Pathophysiology of metabolic changes and malnutrition in colorectal cancer’s patients

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide (1). Metabolic changes and malnutrition are a common feature in this group of patients, affecting treatments, outcomes, and quality of life (2-7). Chemo and radiotherapies, biologics, and surgical therapies, ultimately worse the abovementioned metabolic changes, increasing the risk of malnutrition (8,9).

Metabolic changes of CRC patients regard all metabolic pathways, including the metabolism of glucose, lipids, proteins, and nucleic acids. Glucose metabolism variations lead to hyperglycemia and/or insulin-resistance (IR) (10,11). Lipid metabolism impairment increases cholesterol, triglyceride, and free fatty acid (FFA) blood levels (12,13). Protein metabolism is shifted towards an increased protein degradation with the reduction of protein synthesis, due to increased nucleic acid degradation (14,15). All these changes reduce the amount of available energy for the physiologic cellular activity contributing to the inflammatory status typical of oncologic patients (16-19) and originating a vicious cycle that furtherly worsen the metabolic status, outcomes, and prognosis.

IR, a body adaptation response to situations of severe stress, such as in case of severe hemorrhages, leading to glucose mobilization, fluids shift and plasma refill, can ultimately impair outcomes. In fact, IR is an independent factor responsible of prolonging length of hospital stays, and hyperglycemia increases the risk of post-operative complications, such as surgical site infections (SSIs), and mortality (20-22).

Changes in proteins metabolism causes asthenia and sarcopenia and reduces strength; increase oncologic treatments’ complications rate or make it impossible to offer one (23,24). Together with lipids metabolism changes, these alterations lead to malnutrition, worsen patients’ prognosis, and ultimately bring patients to cancer-related cachexia. In this setting, it is particularly important to assess and re-equilibrate CRC patients metabolic and nutritional status before any therapeutic intervention is planned.

The present review summarizes causes and effects of metabolic changes affecting CRC patients undergoing medical and surgical treatments and offers an overview of clinical interventions to reduce these changes and improve patients’ outcome.

Metabolic changes in CRC patients

Changes in inflammatory signaling

Metabolic disorders, mostly leading to malnutrition, are extremely common and can be considered a multifactorial complication of each cancer. Cancer-related cachexia can be considered a form of end stage metabolic impairment; it might occur in half of all CRC patients and is responsible in up to one fifth of the cases of jeopardizing therapeutic options and, ultimately of cancer-related deaths (25).

The complex interaction between the tumor microenvironment and its host generates an inflammatory response affecting hunger and satiety and promoting tumor progression (26).

Inflammatory cytokines produced in CRC patients include tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), calcitonin gene-related peptide (CGRP) and insulin-like growth factor 1 (IGF-1) (Figure 1).

Figure 1 Metabolic changes in CRC patients. The interaction between CRC and its host generates an inflammatory response. The main inflammatory cytokines produced include TNF-α, IL-6, CGRP and IGF-1. Changes in inflammatory signaling finally lead to muscular atrophy and insulin-resistance and impair hunger and satiety pathways. Picture create with https://www.biorender.com. CRC, colorectal cancer; TNF-α, tumor necrosis factor α; IL-6, interleukin 6; CGRP, calcitonin gene-related peptide; IGF-1, insulin-like growth factor 1.

TNF-α has a catabolic action, but its blood levels are not directly associated with weight loss. It increases gluconeogenesis, glycogen synthesis and proteolysis, reduces proteins synthesis, and causes muscular atrophy (27). Its catabolic effect on skeletal muscle is also mediated by the activation of nuclear factor-kappa B (NF-κB) pathways (28,29). It activates the hypothalamus-pituitary-adrenocortical (HPA) axis (30), affecting metabolism through cortisol production and can interfere with intestinal nutrients absorption (31). Its action on metabolic changes seems to be mediated also by the alteration of leptin effects (32). Leptin is an anorexigenic peptide hormone, usually produced by adipocytes. It has a central action mediated by hypothalamic receptors, stimulating anorexigenic neuropeptides and inhibiting orexigenic neuropeptides production. Moreover, it affects thermogenesis, a homeostatic mechanism that usually limits weight gain in response to caloric excess. However, whether inflammatory cytokines reduce leptin production or impair its action is not clear, yet.

IL-6 is an inflammatory cytokine with pleiotropic effects, associated with increased CRC aggressivity and worse prognosis. Its concentration is correlated with serum-FFAs, both in early and late-stage CRC. This cytokine promotes muscular atrophy, with mechanisms mainly described in animal models, mostly based on the suppression of protein synthesis through Janus Kinase (JAK) pathways (33). Its production may also increase energy expenditure and lead to decreased food intake (34). The metabolic changes it causes are mainly due to leptin function impairment and HPA axis activation, which increases cortisol blood levels.

CGRP affects hungry and satiety pathways, reducing the former and increasing the latter, with mechanisms probably mediated by its interaction with peptide YY (PYY) receptor 2 in the hypothalamus (35). It seems CGRP could also affect the production of neuropeptide Y and other molecules involved in hunger and satiety pathways.

IGF-1 is a peptide hormone usually produced by liver, adipocytes, muscle, and brain. Its anorexigenic action is mediated by the increased production of others anorexigenic molecules such as CGRP, PYY, etc. and the reduction in ghrelin blood levels, which is an orexigenic hormone usually produced by the stomach in case of fasting. Furthermore, IGF-1 directly interferes with brain insulin receptors (36). Many studies suggest IGF-1 and its receptor may also be involved in CRC pathogenesis. Indeed, IGF-1 can promote tumor growth stimulating cellular proliferation and survival through the interaction with its receptor or the pathway PI3K/AKT/mTOR, which is involved in protein synthesis and cellular homeostasis. Its blood levels are associated to increased cancer aggressivity (15,37).

From a clinical point of view, these inflammatory and metabolic changes lead to a remarkably different state of starvation with respect to starvation-associated weight loss, with loss of lean mass and skeletal muscle more than adipose tissue (38).

Clinical changes

Appetite loss in CRC patients can be caused by tumor volume, leading to bowel stenosis causing obstruction, a condition associated with poor oncologic prognosis (39,40). CRC can also alter the mucosal barrier, characterized by the disruption and leakage of the intestinal epithelium, which leads to translocation into the circulation of both bacteria and their components, contributing to the general inflammatory status, participating to the above-mentioned metabolic changes cascade.

Changes in intestinal microbiota

Gut barrier dysfunction also impairs nutrients absorption, worsening the energy imbalance typical of CRC patients (41,42). Furthermore, CRC patients have shown reduced microbiota diversity and richness compared with healthy individuals (43). These patients present a reduction in probiotics bacteria and increased enterobacteria concentration. The formers include butyrate-producers as Clostridium butyicum, that produce short-chain fatty acids with anti-inflammatory effects and may exert a protective function against CRC. On the contrary, enterobacteria such as Fusobacterium nucleatum and Enterococcus faecalis seems to contribute to disease progression from adenoma to cancer and indicated a worse prognosis, probably because of superoxide production, which damages DNA in epithelial cells (44). Beside the detrimental actions of enterobacteria surpassing those of the beneficial commensals, microbiota changes alter intestinal mucosa integrity, impairing its permeability to bacteria and toxic substances, but also affecting nutrients absorption and activating the HPA axis (45).

Metabolic changes induced by neo-adjuvant or adjuvant treatments

Cytotoxic therapy

Beyond cancer-specific metabolic impairment, chemotherapy (CT), radiotherapy (RT) and biologics, further participate to metabolic compromission, eventually contributing to malnutrition and cachexia (Table 1).

CRC medical treatment is mostly based on the administration of fluoropyrimidine, either 5-fluorouracil (FU) or capecitabine, combined with irinotecan or platinum (46,47). Biologics include monoclonal antibodies or proteins against the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Their administration in combination with CT is restricted to metastatic disease (27). RT is used as local treatment for rectal cancer (both in the neoadjuvant and adjuvant setting) (48) and occasionally for locally advanced colon cancer.

Fluoropyrimidines show gastrointestinal toxicity causing dose-related diarrhea, and electrolytes imbalance. When leucovorin is added, the percentage of patients with severe diarrhea rise to 50% (49). The pathophysiology of fluoropyrimidine-induced diarrhea has not been deeply investigated, yet. It seems that fluoropyrimidines cause the interruption of mitosis of intestinal crypt cells, decreasing the resorption surface area leading both to diarrhea and malabsorption (50). Capecitabine shows reduced gastrointestinal toxicity compared to FU (51) whilst irinotecan can cause diarrhea, too. Despite the detailed mechanisms leading to diarrhea are still a matter of debate, it seems they can be attributable to its active metabolite 7-ethyl-10-hydroxycamptothecin (SN38), which is produced in the intestinal lumen by bacterial ß-glucuronidase. Free intestinal SN38 could induce direct mucosal damage, could alter luminal environment favoring proliferation of different bacteria, could increase mucin secretion and/or could cause villous atrophy impairing absorption and causing diarrhea (49).

Cancer platinum-based treatment can affect metabolism causing weight loss, nausea and vomiting, diarrhea, mucositis, stomatitis, anorexia, cachexia, and inflammation. The most common gastrointestinal side effects are caused by 5-hydroxytryptamine (5-HT) released by intestinal cells target of platinum drugs and binding serotonin receptors both in central and peripheral nervous system, thus leading to nausea and vomiting. Cisplatin has the highest rates of nausea and vomiting, which are shown in up to 90% of patients (52). Moreover, it can regulate muscular wasting through the activation of NF-κB pathway (25) and seems to reduce ghrelin production, impairing hunger and satiety pathways (53).

In general, all cytotoxic drugs, share a range of side effects due to their poor selectivity for cancer cells. These drugs are taken up by all fast-reproducing cells, including cancer cells. However, they can affect also fast regenerating tissues such as the mucous membranes of the mouth, stomach, and intestines, causing gastrointestinal toxicity (meaning weight loss, nausea and vomiting, diarrhea, mucositis, stomatitis, and malabsorption) (52). Finally, CT stimulates proteolysis and proinflammatory cytokines production such as TNF-α and IL-6 (54,55), thus indirectly affecting metabolic pathways.

Recent literature focused on the impact CT has on gut microbiota (56-58). Its action is mediated by proinflammatory cytokines increasing mucin secretion. Mucin reduces adhesion sites and affects luminal nutrients availability, inhibiting Lactobacilli and Bifidobacteria proliferation and stimulating Clostridium and E. coli (59). Every imbalance of intestinal microbiota can determine epithelial intestinal mucosa damage or luminal variation in terms of digestive enzymes balance, leading to malabsorption and translocation of bacteria or toxins.

Biological therapies

Biological therapies to treat cancer are derived from living organisms that can modify the immune response, but they can alter patients’ metabolism, too. Anti-EGFR drugs can cause malabsorption and severe diarrhea in up to 30% of patients. The multiple mechanisms leading to gastrointestinal toxicity include impaired electrolytes flux across the enterocyte membrane due to damaged transporters, the presence of hypertonic substances in the intestinal lumen, and increased gut motility (60). Moreover, anti-EGFR drugs inhibit E-cadherin production, reducing mucosal integrity and permeability (61). This process affects nutrients and toxins absorption, leading to an inflammatory general status which contributes to metabolic changes.

RT

RT effects on patient’s metabolism are mainly due to mucositis causing nausea, vomit, diarrhea, malabsorption, and pain, depending on the area of exposure. Both acute and delayed RT-induced gastrointestinal toxicities are caused by intestinal epithelium injury. This is mediated by NF-κB, mitogen-activated protein kinase (MAPK), and matrix metalloproteinases (MMP) in the acute setting, meaning shortly after RT administration and up to 3 months later. Delayed impairment, showed between 18 months and 6 years after RT administration, is mediated by transforming growth factor-b1 (TGF-b1) and thrombomodulin, that alter extracellular matrix (ECM) (62).

Metabolic changes induced by CRC surgery

Surgical stress

Most CRC patients will eventually undergo surgery, which plays a key role in the treatment of both localized disease and in selected advanced metastatic patients (39,40,46-48). It means, CRC patients mostly face metabolic alterations caused by surgery.

It is well known that every injury, thus also an operation, determine a stress response characterized by an inflammatory condition inducing a catabolic state (63). Indeed, inflammatory mediators and stress hormones production leads to catabolism of glycogen, fat, and proteins, reducing peripheral protein mass, especially muscles. Release of glucose, FFA, and amino acids from the body, aims to improve the immune response and healing.

Following surgical trauma, the stress response is activated. The nervous system sends impulses from the injured site to the hypothalamus, which modifies pituitary hormones release and/or production. Inflammatory cytokines also play a key role increasing pituitary hormones secretion. The most involved hormones in metabolic changes are corticotrophin (ACTH) and growth hormone (GH), both acting on their own target organs. This cascade of events leads to increased blood levels of cortisol, glucagon, catecholamines, together with proinflammatory molecules (64). As a result of hormonal changes, peripheral response to insulin release decreases [insulin resistance (IR)], for over than a week after the operation, proportionally to its magnitude (65,66). After a colorectal operation, up to 90% of the preoperative insulin sensitivity can be lost (65). Such a modification in insulin peripheral sensitivity can last up to 2–4 weeks after uncomplicated surgery. This is the central mechanism to achieve the catabolic state. IR causes a compensatory rise in insulin production, leading to the release of glucose from the hepatic stores of glycogen. Decreased peripheral glucose utilization worsens hyperglycemia. Moreover, the post-operative catabolic state resulting from IR, is also characterized by an increased protein breakdown, involving both albumin and other proteins.

Surgery and intestinal microbiota

Colorectal surgery also affects gut microbiota composition, thus indirectly affecting absorption and causing metabolic changes. Microbiota composition during and after surgery is altered because of several factors including stress, the alteration of body homeostasis, exposure of the intestinal lumen to oxygen, and tissue ischemia. All these factors determine a shift in the composition of the microbiota localized both on the intestinal mucosa and in its lumen, with a reduction of the so-called good anaerobes species and a gain of bad facultative aerobes species, as enterococcus. Changes in mucosal-associated microbiota are associated to altered mucin secretion and short-chain fatty acids production, leading to impaired nutrient absorption, damage of the intestinal barrier, bacterial translocation and a general proinflammatory state that contributes to the metabolic changes induced by surgery (67).

Surgical resections

Colorectal resections are known to participate in malabsorption. For transverse and left colon and for rectal cancer patients, the resection is only minimally responsible, even though for anterior resections, a well-known syndrome, the low anterior resection syndrome (LARS), certainly affect nutritional status (68). On the contrary, patients undergoing right hemicolectomy will lose their ileo-cecal valve and terminal ileum, thus biliary acid and microelements.

Perioperative measures

Metabolic changes induced by the surgical operation itself can be furtherly affected by the measures adopted in the perioperative period. Indeed, despite the large amount of evidence supporting reduced perioperative fasting, still many patients face overnight fasting before surgery and long post-operative restriction both in food and oral fluids intake. Tolerance to normal food or enteral nutrition after surgery can be affected by post-operative ileus, which may be exacerbated by laparotomic procedures, intraoperative manipulation and subsequent pan enteric inflammation, excessive intravenous fluid load, both during and after the operation causing intestinal wall oedema, opioids administration, prolonged bed rest (69).

Despite the different sources of metabolic alterations in CRC patients undergoing surgery, recent literature is mostly focusing on the peri-operative stress, seeking for strategies which could minimize catabolism and support anabolism, thus accelerating the post-operative recovery.

Improving metabolic status: a team effort

As previously highlighted, metabolic changes affect outcomes of CRC patient’s treatment. Recognizing and managing them properly is crucial to increasing the chance to complete every step of the scheduled anticancer therapies, and to optimize treatments outcomes including overall survival and quality of life. For this reason, a multidisciplinary approach is required to optimize patients’ metabolic status, maintaining skeletal mass and physical performances. Several professional figures are involved in the process, including nurses, nutritionists, physiotherapists, psychologists, oncologists, gastroenterologists, and surgeons. The whole team works on what is known as a pre-habilitation program. Counselling on nutritional support is offered by nurses and nutritionists. The management of cancer-associated malnutrition includes nutritional counselling informing patients about nutritional topics and showing them healthy eating habits. Moreover, cancer patients frequently need nutritional supplements, nutrient mixtures orally administered if volitional food intake does not guarantee the complete metabolic recovery. If nutrient intake remains inadequate, supplemental nutrition by the enteral or parenteral route may be indicated (70). Physiotherapists should offer and adapt to single needs a correct physical program necessary to gain or re-gain physical strength. If needed a psycho-oncologist will provide the necessary support, whilst oncologists and gastroenterologists will deal with medical therapies to reduce the most detrimental side effects of the oncologic treatment, such as antiemetics, analgesics, drugs increasing or reducing salivary production depending on the specific case, proton pump inhibitors to reduce gastritis or esophagitis. Surgeons and anesthesiologist will apply all the necessary measures to reduce surgical stress, such as programs of enhance recovery and perioperative optimization.

For what concern the management of the metabolic alterations induced by CRC treatments, the literature offers several evidences.

Management of medical treatment-induced alterations

One of the principal efforts is focused on the management of CT-induced diarrhea, which is based on both nonpharmacological and pharmacological strategies. The formers are based on dietary advice, avoiding aliments that worsen numbers and severity of liquid stools, increasing fluids and salts to keep patient hydrated. If the nonpharmacological approach is not sufficient, there are several drugs which have been proposed to treat diarrhea. Budesonide, glutamine, celecoxib, long-acting octreotide, as well as marginally absorbable antibiotics like neomycin, all seems to be of some efficacy in treating CT-induced diarrhea even though, only loperamide and octreotide are suggested by guidelines (49). Loperamide is an opioid which alters the function of the intestinal mucosa smooth muscle and reduces bowel movement frequency and stool weight. Octreotide is a synthetic somatostatin analog, which is used only as second line treatment in case of refractory-to-loperamide diarrhea. Its action is mediated by the reduction of vasoactive intestinal peptide (VIP) blood levels, that slows down intestinal transit, increases fluid absorption, and reduces mucosal secretions (49). Both can be used for the treatment of diarrhea induced by both chemotherapeutic agents and biological therapies.

Platinum-induced nausea and vomiting is another frequent CT side effect. Treatment is based on the administration of a combination of antiemetics, depending on the used platinum regimen. Cisplatin and carboplatin cause more intense gastrointestinal side effects, thus their treatment requires a combination of at least 3–4 drugs including 5-HT antagonists, neurokinin 1 (NK1) antagonists, dexamethasone, and olanzapine. Oxaliplatin side effects are less intense, thus dexamethasone administration is usually sufficient.

Management of surgery-induced alterations

In elective surgery it has been shown that the best way to minimize catabolism and support anabolism is to reduce post-operative stress through perioperative programs collected in enhanced recovery protocols (71-73). The most important items affecting metabolism are the reduction of fasting, preoperative carbohydrate load and early post-operative feeding, avoiding long starvation periods. However, also post-operative nausea and vomiting (PONV) control, pain control, application of standard anesthesia protocols and intra-operative fluid restriction have a role in surgical stress reduction and affect hunger and satiety pathways. The combination of all these treatments can minimize IR, allowing full glucose control without insulin administration even in patients who underwent major colorectal surgery and started early enteral nutrition (74).

The most discussed items are the appropriate pre-operative carbohydrate loading and the length of pre-operative fasting period. Recent evidence recommends reduction of pre-operative fasting, allowing solid assumption up to 6 hours and clear fluids up to 2 hours before surgery (71). These novel protocols improve subjective well-being, reducing thirst, dryness of mouth and anxiety (75).

Pre-operative carbohydrate load reduces post-operative IR, too. Moreover, it can improve thirst and reduce protein loss, easily assessed with muscular strength. In elective colorectal surgery 285 mOsm/kg of complex maltodextrin administration before surgery is suggested: diluted in 800 mL of water to be taken the evening before surgery and in 400 mL of water to drink 2–3 h before the induction of anesthesia (71). Despite the good impact on post-operative metabolic status, carbohydrate load cannot be administered to diabetic patients because of the excessive increase in glycemic values. Its administration is contraindicated also in patients affected by gastroesophageal reflux disease (GERD) or delayed gastric emptying; a large amount of carbohydrates can further slowdown gastric emptying, increasing the risk of aspiration in patients with impaired gastric function.

Immunonutrition also seems to influence host immune response to surgical stress (76-78). It is based on the administration of immune-modulating nutrients in higher doses than standard nutritional protocols. Further evidence is necessary to establish their exact role.

Laparoscopic surgery and, in general, minimally invasive surgery, also seems to improve glucose metabolism compared to open surgery, providing faster recovery of nutritional and immunologic status (31,79-81).

Whether perioperative management or minimally invasive surgery have a major impact on metabolic changes is not clear, yet. Xu et al. compared their effect on the nutritional status of CRC patients through albumin, prealbumin and transferrin levels assessment. The analysis of blood samples collected preoperatively, at 12 and 96 hours after surgery, showed accelerate rising in albumin levels in patients undergoing laparoscopic surgery, regardless of fats-track treatment highlighting both a direct and indirect beneficial effect of laparoscopy on patients’ metabolism (79). However, more recent studies suggest an indirect relation between the surgical technique and metabolic changes, due to the reduction of post-operative inflammation (82,83). Indeed, Siekmann et al. assessed cortisol, insulin and serum cytokines levels in blood samples collected preoperatively, 1–6 hours postoperatively and 3–5 days postoperatively. The study did not show any difference in plasma cortisol and insulin levels between groups. On the contrary, higher cytokines levels were found few hours after the procedure in patients undergoing open surgery rather than laparoscopy (84), indirectly affecting IR and metabolism in general.

The reduction of post-operative inflammation is not the only beneficial effect of laparoscopic surgery. Pędziwiatr et al. showed laparoscopy can also reduce the negative impact of sarcopenia (a result of malnutrition) on post-operative outcomes (85). Sarcopenia is a depletion of skeletal muscle mass and strength, usually associated to myosteatosis (fat infiltration in skeletal muscle) (86). It is the result of the state of chronic inflammation associated to IR and nutritional impairment (87) and is a well-known risk factor for post-operative infections and delayed recovery after traditional CRC surgery (88). Recent literature is focusing on the impact that laparoscopic surgery has on sarcopenic CRC patients, showing that laparoscopy can improve post-operative outcomes, significantly reducing overall complications rate, length of hospital stays, and readmission rate (85,89). The relationship between sarcopenia and laparoscopy needs to be investigated further, but it could be speculated that improving nutritional status before surgery could possibly improve the already excellent results of minimally invasive surgery.

Conclusions

This review summarizes mechanisms leading to metabolic changes and malnutrition in CRC patients undergoing treatment. There is an unequivocal risk that metabolic changes and malnutrition jeopardize cancer treatment and ultimately impairs clinical outcomes and cancer related survival. Unfortunately, not all the mechanisms leading to metabolic changes are completely understood. Some of them have been described only in animal models and others, like fluoropyrimidine- and irinotecan-induced diarrhea, are still unclear. Both, medical and surgical measures adopted in the perioperative treatment period are mostly symptoms bonded. Furthermore, most of the in-use protocols are still under discussion because, despite the many positive results, they often lack proper evidence. Further studies investigating metabolic changes in CRC patients will certainly help to reach a deeper understanding, allowing to increase available therapeutic means.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-23-154/prf

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