The goal of this study is to evaluate the effects of nutritional supplementation and physical activity interventions on recovery, muscle strength, nutritional status, inflammation, and metabolic health in adults with colon cancer undergoing surgery.

Patients with colon cancer frequently experience loss of muscle mass, reduced physical function, and nutritional deterioration both before and after surgery, which may adversely affect recovery and quality of life.

A key objective of this study is to assess whether a postoperative intervention combining nutritional supplementation with beta-hydroxy beta-methylbutyrate (HMB) and vitamin D, together with a structured physical activity program, can improve muscle strength and functional recovery following colon cancer surgery.

This study aims to answer the following questions:

• Does nutritional supplementation with HMB and vitamin D, combined with postoperative physical activity, improve muscle strength and physical function following colon cancer surgery?
• How do nutritional and lifestyle interventions influence nutritional status, gut microbiota composition, and biological markers of inflammation and metabolism during the recovery period?
• Are there differences in recovery outcomes between patients receiving different types of nutritional support, with or without supervised physical activity?

Participants will be adults diagnosed with colon cancer who undergo surgical treatment at the Hospital Universitario Virgen de la Victoria in Málaga, Spain. Patients will be recruited prior to surgery and will enter a prehabilitation phase integrated into routine care provided by the Endocrinology and Nutrition Department.

During this prehabilitation phase, nutritional status will be assessed and optimized using standard clinical care, including oral nutritional supplementation when indicated. The aim is to improve the patient's condition before surgery. Approximately one month after surgery, once initial postoperative recovery has been completed, participants will enter the intervention and assessment phase (baseline visit).

Participants will then be randomly assigned to one of four study groups in a 2×2 factorial design. These groups combine two nutritional strategies (standard care or supplementation with HMB and vitamin D) and two physical activity approaches (supervised exercise or general activity recommendations). The physical activity component, supervised by the Endocrinology and Nutrition team, will be objectively evaluated using an accelerometer-based device. Participants will be followed for approximately six months, with assessments at about 3 and 6 months after the baseline visit.

At each visit, participants will undergo:

• Body composition measurements
• Muscle strength and physical performance tests
• Collection of blood, urine, and stool samples
• Questionnaires on health status and quality of life

The results of this study will contribute to a more profound understanding of how tailored nutritional strategies and postoperative physical activity may support recovery and functional health in patients undergoing surgery for colon cancer.

Colon cancer patients frequently present with nutritional impairment, systemic inflammation, and early loss of muscle mass even before surgical treatment. These conditions may be exacerbated by surgical stress, reduced intake, and postoperative physical inactivity, leading to delayed recovery, functional decline, and impaired quality of life. Interventions targeting nutritional and functional status across the perioperative period may help improve physiological reserve and support postoperative recovery.

The NIMA study (Nutritional, Inflammatory, and Muscular Assessment) is designed to evaluate the impact of perioperative nutritional care and postoperative physical activity strategies on recovery, muscle strength, nutritional status, inflammation, metabolic health, and gut microbiota in adults undergoing surgery for colon cancer. The study combines routine preoperative nutritional management with a structured postoperative intervention and follow-up period, allowing assessment of short- and medium-term changes during recovery.

Study Setting and Population: This study includes adult patients diagnosed with colon cancer stages I to III, (TNM classification) who undergo surgical treatment at the Hospital Universitario Virgen de la Victoria in Málaga, Spain. Participants are identified and recruited before surgery through standard clinical pathways. All participants provide written informed consent before enrollment. The study is conducted in accordance with ethical principles and has been approved by the appropriate ethics committee.

Prehabilitation Phase (Preoperative Nutritional Care): Approximately two weeks before surgery, patients undergo a prehabilitation phase integrated into routine clinical care provided by the Endocrinology and Nutrition Department. This phase includes assessment and optimization of nutritional status through clinical evaluation, follow-up, and oral hypercaloric and hyperproteic supplementation when indicated. The aim is to improve metabolic condition and physiological reserve prior to surgical stress.

Surgical Treatment and Standard Postoperative Care: All participants undergo standard surgical treatment and postoperative oncological management according to institutional clinical practice. Participation in the study does not modify surgical procedures, immediate postoperative care, or oncological treatment.

Postoperative Interventions(Factorial Design): Approximately one month after surgery, once initial postoperative recovery has been achieved, participants enter the intervention phase (baseline visit). Participants are randomly assigned to one of four study groups according to a 2×2 factorial design:

• Standard nutritional care + general physical activity recommendations
• Standard nutritional care + supervised exercise program
• Enhanced nutritional supplementation (beta-hydroxy beta-methylbutyrate [HMB] and vitamin D) + general physical activity recommendations
• Enhanced nutritional supplementation (HMB and vitamin D) + supervised exercise program Enhanced nutritional supplementation consists of HMB combined with vitamin D (and calcium, when applicable), administered in addition to standard nutritional care.

The supervised physical activity program consists of structured, progressive resistance and functional exercises adapted to each participant's postoperative condition, targeting major muscle groups to improve muscle strength and functional capacity. Participants assigned to general physical activity receive standard recommendations according to routine clinical practice. Physical activity levels are objectively assessed using a wearable accelerometer.

Follow-up and Assessments: Approximately one month after surgery, once initial postoperative recovery has been achieved, participants enter the intervention and assessment phase (baseline visit) and are followed for approximately six months, with follow-up assessments at around 3 and 6 months. A comprehensive morphofunctional evaluation is performed at baseline and repeated at 6 months, including body composition, muscle strength, functional performance, and nutritional assessment using techniques such as bioelectrical impedance analysis, nutritional ultrasound, and standardized functional tests. Additional strength and resistance tests are also conducted as part of the study-specific evaluations. Biological samples (blood, urine, and stool) are collected at predefined time points to assess metabolic, inflammatory, and microbiota-related parameters. At the 3-month visit, a partial assessment is carried out, including selected clinical, functional, and questionnaire-based measures(including validated questionnaires assessing health status, quality of life, dietary intake, physical activity levels, and psychological well-being), allowing evaluation of both short- and medium-term changes during postoperative recovery. For participants assigned to the structured and supervised physical activity program, physical activity adherence, intensity, and patterns are objectively monitored using a wearable accelerometer, which is worn for 7 consecutive days monthly throughout the follow-up period, providing quantitative data on real-world physical activity behavior.

Study Relevance: By integrating perioperative nutritional care with structured postoperative interventions within a factorial design, the NIMA study aims to determine the independent and combined effects of nutritional supplementation and physical activity on recovery. The findings may contribute to optimizing perioperative care and improving functional outcomes in patients undergoing colon cancer surgery.

Inclusion Criteria:

• Adults aged 18 to 75 years.
• Male and female participants.
• Diagnosis of colon cancer at localized or locally advanced stages (TNM stages I-III).
• Patients scheduled for primary surgical treatment.

Exclusion Criteria:

• Metastatic disease (stage IV)
• Diagnosis of rectal cancer or tumors involving the rectum
• Prior neoadjuvant chemotherapy or radiotherapy before surgery.
• Presence of synchronous malignant tumors.
• Pregnant or breastfeeding women.
• Presence of severe medical conditions, including acute pancreatitis, severe liver or kidney disease, heart failure, severe pulmonary disease, or peripheral arterial disease affecting the lower limbs.
• Diagnosis of anorexia nervosa or other severe eating disorders.
• Known allergy or intolerance to any nutritional supplements used in the study.
• Medical contraindications to moderate-to-vigorous physical activity.
• Regular participation in high-intensity exercise programs.
• High risk of poor adherence to the study procedures, as determined by the study team.

A decision regarding the sharing of individual participant data (IPD) has not yet been made. The study has received a favorable opinion from the relevant Research Ethics Committee. As described in the participant information and informed consent, data collected in this study are handled under strict confidentiality and in accordance with applicable data protection regulations, and are intended for research purposes within the scope of the project. If IPD is shared in the future, this would occur only in a de-identified format and upon reasonable request for scientific purposes.

Due to the nature of the interventions, participants and care providers are not blinded. Data analysis will be performed using coded group allocation.