Effects of UNICLA-A2 Dairy Products on Patients at High-risk of Colorectal Cancer Development

Study Overview
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Brief Summary
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Dietary intervention with UNICLA-A2 milk products containing beta casein A2 protein, and higher levels of omega-3 fatty acids and selenium may contribute to maintain the intestinal integrity, reduce inflammatory processes, normalize the immune system, protect against oxidative damage and equilibrate the gut microbiota in high-risk colorectal cancer patients who have undergone polypectomy

Detailed Description
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Colorectal cancer (CRC) is one of the most frequent cancers in the world and has a significant impact in terms of mortality and health costs. It is estimated that CRC causes around 900,000 deaths annually, mainly due to diagnoses made in advanced stages. Colorectal adenomas (CRA) are precancerous lesions that develop into colorectal cancer following a well-known process into the adenoma-carcinoma sequence. Prevention programs include screening for CRA and removing precancerous lesions by polypectomy, but the high recurrence rates after polypectomy makes it necessary to research on potential chemopreventive agents that may reduce this risk. Dietary recommendations or chemoprevention with different nutritional substances (diets rich in fiber, or poor in red meat, etc) or pharmacological substances including vitamin D, calcium, fatty acids, salicylic acetyl acid, nonsteroidal anti-inflammatory agents (NSAIDs), etc) have been studied. In this way, it seems reasonable to evaluate the effect caused by the administration of certain nutrients that affect lipid and protein metabolism involved in cellular homeostasis, in the preservation of the colonic mucosa or the development of lesions may have in populations at risk. UNICLA A2 dairy products have a different nutrient profile than conventional ones. UNICLA A2 products have higher content in unsaturated fats, that is to say, increased content of healthy fatty acids such as oleic, linolenic, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and conjugated linoleic acid (CLA). Previous studies have suggested a contribution of ω-3 polyunsaturated fatty acids (PUFAs) to reduce pro-inflammatory markers and, have shown they have antimicrobial and negative properties in relation to biofilm formation. These types of biofilm structures are characteristic of proximal CRC. For these reason, ω-3 PUFAs it is thought that they could modify the altered intestinal microbiota in patients at high risk of CRC towards a less pathogenic environment, correcting the gut dysbiosis. Moreover, they have higher selenium levels (Se), an element with essential biological functions which has been suggested improving effects in combination with other anticancer agents in CRC and taking part in the modulation of several processes, such as the immune response, apoptotic cell death, DNA repair, response to oxidative stress, carcinogenic metabolism, tumorigenesis and angiogenesis. Finally, they contain type A2 beta casein, which differs from A1 beta casein by a single amino acid at position 67 of a 107 amino acid chain. This fact is very important because beta casein contains a chain of amino acids called beta casomorphin (BCM7) with negative health effects reported. The proline 67 in beta casein A2 has a strong bond with BCM7 that does not allow it to separate and flow freely in milk to be absorbed. However, the mild bond due to histidine 67 in beta casein A1 allows BCM7 to reach the intestinal wall and be absorbed, being associated with intestinal discomfort, gastrointestinal transit time and stool consistency disturbances, abdominal pain and, increased levels of some inflammatory markers. For these reasons, in this proposal the investigators aim to determine whether the change from conventional dairy products to UNICLA-A2 products but maintaining the habitual consumption habits in real life conditions, without forcing or inducing greater consumption, will have positive effects on maintaining the intestinal integrity by reducing the inflammatory profile, and leading the gut microbiota to a less pathogenic environment in patients at high-risk of CRC development.

Official Title
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Comparative Analysis of the Effects of UNICLA-A2 Against Conventional Dairy Products Administered Daily in Patients at High-risk Colorectal Cancer Development Who Have Undergone Polypectomy

Conditions
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Colorectal Polyp

Intervention / Treatment
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* Dietary Supplement: Milk from genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium
* Dietary Supplement: Conventional milk
* Dietary Supplement: Yogurt made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium
* Dietary Supplement: Conventional yogurt
* Dietary Supplement: Fresh cheese made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium
* Dietary Supplement: Conventional fresh cheese


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants diagnosed with high-risk polyps in the colorectal cancer screening programme or in the relative's colon cancer prevention program or patients who are in follow-up due to prior detection of polyps with any of the following characteristics: At least 10 adenomas At least 5 proximal serrated polyps (PSP) At least 2 serrated polyps with diameters ≥10 mm Serrated Polyposis Syndrome (SPS) Early invasive CRC (stage pT1) endoscopically resected (surgery not required) A sessile or flat lesion ≥ 20 mm with fragmented resection Patients with previous resection of polyps in which the resection margin was not assessable and are considered susceptible to repeat colonoscopy Regular consumer of milk and dairy products. Informed consent form signed. Exclusion Criteria: History of allergic reaction attributed to compounds of similar chemical composition to the study agents. Incomplete colonoscopy or with poor quality criteria, Boston <6. Concomitant acetylsalicylic acid (ASA), NSAIDs, misoprostol, corticosteroids or statins needed on a regular or predictable basis during the time of the study. Previous gastrointestinal surgery (colon or small intestine or gastric) that affects the absorption of nutrients. History of familial adenomatous polyposis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UNICLA-A2 milk and its subproducts<br>Participants (n=17) ingest milk and dairy products made from cows homozygous for beta casein A2 during 3 months. These products are also enriched in insaturated fatty acids and selenium. The daily intake reflects the habitual consumption habits. Recommended amounts are 250 mL of milk, a yogurt and 50 g fresh cheese per day. | Dietary Supplement: Milk from genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium<br>* The daily intake should reflect habitual consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 250 mL of milk. The intervention duration will be 3 months<br>* Other names: UNICLA-A2 milk;Dietary Supplement: Yogurt made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium<br>* The daily intake should reflect habitual consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of one yogurt. The intervention duration will be 3 months<br>* Other names: UNICLA-A2 yogurt;Dietary Supplement: Fresh cheese made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium<br>* The daily intake should reflect habitual consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 50 g of fresh cheese. The intervention duration will be 3 months<br>* Other names: UNICLA-A2 fresh cheese;|
| Placebo Comparator: Placebo<br>Participants (n=17) ingest conventional dairy products and milk daily during 3 months. As happens in the UNICLA-A2 arm, the daily intake reflects habitual dairy consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, recommended amounts are 250 mL of milk, a yogurt and 50 g fresh cheese per day. | Dietary Supplement: Conventional milk<br>* The daily intake should reflect habitual consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 250 mL of milk. The intervention duration will be 3 months<br>Dietary Supplement: Conventional yogurt<br>* The daily intake should reflect habitual consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of one yogurt. The intervention duration will be 3 months<br>Dietary Supplement: Conventional fresh cheese<br>* The daily intake should reflect habitual consumption habits in real life conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 50 g of fresh cheese. The intervention duration will be 3 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline levels in pro-inflammatory circulating markers C-reactive protein (CRP), interleukin (IL)-6, macrophage inhibitory cytokine 1 (MIC-1) and tumour necrosis factor alpha (TNFα), as well as in fecal calprotectin. | The C-reactive protein and calprotectin are measured by conventional methods in the University Clinic Hospital Lozano Blesa and the circulating biomarkers IL-6, MIC-1 and TNFα by enzyme-linked immunosorbent assay | At baseline, at 3 months and through study completion, an average of 1 year after the colonoscopy that motivated the patient´s inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in fecal microbiota. | Stool samples are collected for DNA extraction and ulterior metagenomic analysis of the fecal microbiota's composition. Library construction is carried out with the Ion 16S™ Metagenomics Kit which permits PCR amplification of hypervariable regions of the 16S rDNA gene from bacteria and the material obtained is subjected to next-generation sequencing (NGS) to see the proportions of the main groups of microorganisms in the sample. | At baseline, at 3 months and through study completion, an average of 1 year after the colonoscopy that motivated the patient´s inclusion | 
| To assess the effect of treatment on colorectal adenoma recurrence | The number of participants in each arm who develop one or more colorectal adenomas is determined in the follow-up colonoscopy (adenoma detection rate), as well as the presence of advanced or not advanced adenomas, serrated polyps, subtype, location and the total number of adenomas per participant. | Through study completion, an average of 1 year after the initial colonoscopy that motivated the suitability of patients inclusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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polyp, inflammation, fecal microbiota