Gallstones are lithic digestive fluid deposits that can develop in the bile ducts or gallbladder as a consequence of the presence of bile containing atypically high bilirubin or cholesterol levels (1). Also referred to as cholelithiasis, gallstones are among the most prevalent diseases of the digestive system, in addition to being the most expensive with respect to their socioeconomic impact as they have a severe negative impact on patient quality of life while requiring the consumption of extensive healthcare resources (2). Gallstones impact an estimated 10–20% of adults in the world, and while they are asymptomatic in most cases, 20% of affected patients develop gallstone disease that is characterized by cholecystitis, abdominal pain, pancreatitis, and cholangitis, often necessitating surgical removal of the gallbladder for effective management (3, 4). Gallstones can also cause localized and systemic inflammation (5) while disrupting normal metabolic activity (6, 7).

In prior studies, a wide range of gallstone-related risk factors have been identified including female sex, advanced age, dietary factors, and metabolic syndrome, characterized by a combination of insulin resistance, diabetes mellitus, obesity, and a lack of physical activity (8, 9). Diet plays a particularly important role in the incidence of gallstones, with the consumption of high levels of carbohydrates, a highly caloric diet, a high glycemic load, and low levels of fiber, vegetable, and fruit consumption all being related to this outcome (10–12). Given a growing focus on the potential importance of diet-related inflammation, the dietary inflammatory index (DII) was designed as a tool capable of capturing and representing the impact of different dietary factors on the production of inflammatory biomarkers including C-reactive protein (CRP), interleukin (IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF)-a (13). The DII provides a comprehensive estimate of the inflammatory potential of a given diet based on the consumption of foods with anti- or pro-inflammatory effects, with higher values being indicative of a diet that is potentially more inflammatory (14, 15). The composite dietary antioxidant index (CDAI) is another index that captures information regarding the antioxidant properties of a given diet (16), with diets rich in selenium, zinc, and other antioxidants being better suited to mitigating oxidative stress, potentially leading to a reduction in gallstone incidence (17, 18).

While each of these indices has previously been leveraged to test the relationships between the inflammatory potential of an individual’s diet and their risk of gallstones (19, 20), these prior studies have been subject to limitations and there have not been any simultaneous investigations of these indices in the general US adult population. Epidemiological data are thus lacking regarding the degree to which DII and CDAI scores represent potential gallstone-related risk factors. Dietary potential is a metric that is increasingly being evaluated when conducting epidemiologic and interventional studies aimed at the treatment and management of gallstones, underscoring a need to validate the associations between these biomarkers and gallstone disease activity. This study was thus developed to separately explore how dietary profiles, as measured with DII and CDAI values, are related to gallstone prevalence and other metrics among adults in the USA.

Here, the associations between dietary indices and gallstone incidence were assessed in a large representative cohort of adults in the USA. This analytical approach revealed an increase in gallstone risk among individuals with higher DII scores, whereas gallstone risk rose with lower CDAI scores even following adjustment for a range of covariates. Higher DII scores were also related to a younger age at first gallbladder surgery, whereas CDAI scores were unrelated to this outcome variable.

In a prior cross-sectional analysis of individuals in Iran (20), higher DII scores were related to a reduction in gallstone risk in direct contrast with the present results in the USA. DII values are computed based on the inflammatory potential of a given diet and these values have been linked to a range of inflammatory diseases (23, 24) including rheumatoid arthritis (25), nonalcoholic fatty liver (26–28), and Helicobacter pylori infections (29). Higher DII scores are also associated with the production of higher concentrations of TNF-α, IL-6, CRP, and a range of other factors that contribute to greater gallstone risk (30–32). A study of subjects in China reported an association between levels of IL-6 and IL-10 and the risk of gallstone development (7). Given that IL-10 and IL-6 are inflammatory biomarkers related to DII calculations (13), this supports the existence of a direct association between DII values and gallstone development. A prospective cohort analysis further demonstrated that CRP levels are independently associated with gallstone risk (33). The present data align well with past reports of strong positive relationships between DII, which serves as a comprehensive index for dietary inflammation, and gallstone incidence. Higher DII values are also related to the incidence of metabolic syndrome (34), obesity (35), and insulin resistance (36), all of which have the potential to directly or indirectly influence gallstone incidence (1, 34, 37), consistent with the positive relationship noted between DII and gallstones.

Higher CDAI scores, which correspond to a diet that is rich in antioxidants, were herein found to be related to a reduction in gallstone risk. Oxidative stress is firmly established as a regulator of gallstone development (18, 38, 39). For example, the intake of low levels of vitamin C (40), which is among the best-characterized antioxidant micronutrients, can contribute to a greater risk of gallstone formation as a result of the disruption of the production of free radicals involved in gallstone formation through changes in the protein and lipid content of the bile. Epithelial cells within the gallbladder secrete mucin, which is a glycoprotein. The secretion of overly high mucin levels in response to oxygen radicals has been reported to contribute to cholesterol destabilization and the biogenesis of gallstones (41). Antioxidant-rich diets can help abrogate gallstone risk, as supported by the present results (42, 43), which revealed a consistent negative association between CDAI values and the prevalence of gallstones in this study population (19). However, the stability of this correlation across diverse populations was not supported by the findings of the stratiffied analysis. The limited sample size in this study might have contributed to the absence of a significant negative association in the subgroup analysis.

The relationship between DII, CDAI, and gallstones indicated that a healthy dietary pattern characterized by low DII and high CDAI value has a protective effect on gallstones. This healthy dietary pattern consists of high consumption of vegetables, fruits, fiber-rich foods, and nuts and low consumption of high-calorie diet, polyunsaturated and monounsaturated fats (44–46). The correlation between the healthy dietary pattern and gallstones may be attributed to the biliary microbiota (10). The relationship between these dietary indices and age at first gallbladder surgery was additionally examined in this analysis. Higher DII values were related to the need for gallbladder surgery at a younger age. Specifically, for every increase in DII by one unit, the age of first gallbladder surgery was reduced by 0.64 years. This is the first article to report this relationship. While additional validation will be essential, this may suggest that efforts to modulate dietary composition at a younger age can better guard against gallstones and related adverse outcomes.

Limitations to this study include that this was a cross-sectional analysis such that the causal nature of associations between gallstone incidence and CDAI or DII values could not be established. Moreover, survey data were derived from questionnaires such that they may be limited by recall bias. In addition, the association between dietary indices and gallstone incidence could be influenced by other unconsidered or residual confounding factors. Lastly, limited sample sizes and poor statistical power may have contributed to some degree of uncertainty in particular subgroup analyses.

In summary, the relationships between the CDAI and DII indices and the incidence of gallstones were evaluated for the general US population. These results suggest that gallstone risk increases when subjects consume a diet that is proinflammatory, as evidenced by a higher DII score, whereas antioxidant-rich diets with higher CDAI scores are conversely associated with a reduction in gallstone risk. This study is also the first to document an association between higher DII scores and the need to undergo gallbladder surgery at a younger age.

Publicly available datasets were analyzed in this study. This data can be found at: https://www.cdc.gov/nchs/nhanes.

The studies involving humans were approved by The National Center for Health Statistics Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

CJ: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. YS: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.