DAMP-ing IBD: Extinguish the Fire and Prevent Smoldering

Abstract

In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a multifactorial inflammation of the intestinal tract, a single-target approach is unlikely to solve this problem, necessitating an alternative strategy that addresses its variability. One approach often overlooked by the pharmaceutically driven therapeutic options is to address the impact of environmental factors. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by such factors, including diet, stress, and environmental pollution-often referred to as the "Western lifestyle". In IBD, intestinal responses result from a complex interplay among the genetic background of the patient, molecules, cells, and the local inflammatory microenvironment where danger- and microbe-associated molecular patterns (D/MAMPs) provide an adjuvant-rich environment. Through activating DAMP receptors, this array of pro-inflammatory factors can stimulate, for example, the NLRP3 inflammasome-a major amplifier of the inflammatory response in IBD, and various immune cells via non-specific bystander activation of myeloid cells (e.g., macrophages) and lymphocytes (e.g., tissue-resident memory T cells). Current single-target biological treatment approaches can dampen the immune response, but without reducing exposure to environmental factors of IBD, e.g., by changing diet (reducing ultra-processed foods), the adjuvant-rich landscape is never resolved and continues to drive intestinal mucosal dysregulation. Thus, such treatment approaches are not enough to put out the inflammatory fire. The resultant smoldering, low-grade inflammation diminishes physiological resilience of the intestinal (micro)environment, perpetuating the state of chronic disease. 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 cytokines, and factors that relate to the (micro)environment. Thus the disease can be comprehensively treated across the nano-, meso-, and microscales, rather than with a focus on single targets. A broader perspective on IBD treatment that also includes options to adapt the DAMPing (micro)environment is warranted.

Keywords: Bystander activation; DAMPs; Environment; IBD; Inflammasomes.

Fig. 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

Fig. 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

Fig. 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

Fig. 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

Fig. 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