Incremental Elevations in TNFα and IL6 in the Human Colon and Procancerous Changes in the Mucosal Transcriptome Accompany Adiposity

Abstract

Background: Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown.Methods: Concentrations of TNFa, IL1b, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined.Results: Plasma IL6 and TNFa were 1.4-to 3-fold elevated in obese subjects [body mass index (BMI) ! 34 kg/m 2 ] compared with the lean controls (P < 0.01). Among individuals with BMI ! 34 kg/m 2 colonic concentrations of IL6 and TNFa were 2-to 3-fold greater than in lean subjects (P < 0.03).In a general linear model, adjusted for NSAID use, colonic IL6 (partial r ¼ 0.41; P < 0.01) and TNFa (partial r ¼ 0.41; P ¼ 0.01) increased incrementally over the entire range of BMIs (18.1-45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (b ¼ À0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFkB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects.Conclusions: Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome.Impact: These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.

Insulin Resistance and Cancer: In Search for a Causal Link

“…For instance, TNF-α has been found in both acute and chronic inflammatory states, where it seems to promote and amplify IR by inhibiting INSR signaling [ 170 , 171 ]. In addition, higher levels of circulating TNF-α have been associated with tumorigenesis in overweight IR patients, in which its anti-apoptotic effect was most likely due to the activation of the NFκB pathway [ 172 ].…”

The Combination of Curcumin and Salsalate is Superior to Either Agent Alone in Suppressing Pro‐Cancerous Molecular Pathways and Colorectal Tumorigenesis in Obese Mice

“…Further, a number of studies in animal models and in human colonocytes have demonstrated the causal roles that cytokines such as TNF‐α and IL‐1β play in promoting carcinogenesis. Importantly, animal and humans studies alike have shown that obesity not only increases the concentration of circulating inflammatory cytokines, but also increases IL‐6 and TNF‐α in the colonic mucosa . IL‐6, in particular, is highly up‐regulated in colorectal neoplasms and considered to be instrumentally important during tumorigenesis and metastasis .…”

“…This phenomenon exists in the colons of obese rodents and humans as well: rodent models have demonstrated that obesity and/or a high‐fat diet (HFD) increases the colonic concentrations of IL‐1β, IL‐6, and TNF‐α, possibly via the TLR4 signaling pathway . Similarly, colonic IL‐6 and TNF‐α have been shown to increase incrementally with BMI in human subjects, achieving concentrations two‐ to threefold among those whose BMI is ≥34 compared to those whose BMI is 18–25 …”

“…This occurs via phosphorylation ( =inactivation) of one of its negative regulatory elements, glycogen synthase kinase 3 beta (GSK3β), which in turn stabilizes the ultimate effector protein of canonical Wnt signaling, β‐catenin . Transcriptomic analyses of colonic mucosa from human subjects have demonstrated that NF‐κB and other pro‐inflammatory/carcinogenic pathways are activated in obese individuals, underscoring the clinical relevance of this phenomenon . In recent decades, much work has gone into developing strategies to block these signaling pathways, with the aim of suppressing tumorigenesis …”

Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota

“…Some of the mediator for inflammation are cytokines and inflammation-related molecules (Hursting et al, 2012). A study reported that increased body mass index (BMI) was associated with increase in two proinflammatory colonic cytokines, namely TNF-a and interleukin 6 (IL6), while obesity coincided with precancerous changes in the transcriptome (Pfalzer et al, 2018). Considering the existing correlation between obesity and gut microbiota changes (Boulangéet al, 2016), finding from Pfalzer et al (2018) implies that inflammation may be one of the mechanisms of how obesityassociated dysbiosis contributes to increased CRC risk.…”