Chronic pancreatitis (CP) is a debilitating fibro-inflammatory syndrome affecting the pancreas. It results from persistent pathological responses to pancreatic injury or stress, leading to recurrent abdominal pain, nausea, maldigestion, and complications like exocrine insufficiency, vitamin deficiencies, metabolic bone disease, and diabetes. Current treatments focus on symptom management, lacking effective therapies to reverse the inflammatory damage. The substantial impact on patients' quality of life underscores the critical need for novel therapeutic interventions. This study focuses on the potential of dietary modification using a soy-tomato enriched diet. Soy and tomatoes contain bioactive metabolites with demonstrated anti-inflammatory properties. Previous research from the authors' group has shown that bioactive agents in soy and tomatoes can effectively reduce pro-inflammatory cytokines and suppressive immune populations, suggesting a potential therapeutic role in CP. A novel soy-tomato juice, already shown to be safe and well-tolerated in healthy individuals, forms the basis of this dietary intervention. The hypothesis is that administering a soy-tomato enriched diet will reduce inflammation and disease severity in a pre-clinical model of CP.

The literature extensively documents the anti-inflammatory effects of soy and tomato components. Soy isoflavones (genistein, daidzein) and their metabolites, produced by gut microbiota, inhibit inflammation and modulate immune responses. Studies have demonstrated the efficacy of soy-enriched diets in reducing pro-inflammatory cytokines and suppressive immune cells in certain cancer patients. Tomatoes contain carotenoids (lycopene) and flavonoids (naringenin, quercetin) that directly modulate inflammation and reduce the risk of inflammation-related diseases such as cardiovascular disease and cancer. The authors' previous work established a novel soy-tomato juice suitable for patient trials, demonstrating good compliance, bioavailability, and impact on blood lipids in healthy participants. This pre-clinical study investigates whether this combination of soy and tomato, known for their anti-inflammatory properties, can effectively mitigate the inflammation and associated pathologies of CP.

This study employed a well-established murine model of caerulein-induced CP. Male C57BL/6 mice received intraperitoneal injections of 50 µg/kg caerulein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks, mice were randomized into two groups: a control diet group and a soy-tomato enriched diet group for 2 weeks. Disease severity was assessed through histological analysis (H&E and Masson's Trichrome staining) of pancreatic tissue, evaluating acinar loss, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were measured to assess pancreatic function. Inflammatory factors in serum and pancreatic tissue were analyzed using cytokine multiplex detection and qRT-PCR. Immune populations in the spleen were characterized by flow cytometry. Spontaneous activity and distress were monitored using infrared (IR) sensing to assess overall mouse health and well-being. Statistical analyses included two-sample t-tests, Wilcoxon rank-sum tests, Kruskal-Wallis tests with Dwass-Steel-Critchlow-Fligner, one-way ANOVA with Tukey's post-hoc tests, as appropriate for the data types and sample sizes. All animal procedures adhered to ethical guidelines and were approved by the Ohio State University IACUC.

Mice fed the soy-tomato enriched diet exhibited significantly reduced inflammation and CP severity compared to the control group (p=0.032). Histological analysis revealed less acinar cell loss and reduced fibrosis in the soy-tomato group. Serum lipase and amylase levels, indicators of acinar function, were restored in the soy-tomato group, suggesting preservation of acinar cell function (p<0.05). The soy-tomato diet led to a significant reduction in serum levels of TNF-alpha, IL-1β, and IL-5 (p<0.05), key inflammatory cytokines. Flow cytometry demonstrated a significant reduction in splenic granulocytic-MDSCs and total MDSCs (p<0.05) in mice fed the soy-tomato diet. IR sensing indicated significantly improved total activity and a reduction in resting time (p<0.05) in the soy-tomato group, suggesting improved overall health and potentially reduced pain. Immunohistochemistry showed fewer CD3+ T cells in the pancreas of soy-tomato fed mice (p=0.007). While qRT-PCR analysis of pancreatic tissue showed a trend towards reduced expression of pro-inflammatory genes (IL-6, IL-1β, Ly6G, CD68), these results did not reach statistical significance due to limitations in sample size.

This study provides strong pre-clinical evidence supporting the anti-inflammatory effects of a soy-tomato enriched diet in CP. The observed reduction in inflammation, improved pancreatic function, and enhanced physical activity strongly suggest the potential for this dietary approach as a novel treatment strategy. The reduction in circulating MDSCs, which are known to contribute to inflammation, is a particularly interesting finding. The significant decrease in serum IL-5 levels suggests a possible modulation of eosinophil activity, which plays a role in CP-related fibrosis. The improved activity levels observed in the soy-tomato fed mice, reflecting a potential reduction in pain, warrant further investigation using more formal pain assays. While the qRT-PCR data on pancreatic tissue were not statistically significant, the trend of reduced pro-inflammatory gene expression suggests a potential local effect, which would benefit from further study with a larger sample size. The findings align with previous research demonstrating the anti-inflammatory properties of soy and tomato components, providing a mechanistic basis for the observed effects.

This pre-clinical study demonstrates that a soy-tomato enriched diet significantly reduces inflammation and disease severity in a murine model of CP. The observed improvements in pancreatic function, reduced inflammatory markers, and enhanced physical activity suggest this dietary intervention holds considerable promise as a novel therapeutic approach for CP. Future studies should focus on identifying the specific bioactive compounds responsible for the observed effects and conduct larger scale studies to confirm the findings and assess its effectiveness in humans. Further research employing nociception assays to directly assess pain reduction and detailed investigation into the impact on specific immune cell populations are needed.

The study used a murine model of CP, which may not perfectly replicate the complexity of human CP. The sample size in some analyses was relatively small, potentially impacting the statistical power. Although a trend towards reduced expression of pro-inflammatory genes was observed in the pancreatic tissue by qRT-PCR, the results did not reach statistical significance; a larger sample size would be necessary to confirm this observation. Pain assessment was indirectly measured using spontaneous activity; future studies could benefit from employing more direct pain assessment methods. The study did not investigate potential long-term effects of the soy-tomato diet on CP progression.