The inflammatory response is a defense mechanism of the innate immune system [7] that protects the host from harmful stimuli such as viruses, bacteria, toxins and infections by eliminating pathogens and promoting the repair of damaged tissues [1]. At the onset of inflammation, the innate immune cells perceive pathogen invasion or cell damage and initiate the inflammatory cascade by actively releasing soluble proinflammatory mediators. These signals also activate leukocytes and microvascular changes, such as increased vasodilation and vascular permeability, allowing leukocytes to reach the affected tissues from the blood [8]. Such inflammatory activity should resolve once the threat is overcome, becoming temporarily restricted and self-limiting to maintain homeostasis [9,10]. However, failure of immune resolution or continued exposure to environmental and biological factors that promote the activation of the inflammatory response can lead to a chronic inflammatory process. This results in the presence of immune cells such as lymphocytes, macrophages and plasma cells in the tissue for long periods of time, as well as of proinflammatory cytokines, chemokines and other proinflammatory molecules [11,12]. Although this condition recognized as low-grade inflammation has minimal or no clinical manifestations, the prolonged inflammatory response can cause consequences for tissue health, which can develop into tissue fibrosis and possible loss of function [13].

The presence of low-grade inflammation disrupts the homeostatic balance, altering the crosstalk between immune and metabolic responses and promoting chronic metabolic inflammation. This so-called “metainflammation” is primarily caused by metabolic and nutrient excess and triggers immune cell infiltration and the secretion of inflammatory cytokines into the tissue environment, which may inhibit glucose uptake or alter lipid metabolism [2,14]. As a result, chronic metabolic inflammation is particularly associated with an increased risk of noncommunicable diseases, such as cancer, diabetes and cardiovascular disease. An example is insulin resistance caused by chronic exposure to inflammatory biomarkers, which often lead to diabetes [15]. Low-grade inflammation plays an important role also in the development of cardiovascular diseases, due to its involvement in atheroprogression [16], and may favor the progression of different types of cancer by promoting cell proliferation, decreasing apoptosis and increasing angiogenesis and metastasis [17]. At present, it is not well-established which biomarkers can best represent low-grade inflammation, although among the most widely used in scientific studies are soluble mediators (chemokines and cytokines), acute-phase proteins (fibrinogen and C-Reactive Protein (CRP)) or blood cellular markers (granulocytes and total white blood cells) [18].

2. Ultra-Processed Foods (UPF)

UPF consumption could contribute to an inflammatory state through several mechanisms. First, it could be the high intake of sugars, salt, saturated fats and trans fatty acids typical of a UPF-rich diet that directly promotes the development of chronic inflammation [61]. When high intakes of these nutrients and their possible relationship to the modulation of inflammation are considered individually, the results to date are mixed. UPF are usually high in simple sugars, in the form of either sucrose or a high-fructose syrup, so they tend to be foods that raise the blood glucose markedly and rapidly, i.e., with a high glycemic index/glycemic load [62]. This postprandial increase in the glucose levels in turn causes an increase in insulin levels, which promotes a proinflammatory state [63]. Although these mechanisms appear to play an important role in diet and the promotion of low-grade inflammation, intervention studies are not very clear in this regard. In the TOSCA.IT study, an association was found between the intake of added sugars ≥10% of the daily energy intake and increased CRP levels in adults with diabetes [64]. Other observational studies associated a higher consumption of sugar-sweetened beverages with increased levels of CRP and IL-6 in adults and children [65,66,67]. Regarding the glycemic response, although an intervention study found a positive association between glycemic load and plasma hs-CRP in healthy middle-aged women [68], a recent meta-analysis including 28 randomized controlled trials found no association between the glycemic index and different markers of inflammation in adults [69].

UPF also have a high salt content, contributing to a high sodium intake. Several cross-sectional studies associated a higher salt intake with higher CRP levels in adults and elderly people [70,71], although this association was not found in adolescents [72]. A recent meta-analysis also found no associations between dietary sodium level and markers of inflammation, although it should be noted that the researchers pointed out that their findings were likely due to methodological errors [73].

As for the fat content of UPF, their inflammatory potential derives not only from a higher consumed quantity with respect to other foods, but also from a poorer quality. In fact, trans fatty acids resulting from the industrial process are associated with a higher presence of low-grade inflammation. Specifically, they have been related to higher levels of hs-CRP, IL-6 and TNF-α [74,75,76]. Diets with a high processed-food content have also been associated with a higher intake of omega-6 fatty acids, resulting in a higher omega-6/omega-3 ratio and the potential promotion of low-grade inflammation [77].

Finally, consuming large amounts of UPF sometimes results in the replacement of foods that are the basis of a healthy and balanced diet. Examples are fruits and vegetables, which are correlated with an anti-inflammatory effect thanks to the presence of numerous phytocompounds [78,79]. Recent studies clearly show how people consuming more UPF have a lower intake of fruit and vegetables [80] and consequently ingest less substances with an anti-inflammatory effect. A low fruit and vegetable consumption also results in a low dietary fiber intake. In the E-DIITM, fiber is considered one of the factors that reduce diet-related inflammation. In previous studies, an adequate fiber intake was shown to be important in maintaining low CRP levels and in maintaining homeostasis of the gut microbiota [81]. A high UPF consumption can also lead to deficiencies of micronutrients considered to be anti-inflammatory factors in the diet, such as magnesium, vitamin C, vitamin D, zinc and niacin [82].

Results from an Italian cohort study suggested that only part of the proinflammatory effect of a high UPF consumption can be directly attributed to the nutritional components of the diet, while the rest could be attributed to non-nutritional factors that may promote low-grade inflammation [59]. One of the non-nutritional factors present in UPF are additives, which are added to mimic or intensify the sensory qualities of foods [83]. Among the most studied are sweeteners, especially non-caloric ones such as acesulfame potassium, sucralose or aspartame, due to their widespread use in soft drinks to provide a sweet taste without the energy value of sugars [84]. Recently, there has also been growing interest in the harmful effect of emulsifiers used to improve the shelf life and texture of food products. Although scientific evidence to date is limited, animal and in vitro studies suggest that sweeteners and emulsifiers may contribute to the inflammatory cascade [85,86,87]. One of the hypothesized mechanisms is the modulation of the microbiota, but data are inconsistent, and further studies are needed to investigate these mechanisms [88,89]. It has also been hypothesized that the non-caloric sweeteners’ harmful effect might be due to an acute metabolic response [90]. However, data from two recent meta-analyses do not support this hypothesis, as they found no association between the consumption of non-caloric sweetened beverages and an increased insulinemic effect or acute glycemic response [91,92].

Non-nutrient components such as bisphenol or phthalates may also be present in UPF due to the migration of chemical substances that are part of food packaging. In fact, several cross-sectional studies reported higher levels of both substances in the urine of people with a high UPF consumption [42,93,94,95,96]. Because of their structure, bisphenol and phthalates can disrupt various aspects of the hormonal action and are therefore called endocrine disruptors. They can interfere with the synthesis, secretion, transport, signaling and metabolism of hormones; therefore, they have been associated with adverse health consequences, including the development of diseases such as obesity, diabetes and cardiovascular disease [97,98].

A recent meta-analysis investigating the role of different endocrine disruptors on the inflammatory response showed that increased exposure to Bisphenol A (BPA) is significantly associated with higher levels of IL-6 and CRP, while increased exposure to phthalates is associated with higher levels of CRP, IL-6 and IL-10 [99]. Although the adverse effects of BPA have led to various restrictions on its use, the analogs that replaced it appear to have similar effects [100]. On the other hand, UPF may contain chemicals derived from food processing, especially due to the heat treatment to which food is subjected. One example is acrylamide as a result of the Maillard reaction between amino acids and sugars, exposure to which in adults has been associated with an increased presence of biomarkers of inflammation such as CRP or Mean Platelet Volume (MPV) [101]. Another chemical instead derived from lipid oxidation is acrolein, high exposure to which has been associated with a higher concentration of Hs-CRP in adults in the United States [102] and of CRP in adults in China [103].

The human gut microbiota is a dynamic and complex network composed of hundreds of thousands of microorganisms, including bacteria, fungi, archaea, viruses and protozoa [104]. When in its normal state of homeostasis, the gut microbiota plays a key role in host health through the immune system function and protection against pathogens. However, when the gut microbiota is altered compared to the community found in healthy individuals, gut dysbiosis occurs [84]. This dysbiosis is associated with a high degree of inflammation, caused by a lower presence of short- chain-fatty-acids-(SCFAs)-producing bacteria, and increased permeability of the gut [105]. Both diet quality and the presence of the additives previously described may influence intestinal dysbiosis, offering a possible explanation for the mechanism linking an increased consumption of UPF with the presence of low-grade inflammation.

In fact, it has been suggested that a diet rich in fiber can decrease the systemic inflammatory response by improving the intestinal barrier function and modulating the intestinal microbiota [81]. This is because dietary fiber is essential for the formation of SCFAs, which are thought to play a key role in neuroimmunoendocrine regulation [106]. In fact, SCFAs are associated with a lower concentration of CRP and plasma lipopolysaccharide, an endotoxin used as a marker to assess intestinal permeability linked to increased low-grade inflammation [107,108,109,110]. In contrast, Western diets with a high fat content have been associated with increased intestinal permeability due to a greater presence of lipopolysaccharides in humans and mice [111,112]. Similar results were observed in mice fed a diet rich in refined sugar, also associated with an atypical composition of the intestinal microbiota [113]. In a cross-sectional study conducted in the U.S.A., the increased consumption of highly processed food was associated with intestinal permeability biomarkers [114]. Also in a study conducted in Italy, intestinal permeability tended to increase in subjects with low adherence to the Mediterranean diet, who also reported a high intake of food high in fat and sugar, referred to as junk food [115]. Finally, a French study involving 862 healthy adults found that the regular consumption of foods such as soft drinks, fatty sweet products, fried foods, processed meats, ready-to-eat meals, cheese and desserts, most of them recognized as UPF, was associated with reduced bacterial diversity, indicating an altered microbiota composition [116]. In contrast, the PREDIMED-PLUS study in older adults found no such association and suggested that perhaps the contradictory results with the previous study were due to the lower UPF consumption of the studied population [117].

Several studies have also highlighted additives as possible factors affecting the microbiota. Studies in murine models suggested different mechanisms through which emulsifying additives could contribute to intestinal dysbiosis, increasing intestinal permeability and promoting a proinflammatory state [89,118]. However, these studies remain limited, and the results in humans are contrasting. For example, a double-blind controlled study comparing seven adults on an emulsifier-rich diet to nine adults on an emulsifier-free diet observed changes in the gut microbiome and metabolome that may be related to chronic inflammatory diseases [119]. In contrast, a cross-sectional study involving 588 adults found no association with biomarkers related to increased intestinal permeability, although it found an association with increased levels of systemic inflammation [114]. Similarly, studies in murine models suggested that artificial sweeteners can alter the intestinal microbiota, favoring the enrichment of proinflammatory bacteria that promote the formation of endotoxins such as lipopolysaccharides [85,86,120]. However, the results to date are inconsistent, and further research will be needed to investigate these mechanisms.