genetic background and housing conditions, resulting in differing immune responsiveness. For example, C57BL/6 mice have been demonstrated to have a Th1-type immune response, in contrast to mice of other backgrounds, such as BALB/c, which tend toward a Th2-predominant response [4].

From mouse models we have also learned that colitis can occur after changes in various immunologic parameters [5]. The fact that sometimes only a small change in immune regulation can induce colitis and that the genetic background of mice determines their susceptibility and capacity to heal [4] can support our understanding of the pathophysiology of IBD. The impact of genetic differences in mice mirrors that of the human situation, where inter-individual diversity might define different immunotypes [6, 7]. From this, we can assume that several different (genetic) abnormalities can lay the groundwork for the development of IBD. Indeed, genome-wide association studies (GWAS) in humans [8, 9] have shown several pathways to be involved: regulation of cytokine production (IFN-γ, IL-12, IL-10, and TNF-α), lymphocyte activation, reaction to bacteria-derived products, and JAK-STAT signal transduction pathways. In addition to genetics, the presence of microbiota is mandatory for the development of colitis [10]. In recent years, the effects of the commensal intestinal bacteria and microbiome-derived metabolites have been shown to profoundly influence host physiology and affect the course of IBD [11, 12].

Current therapies for IBD primarily consist of anti-inflammatory and immunosuppressive drugs, which while capable, of alleviating symptoms, do not offer a cure [13, 14]. These therapies predominantly target innate immunity, such as anti-TNF-α agents, as well as type 1 and type 17 immunity through mechanisms, like lymphocyte trafficking (using anti-integrin and S1PR modulators) and cytokine signaling (with anti-IL-12, anti-IL-23, and JAK inhibitors).

On average, biologics used in current practice demonstrate a ~ 40% efficacy rate [15]. This suggests that a single-target approach is unlikely to solve this problem, necessitating an alternative strategy. One aspect often overlooked in the pharmaceutically driven therapeutic landscape of IBD is addressing the impact of environmental factors on the chronic inflammation of the disease. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by lifestyle factors, including diet, stress, and environmental pollution [16]—often referred to as the “Western lifestyle” [17, 18].

In IBD, responses in the intestine result from a complex interplay among molecules, cells, and the local microenvironment (Fig. 1). There is literature available for each cell type in the intestinal tract suggesting a potential role in inflammation [19]. We propose that the dysregulated immune response is a consequence of intricate interactions within both innate and adaptive immune networks, heavily influenced by a microenvironment rich in adjuvants. Therefore, our hypothesis posits that successful interventions for IBD must address the complexity of the disease by simultaneously targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells, and factors that relate to the (micro)environment to prevent the disease from smoldering. This needs a new approach since it is impossible to identify and eliminate all putative adjuvants.

Fig. 1
figure 1

Successful IBD interventions must address the complexity of the disease. Treatments must target the innate and adaptive response, respectively, in addition to manipulating the (micro)environment of the gastrointestinal lumen and (sub)mucosal layers. Chronic inflammation underlies IBD, characterized by NLRP3 inflammasome activation, a T helper 1 (Th1) cell cytokine profile, bystander activation of tissue-resident macrophages, and T cells. A deteriorated microenvironment, rich in DAMPs, leads to increased permeability of the epithelial membrane and increased translocation of commensal microbes and pathobionts, and environmental factors that contribute to pro-inflammatory signals and cellular stress. Myriad environmental factors, from general lifestyle factors (green), microbial factors (red), intentional food additives and unintentional contaminants (orange), and pollutants (yellow), have all been shown to contribute to the conditions that lead to IBD

Full size image

(Micro)environment

There is a substantial body of literature suggesting that dysregulated inflammation driven by (micro)environmental factors plays a role in IBD [20]. However, the exact mechanism by which these factors trigger the abnormal immune response in IBD remains uncertain. We do know that the immune response in the intestine is tightly regulated to prevent undesirable, harmful reactions to the microbiota and ingested food. A protective layer of dense mucus serves as a barrier, creating an interactive setting with the intestinal immune system. This network allows the passage of water, ions, and nutrients while restricting the entry of excess microbes, endotoxin, and antigens [21]. Dietary factors can influence the well-organized intestinal barrier directly or indirectly through metabolites produced by the microbiota.

In a previous paper [22], our aim was to raise awareness of the impact of increased consumption of intentional food additives like emulsifiers and bulking agents as well as unintentional food contaminants, on the gastrointestinal tract. Exposure to these factors can alter the composition of the intestinal microbiota, increase barrier permeability, lead to dissemination of endotoxins, and induce pro-inflammatory signaling, oxidative stress, and endoplasmic reticulum stress.

Interactions Between Innate and Adaptive Immune Response

The immune response can generally be categorized into two main types: innate and adaptive immune reactions. Traditionally, the innate response was viewed as non-specific and non-adaptive. However, recent discoveries have highlighted the specialization and complexity of this branch of immunity. This paradigm shift began with the introduction of the “danger model” by Matzinger [23]. Her model proposes that the primary purpose of an immune reaction is to detect “danger” signals arising from tissue stress or damage. This redefined the role of the innate immune system, transforming it from a simple barrier or clean-up (phagocytose) system into a coordinator and initiator of the initial immune response, which provides protection against a wide range of pathogens.

Innate immune cells remain quiescent until specific sensors—genetically encoded pattern recognition receptors (PRRs)—are activated by pathogens and pro-inflammatory factors in their immediate environment [23]. These receptors induce a non-specific pro-inflammatory response by upregulating certain chemokines, cytokines, and homeostatic responses, such as autophagy [24, 25]. There are multiple types of PRRs, including Toll-like receptors (TLRs), receptor for advanced glycation end products (RAGE), NOD-like R (NLR), C-type lectin receptors (CLRs), TNF receptors, retinoic acid-inducible gene (RIG-I)-like receptor (RLR), and cyclic GMP-AMP synthase (cGAS). Numerous molecules known as activation signal molecules or alarmins can activate different PPRs. These alarmins include mammalian DNA, RNA, histones, heat shock proteins, interferon-α, IL-1α, IL-33, ATP, CD40L, breakdown products from hyaluron, SAP130 = SF3B3 [26], HMGB1 and 15α hydroxycholestene [27,28,29].

In case of cell injury resulting from stress, pathogens, toxins, mechanical damage and other factors, alarmins, or damage-associated molecular patterns (DAMPs) are released [30]. These factors, along with the multitude of potential PRRs, play a role in triggering a broad and relatively non-specific response involving various innate and adaptive immune cell populations. This non-specific aspect of the response can be considered akin to an adjuvant reaction, as used in vaccines to stimulate the adaptive immunity.

Cells of the innate immune response can initiate an adaptive immune response by presenting antigens. The adaptive response begins when quiescent antigen-presenting cells (APCs) become activated, often in the short term, through innate immune receptors, such as TLRs and NOD2. Activation triggers specific intracellular cascades leading to expression of co-stimulatory molecules like CD40, CD80, and CD86. However, this activation comes at a cost, as danger signals are also generated. These signals are essential endogenous adjuvants and are released through gasdermin-mediated pyroptotic cell death, known as pyroptosis, regulated by Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation [31]. These multiprotein complexes form in the cytosol, leading to caspase-1 cleavage and the secretion of pro-inflammatory cytokines IL-1β and IL-18, along with other DAMPs [32]. While these signals enhance antigen presentation for the initial phase of the adaptive immune response, they also bring about toxicity and systemic changes in critical processes (e.g., elevated body temperature, cardiovascular, and metabolic alterations) necessitating tight regulation [33].

NLRP3 inflammasome activation typically involves a two-step process emphasizing the importance of careful regulation. First, the genes NLRP3, pro-IL1B and pro-IL18 are upregulated by pathogen-associated molecular patterns (PAMPs) and DAMPs via TLRs and NOD2 [34, 35]. Subsequently, NLRP3 activation can be stimulated by various unrelated stimuli and conditions (ATP, K+ ionophores, heme, particulate matter, pathogen-associated RNA, bacterial and fungal toxins and components, crystalline self-molecules, saturated fatty acids, ROS, damaged mitochondria, NAD) and their regulators. Therefore, NLRP3 inflammasome activation is believed to arise from disruptions in cytoplasmic homeostasis and cellular stress [34,35,36]. DAMPs released following NLRP3 inflammasome activation serve a dual function: they facilitate co-stimulatory activation of APCs during a normal immune response, but they also play a role in resolution and tissue regeneration [37]. Only in cases of chronic hyperactivation of the NLRP3 inflammasome are DAMPs released in high concentrations, leading to macrophage activation, neutrophil infiltration, and excessive cytokine production [38]. While the two-step NLRP3 activation is the canonical pathway, other pathways have also been described. These include an alternative pathway involving TLR4 signaling via TLR4-TRIF-RIPK1-FADD-CASP8 [39] and a non-canonical pathway triggered by cytosolic LPS detection via caspase-11 (or human caspase-4 and -5) [40] or the nuclear receptor Nur77, with gasdermin D (GSDMD)-induced mitochondrial dsDNA [41].

When the intestinal barrier is intact there is no interaction between potential immune reactive molecules from the gut microbiota and the host. A damaged barrier can lead to the entry of these molecules. Low-grade inflammation initiated by inflammation triggering moieties, such as LPS that leak into the circulation, leads to systemic low-grade production of pro-inflammatory cytokines. This affects various cells and tissues, including the metabolic and central nervous systems [42, 43]. The association between an overactive immune response, chronic low-grade inflammation, and immune-mediated chronic diseases, including IBD is widely acknowledged [44, 45]. In cases of continuous low-grade inflammation, additional environmental factors [46] can exacerbate inflammation, resulting in recurring cycles of tissue damage and repair. Depending on genetic susceptibility, environmental load, and the degree of micro-ecological/immunological imbalance this might lead to a downward spiral of detrimental chronic inflammation.

As already mentioned, alarmins/DAMPs released after tissue damage contribute to pro-inflammatory signaling. DAMPs can be categorized in proteins, nucleic acids, ions, glycans, and metabolites and are recognized by various cytosolic and-or membrane receptors [47]. One important DAMP that can be actively or passively released and fine-tuned by a number of different factors (reviewed in [48]) is High-Mobility Group Box 1 (HMGB1). HMGB1 was originally discovered to be involved in endotoxin lethality in mice [49]. It serves as a critical late marker of sepsis [50] and infection, contributing to epithelial barrier failure, organ dysfunction, vascular leakage, and even death [51]. High levels of HMGB1 serve as a central mediator of an excessive inflammatory response and an increased disease severity during viral infections [52, 53]. In contrast, low levels of HMGB1 mediate sickness behavior [54], antibacterial activities [55], and may be beneficial in accelerating alveolar epithelial repair [56]. Increased HMGB1 is also responsible for neutrophil infiltration, regulated via IL-17 [57]. Collectively, overactive DAMP-triggered pathways, along with neutrophil infiltration, Th17 response, HMGB1 release, and macrophage activation, likely contribute significantly to the pathological findings in chronic immune diseases like IBD, exacerbated by positive feedback loops [58, 59].

In addition, various other DAMPs have been described to trigger pro-inflammatory signaling in IBD (reviewed in [28, 47, 60]).

One other notable example is adenosine triphosphate (ATP), a DAMP that triggers immune activation via its interaction with the purinoreceptor P2X7R [61]. P2X7 receptor activation subsequently leads to the activation of the NLRP3 inflammasome, resulting in IL-1β and IL-18 release. In the inflamed mucosa of patients with CD, this receptor has demonstrated upregulated expression [62], and recent systematic reviews highlight P2X7R as an important mediator of inflammation in the gastrointestinal tract [63].

Triggers of Immune Response in the Intestine

Ultra-processed Foods, Intentional Food Additives

There are several environmental triggers responsible for interacting with innate and adaptive components that regulate intestinal immunity, particularly in relation to IBD. While most of the attention has been directed toward factors that generate a harmful microenvironment resulting in intestinal inflammation, we should also consider protective factors and acknowledge that their absence or reduction may have detrimental consequences in the course of IBD.

In prospective cohort studies [64, 65], researchers studied large populations of adults from different countries with varying income levels. Their findings revealed a positive association between a higher intake of ultra-processed foods and the risk of developing IBD. These studies also point out the need for further investigation into the specific contributing factors within ultra-processed foods.

Ultra-processed foods are characterized by their high sugar, salt, and fat content, coupled with low fiber levels (for a working definition, see [66, 67]). The effects of these components commonly found in the so-called Western diet have been extensively studied and reported [68,69,70]. Public health advice consistently emphasizes the importance of reducing salt, sugar, and fat intake while increasing fiber consumption [71,72,73]. However, recommendations often do not address the effects of other intentional food additives [22], which the food industry increasingly uses to compensate for reduced salt, sugar, and fat. These additives include artificial sweeteners, bulking agents, and emulsifiers and are identified by specific individual E numbers. Initially, these additives appeared harmless when introduced to our diets, especially in the 1960s and 1970s, a time when our understanding of the gut microbiome was limited.

However, recent scientific literature has shed light on the potential detrimental effects of many of these additives on the gut microbiota, with far-reaching consequences for our health [74]. Most of these studies have been conducted in experimental models, where factors commonly found in ultra-processed foods triggered colitis development. Examples of such additives include carrageenan (E407), carboxymethylcellulose (CMC, E466), and maltodextrin (E1400). Carrageenan and CMC, for instance, have been shown to induce colitis with intestinal ulceration and histopathological changes resembling human IBD. These changes are associated with an unfavorable shift in the bacterial composition within the gut [74,75,76,77,78,79,80,81].

Maltodextrin has been shown to impact the mucus layer of the gut and suppress the body’s intestinal antimicrobial defense mechanisms [82, 83]. While some might initially downplay these findings, believing they are limited to isolated cell and tissue systems or laboratory animals, recent controlled studies in humans have provided further evidence. These studies have demonstrated that carrageenan intake can contribute to early relapses in patients with UC in remission [84]. Additionally, another study showed that CMC, a dietary emulsifier has detrimental effects on the intestinal microbiota and metabolome [85].

In the case of CMC, researchers introduced it into an additive-free diet using a controlled inpatient study setup. The results revealed that CMC consumption alters the fecal metabolome, leading to a reduced presence of health-promoting metabolites such as short chain fatty acids (SCFA) and amino acids. Furthermore, in some individuals, bacteria were found in the impenetrable firm inner mucus layer, a phenomenon reminiscent of findings reported by Johansson et al., who observed bacteria in the inner mucus layer in cases of dextran sodium sulfate (DSS) exposure and UC [86, 87].

Other additives like food colorants have been shown to induce experimental colitis when there is dysregulation of IL-23, leading to the presence of pro-inflammatory CD4+ T cells [88,89,90]. Notably, in one of these studies, it was observed that widely used food colorants become colitogenic only after being metabolized by microbiota. Additionally, caspase-induced apoptosis of intestinal epithelial cells was demonstrated both in vivo and ex vivo following exposure to Red 40 [88].

As the obesity pandemic continues, there is an increasing availability of “sugar-free” products which have been shown to increase inflammation and induce intestinal dysbiosis in various experimental models (reviewed in [91,92,93]). Interestingly, the most significant effects were observed in models with pre-existing inflammation. Similar exacerbating effects were found for another industrially added ingredient, titanium dioxide (TiO2) nanoparticles. These nanoparticles worsen experimental colitis, accumulate in intestinal epithelial cells and macrophages, and activate NLRP3 [94]. In mice with a protective PTPN22 variant, TiO2 nanoparticles nullify this protective effect, highlighting the consequences of interaction between environmental factors and genetic variants [95].

Unintentional Food Contaminants

During food processing, unintentional food contaminants [22] can pollute the food from the environment, including persistent organic pollutants (PFAS, PFOA [96]), pesticides (e.g., propyzamide [97]), micro- and nanoplastics [98, 99], particulate matter [100], and heavy metals. Perfluoroctanoate used in Teflon production is associated with UC [101]. Additionally, advanced glycation end products, AGEs [102], benzoapyrene [96], and acrylamide [103] can form during food preparation and upon ingestion can have pro-inflammatory effects in the intestine. RAGE, a specific receptor for AGEs, is upregulated in IBD and plays a role in immune activation [104]. Recently, it was demonstrated that ingested nanoplastics (~ 500 nm, compared to microplastics, ~ 2 µm) exacerbate LPS-modulated duodenal permeability and inflammation through ROS production and the NF-κB/NLRP3 pathway [98]. Moreover, nanoplastics can trigger intestinal IL-1-producing macrophages by inducing lysosomal damage, with potential effects on brain immunity, including microglial activation and Th17 differentiation [105].

While most studies focus on individual unintentional food contaminants, they often overlook the complex and variable effects of mixed contaminants on the intestinal barrier. For instance, synergistic effects of pesticide mixes have been observed [106], and microplastics can act as carriers for other contaminants [107].

Microbial Dysbiosis

Direct effects of the environment, particularly diet, on the composition of the microbiota and the production of metabolites by the intestinal bacteria have been extensively documented [108, 109]. Immigration to Western societies and the adoption of a Western diet have been associated with a loss of diversity and function in the microbiome, often linked to the presence of a specific Bacteroides 2 enterotype known for its pro-inflammatory effects [110, 111]. Moreover, specific microbial communities have been identified as preclinical gut microbiome signatures that appear to be related to the future onset of CD. These signatures are characterized by an increase in mucin-degrading taxa and a decrease in species associated with anti-inflammatory properties [112]. Detrimental bacterial metabolites, such as trimethylamine-N-oxide (TMAO), have been linked to the consumption of red meat and have been shown to stimulate inflammatory M1 macrophages [113]. Additionally, certain medications are demonstrated to have an impact on intestinal bacteria and intestinal health. While this is evident for antibiotics, medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), affect intestinal epithelial cells and can exacerbate experimental colitis through the activation of NLRP3 [114].

Lastly, alcohol and smoking (in the context of CD) have notable effects on the intestinal tract. Alcohol impairs the barrier function, leading to translocation of endotoxins [115], while smoking has multiple negative effects in CD patients (but not in UC) [116].

In essence, we can speak of an aggregate effect—the cumulative impact on health resulting from a cocktail of all environmental triggers. However, we still lack a comprehensive understanding of the combined effects of the myriad chemical substances added to food and their impact on health, making this area of research particularly challenging.

In the context of IBD, specific receptors have been described, including the C-type receptor MINCLE, which has been shown to have numerous potential agonists that support its adjuvanticity [29]. Previous hypotheses regarding the role of Mycobacteria in relation to Crohn’s disease, coupled with the fact that nearly a quarter of the global population is latently infected with Mycobacterium tuberculosis [117], might define a subgroup of IBD patients (referred to as the granuloma-positive group). Additionally, another hypothesis regarding the beneficial effects of a Th2 immune response shift following helminth infection in IBD [118] could be linked to these findings. A recent publication has demonstrated that IL-4 downregulates MINCLE expression on monocytes and macrophages, resulting in a reduced IL-17 response [119].

Apart from Mycobacteria, in theory other infectious agents may also play a role in creating an inflammatory microenvironment in the context of IBD. Experimental animal studies have shown that colitis does not develop in a germ-free animals [120]. Specific enterotoxins produced by certain intestinal pathogens can destroy the epithelial barrier, and Cytomegalovirus infection can disrupt the intestinal epithelial barrier and the altered intestinal homeostasis can lead to transient colitis in an immune-compromised host [121,122,123]. Enteric infections with bacteria like Helicobacter spp. (EHS) and Campylobacter spp. have shown negative associations with IBD, whereas Helicobacter pylori demonstrates a positive association [124]. Hepatitis B viral protein found in UC patients might also contribute to the UC pathogenesis [125].

Regarding viral infections, a recent review focused on studies involving Epstein–Barr virus (EBV), enteric viruses (EV), hepatitis B virus (HBV), cytomegalovirus (CMV), and SARS-CoV-2. It suggested that the risk of viral infections might be higher in IBD patients, but more research is needed to understand the effects on the microenvironment [126].

Beneficial Dietary Factors

In contrast to the negative effects of many elements in the Western diet, there are numerous dietary factors that have demonstrably positive effects on the microbiota and the health of the intestinal mucosa. Unfortunately, in the Western diet, many of these beneficial factors are either present in reduced amounts or entirely absent. As mentioned earlier, one of the prominent shortcomings of the Western diet is the scarcity of dietary fibers in ultra-processed foods. Attempts to restore the deficiency of fibers through dietary supplementation have yielded variable results, often dependent on the type of fiber and the presence of specific intestinal bacteria capable of fermenting these fibers [127,128,129,130,131]. These beneficial fiber-degrading bacteria are known to produce metabolites that exert a positive influence on the immune system, with short chain fatty acids (SCFAs) being a prime example [132]. SCFAs have demonstrated anti-inflammatory properties, promoting the generation of regulatory T cells (Tregs), influencing cytokine production, enhancing the production of antimicrobial peptides, and supporting mucus secretion through the activation of G-protein-coupled receptors [133, 134].

Metabolites such as SCFAs exert a profound influence on the tight junction proteins that maintain the integrity of the intestinal epithelial barrier, ultimately impacting intestinal permeability. In a healthy individual, SCFAs serve as crucial energy sources for epithelial cells and facilitate oxidative phosphorylation (OXPHOS), resulting in high oxygen consumption and the creation of a hypoxic environment that is advantageous for obligate anaerobic bacteria [135]. A decrease in SCFAs can shift intestinal metabolism from OXPHOS to glycolysis, potentially leading to alterations in mitochondrial structure and function, hypoxia, and the activation of inflammasomes [136]. Furthermore, various other metabolites produced by the intestinal microbiota have shown to confer health benefits, including amino acids, phenolic metabolites, and bile acids [137]. These findings underscore the importance of dietary choices in modulating the gut microbiota and maintaining intestinal health. Numerous food components have been identified for their ability to influence immune fitness and reduce intestinal inflammation, as evidenced by a wealth of studies in experimental models. These food components encompass a wide range of dietary elements that have demonstrated positive effects on various aspects of intestinal health [138].

Of particular interest, in the context of environmental influence on gut health are dietary tryptophan-enriched proteins that have anti-inflammatory properties by activation of the aryl-hydrocarbon receptor (AHR). This receptor can be activated by various exogenous and endogenous ligands, including environmental toxins, dietary compounds, and microbial metabolites from tryptophan metabolism. Tryptophan metabolism comprises three interconnected pathways: the kynurenine pathway, the serotonin pathway, and the indole pathway, the final one mentioned is regulated by gut microbiota. The three pathways are tightly interconnected and play a role in gut homeostasis. Dysregulation of any of these pathways can contribute to intestinal inflammation [139].

Role of the Adaptive Response: TRM T Cells Are Key Inflammatory Drivers Associated with IBD Relapse

There are numerous environmental factors that can directly trigger immune reactivity within the intestine, but the question remains: do these triggers also lead to an adaptive immune response and the development of specific T cell populations? Recent years have witnessed a surge in studies that delve into single-cell analyses of tissues from IBD patients. These studies have revealed increased numbers of various T cell subpopulations in the inflamed tissues of these patients. However, the precise nature of these T cell subpopulations and their interrelationships remain largely unknown. Over the past few decades, efforts have been made to identify specific antigens responsible for generating pathogenic T cells in IBD, but these efforts have yielded no conclusive results. In our own observations of CD patients, we noted excessive mucosal T cell expansions, with certain clones representing as much as 30–60% of the T cell repertoire [140]. Interestingly, after successful therapy, a number of these clones appeared to persist, suggesting that current therapies do not eradicate these T cells but merely inhibit their expansion or migration. This observation may also explain the phenomenon of CD presenting as discrete, alternating skip lesions, where the presence of specific T cells causes the disease to recur at its initial location in the tissue.

One category of T cells that could potentially fit the criteria of resident T cells and be non-specifically activated is the tissue-resident memory T cell (TRM T cell). TRM T cells can be either CD8+ or CD4+ and play a role in the memory response following infection with dangerous environmental pathogens. They are situated at the interface of the external environment, rapidly responding upon reinfection with these pathogens and can persist for years often displaying a Th1 cytokine profile [141, 142]. While they are part of a physiological response to foreign antigens, TRM T cells can also be induced by normal microbiota and harmless environmental proteins, potentially leading to pathological accumulation.

It has been demonstrated that patients with active IBD exhibit an increased number of TRM T cells within the intestinal mucosa [143, 144]. However, the field has not yet reached a consensus regarding the precise markers necessary for characterization of TRM T cells. Some studies emphasize CD103 as the distinguishing marker, while others focus on CD69 [145]. The lack of a clear-cut definition is further complicated by the observed heterogeneity of these cells [146]. Nevertheless, all studies seem to concur on one point: TRM T cells can serve as a major source of pro-inflammatory cytokines. The heightened cytokine production by these cells may be triggered by the adjuvant response following exposure to specific environmental factors, as described earlier. Additionally, TRM T cells have been shown to exert a cytotoxic effect on intestinal epithelial cells [144]. Different experiments using experimental colitis models demonstrated their function as effector cells in vivo [147].

Considering these characteristics, TRM T cells, which can persist in the intestinal mucosa without recirculating, may represent a highly significant cell type associated with disease relapse in IBD patients. This notion is further supported by the observation that TRM T cells demonstrate site-specific spatial confinement, explaining the endoscopic observation that recurrent flares often localize in the same regions [148]. Moreover, the fact that TRM T cells can be activated by cytokine cocktails independently of T cell receptors (TCRs) makes them a potential player in disease recurrence that would also explain the unresolved search for specific antigens allegedly needed to fuel chronic inflammation in IBD (bystander activation).

Within the T cell populations, the regulation of the adaptive response is finely tuned by the presence of regulatory T cells, which are crucial for maintaining tissue repair and homeostasis in the local tissue microenvironment [149, 150].

Pre-priming: Persistent Danger Signals Sustain a Pro-inflammatory Microenvironment and DAMP Release

As previously mentioned, the initiation of an adaptive response relies on exposure to danger signals that activate the antigen-presenting cells, enabling them to provide co-stimulation signals and produce specific cytokines required for the development of distinct T helper cell subsets. Antigen-specific T cells then execute their functions, with part of the T cells transitioning into memory cells. Subsequently, the processes induced by the initial danger signals, such as the inflammasome activation, are gradually downregulated.

However, consider the scenario in which a multitude of these triggers persists, creating a chronically pro-inflammatory microenvironment within the intestine. Many of these triggers either directly or indirectly can lead to the activation of the NLRP3 inflammasome, among others [47]. In a recent meta-analysis, we observed that IBD patients exhibit higher expression levels of NLRP3 and pro-IL-1β compared to healthy controls, suggesting that their inflammasomes may be pre-primed and easily activated (manuscript in preparation).

Daily consumption of ultra-processed foods contributes to a continuous influx of environmental triggers with pro-inflammatory potential, potentially disrupting the immune homeostasis. This lowered activation threshold due to the pre-priming may render the intestine more susceptible. Consequently, the gut barrier could become compromised, allowing P/MAMPs and DAMPs to penetrate the lamina propria or become present in the tissue due to cell death [151]. Myeloid cells in the lamina propria express various PRRs, such as TLRs and C-type lectins as well as inflammasomes. These PRRs can be activated by P/MAMPs and DAMPs resulting in secretion of innate cytokines, such as IL-1β, IL-6, IL-18, IL-23, and TNF-α [29, 152].

Bystander Activation: A Potential Link Between Environment and Development of Autoimmunity

Recent studies have shed light on memory T cells present in the lamina propria, revealing that these cells can be re-activated through non-conventional pathways, independent of the stringent and conventional TCR-triggering [153, 154]. These studies have shown that IL-1β, in synergy with IL-23, plays a pivotal role initiating this antigen-independent activation, leading to the production of pathogenic Th17 cytokines. The basis for this bystander reaction could be the presence of TRM T cells in the intestine, which remain after an infection is resolved. Consequently, there might be a plausible link between the primary infection and the development of IBD when tissue damage generates an adjuvant-rich microenvironment that is not adequately resolved [155].

T cells, including memory T cells, express PRRs and various cytokine and chemokine receptors. Activation via PRRs, combined with signaling through cytokine receptors, such as IL-1R and IL-23R, can stimulate TRM T cells in a non-specific bystander fashion (Fig. 2). When bystander-activated, memory T cells can adopt an effector phenotype characterized by the expression of granzyme B and IFN-γ [156,157,158]. Additionally, they may express NKG2D ligands, when encountering stressed cells and activated macrophages [159, 160]. This process can be advantageous for the host in the early control of pathogens: however, if this activation persists, it can have detrimental consequences [161, 162]. Indeed, in an IBD model system utilizing ex vivo autologous organoid-mucosal T cell co-cultures, researchers demonstrated epithelial cell death that depended on the presence of CD103 and NKG2D [163]. NKG2D expression is upregulated by IL-15, a cytokine found to be highly expressed in patients with IBD. IL-15 is considered a danger signal, and its chronic dysregulation can lead to the activation of TRM T cells and tissue destruction [164, 165].

Fig. 2
figure 2

Microscale process of a activation of DAMPs by endogenous and exogenous factors and b bystander activation of myeloid cells and tissue-resident memory (TRM) T cells. Environmental triggers pre-prime the intestine to inflammatory signals directly and indirectly through damaging integrity of the epithelial monolayer. Bystander-activated TRM T Cells and myeloid cells provide positive feedback to further amplify the pro-inflammatory response. UFC Unintentional food contaminants, IFA Intentional food additive, DAMP Damage-associated molecular pattern, PRR Pattern recognition receptor, LPS Lipopolysaccharide, TLR Toll-like receptor, NOD2 Nucleotide-binding oligomerization domain-containing 2, ROS Reactive oxygen species, NLRP3 Inflammasome NLR family pyrin domain-containing 3, NKG2D Natural killer group 2D, P/MAMPs Pathogen/microbe-associated molecular patterns, IL- Interleukin-, HMGB1 High-mobility group box 1

Full size image

Recent studies have suggested that myeloid cells, residing in a pro-inflammatory microenvironment, can be considered myeloid bystanders, and might inadvertently fuel a pro-inflammatory loop [166]. An additional factor to consider is that negative feedback circuits in a pro-inflammatory environment may not be well-established, as previous research has indicated that IL-1β can inhibit IL-10 production in memory TH17 cells [167]. Furthermore, it is important to note that within the complex immune network, non-immune cells such as epithelial cells and fibroblasts also play crucial roles [168].

Bystander activation, therefore, emerges as a potential link between the environment and the development of autoimmunity [151, 169]. However, more studies are needed to prove that this is an actual in vivo event that takes place during chronic inflammation. Among the P/MAMPS that might be involved, LPS is a well-known factor capable of activating myeloid and T cells in vivo, as demonstrated in experimental models [170]. In experimental autoimmune encephalomyelitis, for instance, bystander-activated memory-like CD4+ Th17 T cells were found to be pathogenic, producing IFN-γ and IL-17A in response to IL-1β and IL-23 [171]. In the lung, LPS and other bacteria have been shown to reactivate B. pertussis-induced TRM CD4 T cells, leading to IL-17A production. This phenomenon is referred to as heterologous immunity, where bystander activation results in broader protection [172].

Unraveling the IBD Interaction Network

Grasping Complexity in IBD

In most literature, the focus is on the effects of separate groups of food products, various diets, specific environmental factors, or innate and adaptive immunity. A comprehensive understanding of all these factors integrated into a food/environment/immune system network is rarely achieved due to the multitude of factors and pathways involved. There are numerous potential environmental factors that can influence intestinal health and without proper integration there will be no breakthroughs [173]. While each of these factors has an individual impact, they likely interact and mutually reinforce each other. Testing this complex interaction comprehensibly is practically impossible. Multiple disrupting signals from the environment, alterations in the microbiota, and microbiota-associated molecules/metabolites, combined with genetic susceptibility, destabilize the intestinal barrier. This leads to a persistent and self-amplifying innate and adaptive immune response that contributes to disease development and exacerbates barrier dysfunction [174, 175]. IBD is constantly described as a complex disease. To truly grasp this complexity, it is essential to understand the scientific definition of “complex.” The work of Sturmberg provides guidance in this regard:

Complex refers to interconnectedness, that is, several discrete entities are connected in a network pattern (constituting a system) and interactions among entities form feedback loops resulting in typically nonlinear behaviors. Nonlinear behavior results from disproportionate response to proportional increases/decreases of an input on an output variable. In a system, each variable is connected to many other variables each showing a different response to an input, ranging from no response to – at times – unexpectedly large responses. In a network change to one variable affects all other variables and feedback loops modulate the overall behavior of a system. These type of systems are called complex adaptive systems and typically show emergent behaviors leading to outcomes that cannot be precisely predicted. It is this emergent behavior that leads to complexity – a property – of systems” [176].

The immune system is inherently a complex adaptive system without a discernible master regulator, operating as part of a larger system where collective actions of its components give rise to unpredictable emergent properties. While tangible environmental factors can partly lead to understandable emergent properties, other elusive patterns such as disrupted endosome trafficking, perturbations in cytoplasmic homeostasis, homeostasis-altering molecular processes (HAMPs), or alterations in tissue mechanics and mechanotransduction processes contribute to even more complexity [36, 177, 178].

Portions of this intricate network can be elucidated by acknowledging the interdependence among agents within a system. Populations of specific immune cells and their products exhibit significant variation among healthy individuals and rely on each other for both stimulation and inhibition [179, 180]. Much of our knowledge concerning therapeutic interventions in IBD stems from rigid research designs that simplify real-world complexities (see recent review on IBD therapy [181]). The efficacy of a particular drug hinges on intricate many-to-many relationships spanning from the nano/microscale (genomic/metabolomic/proteomic level) to mesoscale (cell/tissue level) to macroscale, encompassing various patient context domains [182] (Fig. 3). Variability is constantly overlooked, yet there is no evidence that a limited number of causes are responsible for the disease. Multiple interconnected causes can be illustrated through interdependent networks, highlighting the significance of specific agents and their relationships using nodes and edges of various sizes [182].

Fig. 3
figure 3

In silico modeling of a complex biological system connects macroscopic effects to microscopic dynamics. DAMPs Damage-associated molecular patterns, GPCRs G-protein-coupled receptors, HM Hyperactivated macrophage, HMGB1 High-mobility group box 1, IL-1β Interleukin-1 beta, LPS Lipopolysaccharide, NLRP3 Nod-like receptor family, pyrin domain-containing 3, PRRs Pattern recognition receptors, PTM Post-translational modification

Full size image

Resilience in Complex Systems

Numerous known and unknown interactions exists, and predicting individual behaviors or patient responses is always uncertain. Context is influential, but does not guarantee specific outcomes. A significant consideration in this context is resilience, the ability of a system to return to its original state after disruptions [183]. Extensive literature delves into ecological resilience and how complex systems undergo critical transitions when resilience is low [184, 185]. A human body can also be viewed as a complex ecosystem, and drawing parallels with complex diseases can aid in comprehending shifts from a healthy state to an opposing state, such as chronic complex disease. In complex systems, this phenomenon is known as a tipping point, a state where the system cannot absorb minor perturbations and emerges into a state of catastrophic change (Fig. 4) [186]. Systems exhibit greater resilience further from this tipping point and a decline in system resilience serves as an early warning sign of an impending critical transition. In the human intestinal ecosystem, bimodal distribution of bacteria—present in one individual or nearly absent in another—have been identified as contrasting tipping elements with potentially profound implications for health and disease [187]. Identifying markers that define critical transitions and delineate disease progression from a healthy to a pre-disease state and eventually to a stable disease state is crucial, emphasizing the pivotal role of prevention and early diagnosis [188, 189]. Innovative machine learning techniques may assist in predicting collapsing ecosystems [190], but due to the nature of the system and the rapidity of changes, such as when studying the environment’s influence on IBD development, meticulous modeling is essential [191].

Fig. 4
figure 4

The impact of pre-priming of the gastrointestinal tract on increased pro-inflammatory activity and subsequent impact on the tipping point, or activation threshold, required for a critical transition from a healthy state into a diseased state. a In a healthy scenario, environmental factors, such as general lifestyle factors (e.g., healthy diet, exercise), a healthy microbiota [209], low ultra-processed food (UPF), and limited exposure to unintentional food contaminants, support gastrointestinal health and a stable state. b This scenario shows a pre-disease state, wherein environmental factors provide sustained perturbation of the healthy homeostatic equilibrium, pre-priming the immune system and resulting in a highly unstable physiological state, closer to the tipping point and a rapid shift toward a diseased state

Full size image

Critical Nodes in the Immune System Network Within the Intestinal Mucosal Environment

In experimental setups, specific critical nodes within the immune system network can be identified, such as the effects of certain cytokines on cells. Th1 cytokines, TNF-α and IFN-γ, occupy crucial positions-nodes and are associated with the disruption of intestinal epithelial cells. Additionally, they have been shown to collaborate, leading to IEC death through a CASP8-JAK1/2-STAT1 module [192]. IL-23 and IL-1β induce the development of human Th17 cells that express cytokines like IL-17 A and F, IL-22, IL-26, and INF-γ, chemokine CCL20, and transcription factor RORγt [193]. The ubiquitous expression of IL-23 p19 subunit results in multi-organ inflammation characterized by elevated serum concentrations of IL-1β and TNF-α, as well as an increase in neutrophils [194].

Translating this network to the specific environment of the intestinal mucosa reveals numerous potential factors that can positively or negatively influence, modulate, or impact the network.

Genetic studies have implicated genes and pathways underlying dysregulated inflammatory responses associated with hyperinflammation or immunodeficiencies in the intestinal mucosa [9]. These findings implicate core cytokine pathways, microbe sensing, epithelial barrier functions, antibacterial mechanisms, autophagy (cell stress responses), and inflammasomes, providing insight into parts of the local network. Recent insights into the role of gut bacteria highlight their key interaction with the intestinal environment, adding another layer of complexity [195]. Complex microbe–microbe interactions within trophic networks, involving diverse microbial communities, are influenced by both diet and mucin [196]. Gut bacterial metabolites introduce yet further complexity. These microbial-derived or transformed metabolites interact with host G-protein-coupled receptors (GPCRs) and modulate host physiology [197,198,199,200,201]. They can be directly produced by bacteria, result from metabolized dietary substrates, or stem from modified host molecules, such as bile acids. These metabolites are capable of performing various immune and metabolic functions, which may be beneficial or damaging, as exemplified by genotoxic metabolites that can induce DNA damage and potentially contribute to colorectal cancer [202]. Currently, we are only aware of the tip of the iceberg, and exploring microbial metabolites and their functions holds great potential for new treatment options.

Contribution of (Epi)genetics

As mentioned previously we have learned a lot from GWAS studies in IBD cohorts about the different pathways involved in the pathophysiology of IBD. While multiple gene variants are likely to be involved, the genetic loci defined in these GWAS only explain a minority of the variance in disease risk [8]. For the remaining variance gene–environmental (G × E) interactions, including epigenetic changes, may play a crucial role in determining disease progression in IBD for the so-called “missing heritability.” A recent review focusing on the genome, epigenome, and the environment suggests that potential underlying biological epigenetic mechanisms may help us understand causative risk factors in the exposome and lifestyle, especially in relation to the microbiome, diet and nutrition, and tobacco exposure [203]. The impact of various environmental factors, collectively referred to as the exposome, on the epigenome has been summarized by Vieujean et al. This encompasses DNA methylation, histone modifications, and different microRNAs with effects on cell types relevant to IBD pathogenesis [204]. One of the environmental factors that can directly induce epigenetic changes is poor dietary habits. Changes in diet may have the potential to reverse these epigenetic aberrations, which is also important for future generations [205]. The Western diet, in particular, has long-lasting effects on chronic metabolic inflammation [206] through a phenomenon known as innate immune memory, or “trained immunity,” involving antigen-independent epigenetic reprogramming (as reviewed recently by [207]). Inappropriately activated trained immunity can lead to hyperinflammation, characterized by an increased production of innate cytokines IL-1β, IL-6, and TNF-α, as well as enhanced ROS production [208].

Approaches to Treating IBD

Complexity and Treatment Options

To answer the question of the best treatment option for IBD, it appears that there is a divergence in perspectives. Some view the issue through pharmaceutical lenses, while others look via lenses of diet and lifestyle. It often seems like it is one or the other. Therefore, it is crucial to embrace the complexity and bring both worlds together, as this approach might lead to greater effectiveness and help overcome the therapeutic limitations.

The innate and adaptive immune interaction network characterized by its self-perpetuating nature results in a reconfiguration of the host cytokine network. To truly understand diseases, we must grasp the interconnected nature of the external environment and the perpetuating dysfunction of the system that leads to disease development [210]. There are a wide variety of factors that influence immune function and, ultimately, immune fitness [211]. Given this perspective, it is neither logical nor rational to limit therapeutic approaches of complex diseases to single-focused interventions, such as targeting (pro)-inflammatory cytokines [212, 213] or restricting specific food groups, like only focusing on reducing red meat intake [214].

Besides already mentioned cells, numerous other cell types can also play a role in the intricate mucosal immune network, such as different innate lymphoid cells (ILCs), IFN-γ-producing IEL1 accumulate in intestinal mucosa in CD [215], mucosal-associated invariant T cells (MAIT) cells [216], or IgA/IgG producing B lymphocytes [217]. These and other cells are important to maintain intestinal homeostasis [218].

Pharmaceutical Lens

Current treatment options for IBD are based on evidence-based interventions, as exemplified by the British Society of Gastroenterology consensus guidelines on the management of IBD in adults [219]. The therapeutic options in IBD include conventional medications, which encompass immunomodulators, corticosteroids and aminosalicylates, biologicals such as monoclonal antibodies targeting TNF-α (infliximab, adalimumab, golimumab), IL-23 (ustekinumab) and integrins (vedolizumab), or small molecules, including JAK inhibitors and S1PR modulators. Given the complexity of the disease, it is impossible to predict which biological will be effective for an individual patient. Consequently, biological treatments are often prescribed through a “trial and error” approach. The limited efficacy of current treatments highlights the need for development of new treatment modalities, leading to a growing number of potential new drugs in the pipeline [220]. Unfortunately, many of these drugs are studied with a reductionist approach, focusing solely on collecting knowledge about specific subsystems.

Consequently, the blockade of a single cytokine or receptor believed to be involved in intestinal inflammation (based on biological responses) has resulted in limited clinical benefit, with remission rates ranging from 30 to 50% in subgroups of patients [221,222,223]. There is both a predictable loss of clinical effectiveness of the drugs and a predictable recurrence of active inflammation. A critical consideration is whether these subgroups can be further characterized to determine what defines them. Therefore, it is essential to assess whether clinical trials take dietary factors into account when evaluating treatment outcomes.

In clinical trials evaluating new biologicals or small molecules, there is typically no information provided about the dietary habits of the patients included in the patient characteristics. The detailed inclusion and exclusion criteria primarily focus on medication usage but do not include information on diet or microbiome composition [224, 225]. As an example, a recent clinical phase 2 randomized controlled trial (RCT) investigating Mirikizumab, a new anti-IL-23 p19 antibody, was conducted by leading IBD research groups and published in a high-impact journal. However, this trial did not provide information about the dietary habits or microbiome of the participants [225]. It is well established that long-term dietary habits are associated with pro- and anti-inflammatory features of the gut microbiome [226]. While the authors of the Mirikizumab trial noted that patients’ characteristics were generally similar between the intervention and placebo groups, including factors like disease duration, medical history and prior treatment, and other factors such as lifestyle, including diet, were not assessed. Consequently, we cannot be certain whether the small percentage of patients who responded positively to the drug had a different microbiome due to a relatively healthier lifestyle. Additionally, we do not have information on whether any changes in lifestyle occurred during the trial because this aspect was not investigated. Therefore, it is plausible that the subpopulation with a healthier lifestyle may have exhibited a prolonged response to the intervention, possibly because they lacked triggers that could fuel inflammation and subsequent exacerbation.

The design of RCTs typically does not account for the complexity and variability present in the real world [7, 227, 228]. Due to this substantial variability, it has been estimated that only one-third of IBD patients meet the strict inclusion and exclusion criteria required for participation in clinical trials [229]. Recent research has also revealed that interactions between drugs and microbiome metabolites can be associated with an increased risk of treatment failure in patients using 5-ASA [230]. Furthermore, analyses of metabolites in UC have shown a wide range of data, suggesting the presence of different metabolomics signatures [198, 231].

In the realm of clinical pharmaceutical development, there is a tendency toward linear thinking, often leading to the exploration of drug combinations. This can involve combining two already marketed biologic drugs or small molecules with the assumption that their effect might be additive [232, 233]. Innovative approaches, such as bispecific antibodies targeting both IL-1β and IL-17, have been investigated. In an experimental setting this antibody has shown promise in inhibiting DSS colitis [234]. Another experimental approach with potential involves oral nanomedicine, where quantum dots, secondary plant metabolites like polyphenol and TNF-α siRNA are combined [235]. Several drug combinations are currently in a phase 2 of clinical testing as part of the drug development pipeline [220]. Additionally, recent research in UC has demonstrated that subgroups of patients can be defined based on the prediction of therapy response to tofacitinib using an epigenetic prediction algorithm derived from a genome-wide peripheral blood DNA methylation signature [236].

Lifestyle and Dietary Lens

Viewed through the lifestylen and dietary lens, it becomes apparent that lifestyle and dietary factors play a significant role in IBD. Recent studies have highlighted the potential for lifestyle modifications to be key in prevention strategies [16]. These studies suggest that adherence to healthy lifestyle could have prevented 61.1% of CD and 42.2% of UC cases. Therefore, reducing exposure to harmful dietary substances in the diet should be an essential part of a therapeutic approach to maintaining remission. There is however a substantial knowledge gap among health professionals regarding nutrition, especially on the role of food symptom triggers [237].

Research has shown that patients who followed exclusion diet were more likely to maintain remission [238]. Various recent studies have recommended limiting or avoiding specific dietary compounds, such as emulsifiers [81], in particular carrageenan [84], or sorbitol [239]. It is noteworthy that many patients are diagnosed with IBD during the ages of 15–35, which might be related to lifestyle changes and environmental influences during adulthood. Genetic susceptibility combined with detrimental lifestyle factors could contribute to the development of IBD. Utilizing this knowledge, we may identify new therapeutic targets that could enhance treatment efficacy and help address the substantial gap in treatment success rates (50–100%).

In a large cohort study in the UK Biobank demonstrated that a favorable lifestyle was associated with a 50% lower risk of IBD in individuals with a high genetic risk [18]. Another study found that 60% of IBD patients reported worsening of their condition due to certain foods, yet nearly half of them had never received any formal dietary advice [240]. While there may not be a single universally accepted environmental factor responsible for IBD, it is likely that a combination of factors, primarily stemming from a Westernized lifestyle with a strong emphasis on highly processed, omnivorous diets, contributes significantly to the disease. This suggests a potential for secondary prevention through lifestyle modifications [16]. Recent research has also explored experimental therapies, such as fecal microbiome transplantation combined with an anti-inflammatory diet (FMT-AID) or exclusion diet, which has shown effectiveness in inducing and maintaining remission in mild to moderate UC in RCTs [241, 242]. Additionally, systematic reviews and meta-analyses have suggested that high fiber diets may help maintain remission in CD, either alone or in conjunction with routine therapies [243]. A combined lifestyle intervention that encompasses both diet and improvements in physical activity has been shown to enhance diet quality, reduce the impact of disease on daily life, and alleviate fatigue in IBD patients who are in remission or have mild disease [244]. A recent paper from Japan reinforces the idea that diet can play a significant role in combination with medication in IBD. In their review, they discuss their practice of providing a plant-based diet alongside infliximab therapy [245]. They observed that the combination of these treatments, coupled with the patient’s commitment to following the diet, led to notably improved outcomes when compared to conventional treatment methods. Although there are limitations to the study designs mentioned, such as challenges in restricting dietary regimens, a meta-analysis examining enteral nutrition combined with anti-TNF-α therapy suggests that this approach can be effective for maintaining remission [246].

Personalization is crucial in addressing the diverse responses of IBD patients [247]. For example, patients and healthy controls can exhibit differential responses to dietary fiber administration [127, 129] highlighting the need for tailored approaches. In a recent consensus regarding the role of lifestyle, behavior, and environmental modifications, a group of medical professionals recommended adopting diets that are well supported by evidence and monitoring their effectiveness through objective measurement of inflammation resolution [248]. The ideal approach should involve all stakeholders and encourage bottom-up initiatives within communities, as outlined in models like the Assessing Community Engagement, ACE [249]. These findings underscore the importance of dietary and lifestyle factors and a holistic and collaborative approach in IBD management and prevention.

In many cases, patients with chronic illnesses are subjected to symptomatic treatments for extended periods, often involving aggressive and costly medication. Unfortunately, these treatments do not always prove effective, leaving patients to cope with their illnesses. Consequently, individuals with chronic illnesses frequently take it upon themselves to investigate the causes of their conditions and search for potential solutions, including health products, exercise regimens, and dietary adjustments in a trial-and-error way. This trend, where patients become actively engaged in researching their own diseases and effectively become citizen scientists, is gaining recognition among experts, including scientists and doctors. They view this active patient involvement as a unique opportunity to gather new insights into the factors and conditions that impact patient well-being. This knowledge can, in turn, contribute to the development of fresh perspectives for enhancing the patients’ quality of life and potentially even lead to the creation of novel therapies. Incorporating patients as co-researchers presents a form of patient participation and has the potential to yield innovative patient-centered solutions. In the field of IBD, there are promising citizen science initiatives taking shape within various online communities [250].

Emerging Therapeutic Strategies Disrupting Inflammatory Pathways

Maintaining immune homeostasis requires a deep understanding of the factors that determine the regulation of DAMP release and sensing receptors. Targeting DAMPs and their receptors represents a potential therapeutic strategy. Most research so far has been conducted in experimental models using antagonists targeting DAMP receptors. Some research has explored TLR inhibition [251], primarily focusing on recognizing PAMPs but also addressing other DAMP sensing receptors, such as cGAS [252].

The most extensively studied inflammasome is the NLRP3 inflammasome, which appears to be a potential target for therapeutic interventions in the context of immune activation by environmental factors in IBD. This is because various agents and ligands from pathogens, DAMPs, and the environment can induce the formation of the NLRP3 inflammasome and as a consequently activating pro-inflammatory pathways.

Various medicinal plants and phytochemicals have been shown to regulate NLRP3 inflammasome activity, potentially offering treatment options for IBD [253, 254]. Sulphoraphane, an ingredient found in broccoli, is one such compound known for its positive effects on NLRP3 inflammasome activity [255]. Furthermore, researchers are actively developing pharmacologic compounds aimed at inhibiting NLRP3 inflammasome activation, further expanding the potential therapeutic options for addressing inflammation in IBD [256,257,258,259]. Among these are also “old” drugs that are now demonstrated to affect the NLRP3 inflammasome, for example, Tranilast, an analogue of a tryptophan metabolite [260] or glibenclamide, a drug for type II diabetes [261, 262] and other drug repurposing candidates like diacetylrhein [263, 264]. Lastly, inhibition of HMGB1 could also be a potential option to consider [265].

The gut microbiota plays a significant role in the development and progression of IBD, which has led to the exploration of microbiota-based therapies as potential options for modulating the immune response. These therapies encompass a wide range of interventions, including prebiotics, probiotics, and postbiotics, offering a spectrum of approaches [266,267,268]. Dietary changes can influence the composition of the intestinal microbiome [269], making diet a potential tool for microbiome modulation. Interventions involving the introduction of specific bacteria in the gut can range from single bacterial species to fecal microbiota transplantation (FMT) where a community of bacteria is transplanted from a healthy donor to a recipient. A recent example highlighted the beneficial effects of the mucus fortifying bacterium Akkermansia muciniphila in counteracting the adverse effects of dietary emulsifiers [270]. FMT’s have been a focus of numerous clinical studies [271] and have shown potential as a therapeutic intervention in UC [272].

In addition to live bacteria, bioactive microbe-associated metabolites are considered postbiotics and hold promise for personalized precision medicine [11]. SCFAs are one such example of postbiotic metabolites. SCFAs can exert anti-inflammatory effects through various GPCRs by promoting the differentiation of Tregs while inhibiting Th17 T cells, partly through the inhibition of histone deacetylases, HDACs [273,274,275]. Moreover, the direct inhibition of the NLRP3 inflammasome in experimental colitis models has been shown to regulate the microbiome composition, favorably shifting the balance between Firmicutes and Bacteroidetes [276].

The effect of the surrounding context on normal healing responses, causes them to deviate from their intended course due to persistent environmental pressures and the release of DAMPs that result in the bystander activation of typically non-reactive cells in the intestinal mucosa. To break this vicious circle, one potential approach is to target TRM T cells and macrophages that have been bystander activated. These cells are challenging to remove from the tissue once established, contributing to the chronic nature of IBD, where initial treatment with anti-inflammatory agents may provide temporary relief followed by disease flares. For the survival of these TRM T cells and macrophages, various metabolic adaptations are in place and are dynamically regulated by key cellular kinases and transcription factors. These adaptations encompass mitochondrial function, glucose metabolism, amino acid uptake and cholesterol, and lipid synthesis [277, 278]. In the case of CD8+ TRM T cells, it has been observed that these cells rely on lipid metabolism involving the uptake of exogenous FFAs to persist in tissues [279]. A potential pharmacologic intervention to disrupt this metabolic pathway is trimetazidine, originally marketed as an anti-ischemic drug, which has demonstrated efficacy in reducing experimental colitis [280]. Another promising therapeutic option was recently proposed in a murine primary sclerosing cholangitis (PSC) model, where the pathogenic activity of CD103+ TRM was downmodulated using itaconate, an immunomodulatory metabolite [281]. Itaconate has also shown as a potent immunomodulator for macrophages [282] and a central mediator in metabolic reprogramming [283]. Additionally, TRM T cells may be a target of certain IBD drugs, such as the JAK inhibitor tofacitinib, which has been employed in the treatment of immune checkpoint inhibitor-induced colitis [284, 285]. In the case of macrophages we previously found that anti-TNF monoclonal antibodies act through Fcγ-receptor (FcγR) and IL-10 signaling promoting repolarisation of pro-inflammatory intestinal macrophages to a CD206+ regulatory phenotype [286, 287]. These emerging therapeutic strategies aim to disrupt the chronic inflammatory processes in IBD by targeting the metabolic and immunological adaptations of TRM T cells and macrophages within the tissue, offering new avenues for intervention.

As mentioned, IBD is a complex disease influenced by various factors, including physical and psychological stress. The role of psychological stress and the gut-brain axis in IBD is an important aspect that should not be overlooked in the development of future strategies [211, 288,289,290].

IBD Requires a Multifaceted Treatment Approach

Our hypothesis is that interventions to effectively combat IBD must address its complexity by targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells, and factors that relate to the (micro)environment. In the preceding sections, we have discussed various aspects of environmental targets and the often divergent approaches in IBD treatment. While there are already compounds targeting some of these factors in clinical practice, there is still no permanent remission for this chronic disease, resulting in persistent low-level inflammation (smoldering). To achieve permanent remission in IBD, we propose a two-phase approach. First, a rigorous “resetting” of the immune system should be performed. This may involve various interventions to modulate the immune response. Following this reset phase, exposure of the immune system to potential triggers that can again ignite inflammation (the fire) in the intestinal mucosa should be minimized.

The involvement of multiple environmental factors in the development of IBD is widely acknowledged, although the specifics are still debated due to varying epidemiological evidence and uncertain mechanisms (see recent seminar in the Lancet dealing with UC [291]). Current therapies primarily focus on medical interventions to reduce inflammation (such as corticosteroids and aminosalicylates) and maintenance therapy (including thiopurines, biologicals targeting cytokines and integrins, and small molecules, like JAK inhibitors and S1PR modulators). Current initiatives exploring combination therapies need a solid foundation of background knowledge to avoid adding another layer of trial-and-error complexity to the treatment landscape [233]. The initial rationale for combination therapies was the addition of an immunosuppressor to anti-TNF-α antibodies in order to reduce antidrug antibodies [292]. In addition, a number of ongoing combination therapies are described for which the rationale is limited to observation that there is a therapeutic ceiling for single agents and the intended interventions should have a differential mechanistic pathway and therefore might have an additive or synergistic effect [233].

The current treatment options for IBD target specific cells and pathways known to be involved in the disease process. While these treatments can have a positive effect on managing IBD, they may also influence the microenvironment within the inflamed intestinal tissue. In this environment, a multitude of cytokines is produced in response to various signals, including P/MAMPs from the microbiome, intestinal leakage, and DAMPs from dying cells. One critical aspect of managing IBD is to address the explosive and inflammatory microenvironment. This involves taking potent anti-inflammatory actions to deactivate key pathways, such as NF-κB and the NLRP3 inflammasome. Simultaneously, efforts should be made to restore homeostasis, which includes limiting the ingestion of intentional food additives and unintentional food contaminants, and use all actual knowledge to restore the microbiome and the intestinal barrier.

Patients with IBD should be provided with dietary and lifestyle guidance based on the best available knowledge and expert opinions with additional help to learn to become a citizen scientist [293, 294]. It is not possible to make general dietary recommendations for all IBD patients, but this guidance can be based on harm reduction by avoiding elements that have been demonstrated to induce barrier permeability, inflammation, and shift toward an unhealthy gut microbiota composition [209] in the gut. This can be incorporated in a holistic treatment plan with the indication that patients may benefit from supplementary interventions, such as providing extra prebiotics or probiotics and using supplements to improve intestinal barrier function [295].

It is crucial to understand that plant-derived microbiota-accessible carbohydrates (MACs) are necessary for maintaining the growth of preferred bacterial species in the intestine [296]. However in individuals with IBD who lack fermentative microbe activities, adding prebiotics may have negative effects [127]. In dietary considerations, the focus should be on ensuring the presence of dietary phytochemicals that have demonstrated the ability to restore intestinal metabolism and function [297].

Additionally, it is important to recognize the role of the microbiome in dietary interventions. Patients should be encouraged to make dietary choices that promote beneficial commensal bacteria and avoid detrimental gut microbiota shifts [298]. Interventions can improve the metabolic output of the intestinal microbiome, and microbial-derived metabolites have the potential to modulate immune functions and serve as a promising avenue for therapy [299].

In summary, addressing the inflammatory microenvironment in IBD requires a multifaceted approach that combines anti-inflammatory strategies with efforts to restore the balance in the gut microbiome and enhance the intestinal barrier function. This comprehensive approach aims to achieve better management of IBD and improved patient outcomes (Fig. 5).

Fig. 5
figure 5

Different interventions can be used in patient responsiveness. The different patient types indicate the variability in patient responsiveness, which can serve as a guide toward different combinations of interventions

Full size image

Microbiota-based interventions, spanning from dietary modifications to live bacteria and bioactive metabolites, offer a diverse array of potential strategies for influencing the gut microbiome and immune response in the context of IBD, contributing to the growing field of personalized medicine.

Targeting DAMPs and DAMP pathways is a promising treatment strategy, but should not be focused on individual DAMPs but on a holistic approach to IBD treatment that integrates the complexity of the disease, targets multiple contributing factors, including the (micro)environment, and strives for permanent remission rather than just symptom reduction.