Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa

Abstract

BackgroundCachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia‐related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour.MethodsBlood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® xMAP) analyses.ResultsThere was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL‐6) and IL‐8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL‐7, IL‐13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte‐colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL‐13 and transforming growth factor beta 3.ConclusionsThe changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.

The pretreatment Controlling Nutritional Status (CONUT) score is an independent prognostic factor in patients undergoing resection for colorectal cancer

“…The PNI, which is the nutritional index calculated using the peripheral lymphocyte count and the serum albumin level, was reported to be associated with the survival of CRC patients 21 . The GPS has been used in several different oncological field and could, due to the routine assessment of albumin and CRP, be assessed in all aspects of the prospective care of patients with cancer 22,23 . In the present study, although the PNI and the CONUT score were found to be predictive factors for RFS and OS in the univariate analyses, the results of the multivariate analysis demonstrated that only the CONUT score was an independent prognostic factor for these patients with CRC.…”

Cachexia, a Systemic Disease beyond Muscle Atrophy

“…The same cytokines together with the receptor activator of nuclear factor kappa-Β ligand (RANKL) can induce bone loss by apoptosis of osteoblasts and the differentiation of osteoclast precursor cells (OCPs) into activated bone resorbing cells [ 47 ]. Immune cell infiltration and other inflammatory changes can perturbate the intestinal microbiota composition and exacerbate mucosal damage and gut permeability [ 48 ]. Studies on murine models of cancer cachexia have demonstrated that neutrophils infiltration and microglia activation can contribute to brain dysfunction, probably through affecting sympathoexcitatory and anorexigenic neurons [ 49 , 50 ].…”

“…Whether these observations are clinically relevant remains to be determined. Interestingly, Costa et al reported morphological and inflammatory changes in the intestinal mucosa in healthy tissues of cachectic colon cancer patients compared to weight-stable colon cancer patients [ 48 ]. A full characterization of the gut microbiota of leukemia patients with and without cachexia is currently ongoing in an academic multi-centric prospective study (NCT03881826) and it should bring more light on this topic.…”

A Pound of Flesh: What Cachexia Is and What It Is Not

“…Beyond the well-characterized muscle–liver–adipose tissue axis, newly emerging evidence of possible interactions between skeletal muscle and the gut microbiota, the composition of which appears to be strongly influenced by physical activity and general performance status, suggests they may play a role in muscle wasting associated with diabetes, frailty, sarcopenia, and other cachectic conditions [ 108 ]. In aging subjects, as well as in patients with anorexia nervosa and in sedentary versus trained, shifts in the microbiota toward a less diversified composition have been correlated with decreased muscle function [ 109 ].…”