The exposome encompasses all endogenous and exogenous exposure individuals encounter throughout their lives, including biological, chemical, physical, psychological, relational, and socioeconomic factors. It examines the duration and intensity of these types of exposure and their complex interactions over time. This interdisciplinary approach involves various scientific disciplines, particularly toxicology, to understand the long-term effects of toxic exposure on health. Factors like air pollution, racial background, and socioeconomic status significantly contribute to diseases such as metabolic, cardiovascular, neurodegenerative diseases, infertility, and cancer. Advanced analytical methods measure contaminants in biofluids, food, air, water, and soil, but often overlook the cumulative risk of multiple chemicals. An exposome analysis necessitates sophisticated tools and methodologies to understand health interactions and integrate findings into precision medicine for better disease diagnosis and treatment. Chronic exposure to environmental and biological stimuli can lead to persistent low-grade inflammation, which is a key factor in chronic non-communicable diseases (NCDs), such as obesity, cardiometabolic disorders, cancer, respiratory diseases, autoimmune conditions, and depression. These NCDs are influenced by smoking, unhealthy diets, physical inactivity, and alcohol abuse, all shaped by genetic, environmental, and social factors. Dietary patterns, especially ultra-processed foods, can exacerbate inflammation and alter gut microbiota. This study investigates the exposome’s role in the prevention, development, and progression of NCDs, focusing on endogenous and exogenous factors.

The incidence of pancreatic cancer is increasing worldwide. The most common form is represented by pancreatic ductal adenocarcinoma (PDAC) which has been shown to be linked to chronic inflammation. Notably, the gut microbiota has emerged as a critical player in regulating immune responses and inflammation. Indeed, intestinal dysbiosis, characterized by an imbalance in the gut microbiota composition, can contribute to the initiation of chronic inflammation. Sterile chronic inflammation can occur, probably activated by the translocation of bacterial components, such as lipopolysaccharide (LPS), the major component of Gram-negative microbiota, with the consequent induction of innate mucosal immunity, through the activation of Toll-like receptors (TLRs). Furthermore, the interaction between LPS and TLRs could enhance cancer progression. Recent research has shed light on the pivotal role of nutrition, as a modifiable risk factor, in PDAC immunological processes, particularly focusing on the immuno-modulatory effects of the gut microbiota. Different dietary regimens, fiber intake, immunonutrients, and antioxidants have the potential to either exacerbate or mitigate chronic inflammation, thereby influencing the pathogenesis and natural history of PDAC. These dietary components may affect the gut microbiota composition and, consequently, the level of inflammation, either promoting or protecting against PDAC. In this review of reviews, we discuss the modulatory role of nutrition and the gut microbiota in PDAC’s immunological processes to explore a translational therapeutic approach that could improve the survival and quality of life of these patients.

Background/Objectives: The gut microbiome modulates chemotherapy efficacy in pancreatic ductal adenocarcinoma (PDAC), yet its relationship with the clinically relevant endpoint of post-chemotherapy surgical eligibility remains poorly characterised. We explored whether baseline gut microbiome composition and metagenomically predicted metabolic function differ between chemotherapy responders and non-responders in PDAC. Methods: In this prospective single-centre exploratory cohort study, faecal samples were collected from 15 patients with non-immediately resectable PDAC at diagnosis, before chemotherapy. Whole-genome shotgun metagenomics was performed, and microbial functional capacity was inferred through an assembly-based pipeline. Patients were classified as responders (achieved surgical eligibility, n = 6) or non-responders (n = 9). Results: At baseline, responders showed enrichment of Collinsella aerofaciens (p = 0.026) and Butyrivibrio fibrisolvens (p = 0.012), while non-responders were enriched in oral-origin bacteria (Streptococcus gordonii, Actinomyces spp., Rothia dentocariosa). Predicted butyrate showed the largest effect size difference between groups but did not reach significance (p = 0.179); responders also had broadly elevated predicted SCFAs and bile acids. However, chemotherapy regimen (mFOLFIRINOX in 5/6 responders vs. 2/9 non-responders; Fisher p = 0.041) and disease stage were unevenly distributed between groups. Conclusions: This exploratory study identifies the compositional and functional microbiome features distinguishing PDAC chemotherapy responders from non-responders. These associations are confounded by disease stage and regimen and require validation in larger, regimen-stratified cohorts before predictive or mechanistic claims can be made.