Adult height was reported on the baseline questionnaire. Current weight, physician-diagnosed diabetes, and physician-diagnosed hypertension were reported at baseline and on each follow-up questionnaire. BMI was defined as weight in kilograms divided by height in meters squared.
Women who reported diabetes diagnosed after 30 years of age were considered to have T2D. Women who reported hypertension and treatment with hypertension medications or diuretics were considered to have hypertension, as in our previous BWHS analyses. Plasma was collected from thirty nine female donors through the Susan G. Health histories were obtained, including medications for T2D metformin , hypertension, hypercholesterolemia or inflammatory conditions that required NSAIDs, and co-morbidities.
Clinical and demographic characteristics of the Komen subjects are reported in Table 7. This validation cohort consisted of sixteen women without cancer diagnosis; all were pre-menopausal confirmed by blood hormones age range 19—51, except one age 58 years. Aliquots for cytokine measurements were not subjected to more than two freeze thaw cycles.
Subjects with Type 1 diabetes were excluded. Thus, we defined one subject as T2D and twelve subjects as neither diabetic nor pre-diabetic, to yield a final cohort of thirteen subjects. Clinical and demographic characteristics of the surgical subjects are reported in Table 9. Beads were handled with a miniaturization drop array and washer system Curiox Biosystems, Inc. Mean Fluorescence Intensities for each analyte were recorded in independent duplicates obtained from a single biological sample and used for statistical analyses.
Median fluorescence intensity of sixty four cytokines were analyzed as follows. Outliers were removed, as defined by absolute difference from the mean greater than three standard deviations. Data were log-transformed and replicated samples were analyzed with regression models for repeated measures to account for within- and between-subject variability.
The models were adjusted by BMI, age and medications as specified. Plate to plate variation was coded as a random effect in the models. Selected markers were used to generate initial signatures, then duplicates were averaged to conduct the cluster analysis. Hierarchical clustering with complete linkage was used to derive clusters and the number of six significant clusters was derived using resampling [ 51 ].
See Fig 3 and S2 Fig for details. The inflammation score of each subject was computed as the sum of standardized cytokines. To infer the cytokine signatures in the three independent datasets, a multi-label Bayesian classifier was trained in the discovery set as described [ 26 ]. The classifier computes the probability that each subject in a new data set has signatures of Clusters 1—6, and assigns the signature with maximum posterior probability. Additional statistical methods and clustering of cytokine signatures from subjects who were treated with metformin or nonsteroidal anti-inflammatory medications.
We thank M. Lye of Curiox Biosystems, Inc. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Obesity-driven Type 2 diabetes T2D is a systemic inflammatory condition associated with cardiovascular disease. Introduction Unresolved, low level inflammation is a defining feature of Type 2 diabetes T2D , in which specific pro-inflammatory cytokines drive disease pathogenesis [ 1 , 2 ]. Download: PPT. Fig 1. Table 2. Characteristics of BWHS subjects after exclusion of subjects taking metformin or non-steroidal anti-inflammatory medications.
Table 4. Correlation of signatures and metabolic groups in BWHS subjects without reported use of metformin or non-steroidal anti-inflammatory medications. Fig 3. Table 5. Clinical characteristics and metabolic groups of BWHS subjects with reported use of metformin or non-steroidal anti-inflammatory medications.
Table 6. Correlation of signatures and metabolic groups in BWHS subjects with reported use of metformin or anti-inflammatory drugs. Validation of clusters in independent cohorts Although the cluster signature appeared to be robust and reproducible within the BWHS cohort, it was important to test the validity of the signature in other stand-alone cohorts, who had been recruited through unrelated methodology, but share African American self-reported race and obesity. Fig 4.
Table 7. Characteristics of African American female volunteers with obesity, who participate in the Susan G. Table 8. Correlation of signatures and metabolic groups in Komen subjects with reported use of metformin or anti-inflammatory drugs.
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Fig 5. Cluster signature in breast reduction surgical subjects for validation of BWHS—derived signature. Table 9. Characteristics of African American female surgical patients with obesity, who presented at Boston Medical Center for elective breast reduction. Table Correlation of signatures and metabolic groups in Boston Medical Center surgical cohort.
Discussion Nearly one in five deaths in adults age 40—85 years in the U. Conclusions BMI alone is a misleading measure of obesity-associated disease risks, and should be combined with profiling of inflammatory cytokines and metabolism to create more personalized risk assessment for African American women with obesity. Materials and methods Subjects Ethics statement.
Study design. Validation cohort 1: Komen volunteers. Validation cohort 2: Plastic surgery patients.
Validation cohort 2 exclusions. Assay of plasma cytokines. Supporting information. S1 Fig. Initial analysis of all sixty-four cytokines. S2 Fig. QQ plot. Acknowledgments We thank M. References 1. Diabetologia — Similar to GLP1, peptide YY PYY is also released by the same enteroendocrine cells L cells in response to nutrients, and this peptide reduces food intake and promotes energy expenditure Interestingly, GLP2 is another peptide co-secreted with GLP1; however, this peptide is involved in the reinforcement of the gut barrier by promoting intestinal epithelial cell renewal and reinforced tight junction proteins Thus, by stimulating the secretion of GLP1, PYY and GLP2, the gut microorganisms not only contribute to the control of food intake and glucose and lipid metabolism but also reinforce gut barrier function, which in turn reduces low-grade inflammation discussed further later.
Whether the regulation of gut peptides is one of the mechanisms influencing obesity and the onset of cancer warrants further studies, but data suggest that a GLP1 analogue will counteract the development of cancers associated with obesity, such a liver cancer 45 , 46 , epithelial ovarian cancer 47 and breast cancer Thus, the gut microbiota is considered an important source of factors that can contribute to interbacterial communication.
However, identifying the bacterial metabolites that modulate host physiology and metabolic processes will help in understanding the mechanisms by which gut microorganisms affect distant organs and tissues. Obesity and cancer development are both closely dependent on energy intake and nutrient availability, but they are also characterized by low-grade inflammation a small but chronic increase of different inflammatory markers in the blood and organs 49 , 50 , 51 Fig.
In a study in , the inflammation associated with obesity in mice was found to have its origin inside the gut and more precisely through the leakage of specific gut microbiota-derived molecules such as LPS, a condition termed metabolic endotoxaemia Gut barrier function is a complex assembly of factors that contribute to maintaining the gut microbiota at a distance from epithelial cells and limiting the entry of microorganism-associated molecular patterns MAMPs , such as lipopolysaccharide LPS. The alteration of gut microbiota composition dysbiosis observed during obesity is associated with a thinner mucous layer, a disruption of the tight junction protein TJP distribution and localization, and an abnormal host immune response in terms of antimicrobial peptide production as well as immunoglobulin A IgA production.
This low-grade inflammation is a primary hallmark and key factor triggering the onset of diabetes and cardiovascular diseases but is also seen in cancer observed during obesity. From a molecular point of view, LPS and other microorganism-associated molecular patterns MAMPs engage in a complex signalling cascade through different receptors of the innate immune system.
MYD88 is, therefore, a protein localized at the interface of interactions between microorganisms and the host. Indeed, in , two papers published by Pikarsky et al. For instance, Pikarsky et al.
Obesity is characterized by a dysbiotic gut microbiota with a lower abundance of short-chain fatty acid SCFA -producing bacteria, specifically butyrate producers. This effect will reduce the activation of G protein-coupled receptor 43 GPR43; also known as FFAR2 and GPRA also known as HCAR2 , which are both known to trigger an anti-inflammatory response at the level of epithelial cells via antimicrobial peptides and tight junction proteins and to elicit a regulatory T T reg cell-associated response. Specific microorganisms within the gut microbiota transform bile acids into secondary bile acids.
Deoxycholic acid DCA , which is promoted in the context of obesity, is a secondary bile acid considered as a cancer-promoting metabolite in the colon and liver. The intestinal origin of LPS is linked to inflammatory-induced carcinogenesis in the colon and in the liver hepatocellular carcinoma , whereas LPS from the oral route is mostly associated with pancreatic cancer. IgA, immunoglobulin A. Thus, the low-grade inflammatory states associated with obesity and cancer share similar triggering factors, and LPS is one of the best studied examples of these triggers.
Physiologically, LPS is continuously released in the gut by the death of Gram-negative bacteria and then translocated into intestinal cells through a TLR4-dependent mechanism It is then transported from the intestines towards target tissues in the circulation by a mechanism involving chylomicrons freshly synthesized from epithelial intestinal cells in response to fat ingestion In normal situations, the entry of LPS into the circulation is adequately managed by the immune system and detoxification mechanisms 62 , but in both humans and rodents with obesity and diabetes, plasma LPS levels are at least doubled compared with those in healthy controls, even in a fasted state 52 , 53 , 63 , 64 , 65 , However, despite the fact that a large volume of microorganisms live inside the gut, separated from the internal milieu by only a unique single cell epithelial layer, none or only few microorganisms or bacterial membrane components are found in the systemic circulation.
Thus, gut barrier function must be highly efficient. This assumption has been unequivocally validated by several studies showing that alterations of gut barrier function were involved in the development of metabolic endotoxaemia and eventually inflammation 44 , However, whether intestinal inflammation per se is required as a driver of gut barrier dysfunction remains controversial. Indeed, an alteration of the gut barrier and the eventual translocation of microbial compounds observed during obesity might occur independently of intestinal lesions and even in the presence of marginal inflammation.
This important issue will be discussed in the next section. Gut barrier function is the result of complex mechanisms involving physical, biological and immunological factors reviewed elsewhere For example, gut barrier function is improved by the presence of specific glycoproteins called mucins that are secreted by goblet cells and constituents of the mucous layer 68 , and these proteins constitute a considerable physical barrier against enteric resident bacteria and putative pathogens.
A reduced mucous layer thickness, although not directly associated with intestinal inflammation, has been linked with metabolic endotoxaemia, obesity and diabetes in rodents 69 , 70 , and in humans, the mucous layer thickness and the bacterial-to-host-epithelium distance were inversely correlated with BMI, fasting glucose levels and glycated haemoglobin 71 Fig. Moreover, the presence of specific microorganisms such as Akkermansia muciniphila seems to be necessary to replenish the mucous barrier 16 , 69 , 72 , Indeed, numerous studies show that although A.
Following this discovery, it has been demonstrated that A. The administration of A. It has also been discovered that A. In addition to strengthening the mucous layer as a physical barrier, A. Various antimicrobial factors produced by intestinal cells and cells of the innate immune system contribute to segregating microorganisms from the intestinal epithelial cells. Conversely, the administration of A. The gut bacteria are also under the influence of secreted immunoglobulin A sIgA , which is produced via the adaptive immune system and secreted into the intestinal lumen to restrict bacterial penetration into the host mucus and mucosal tissue This and other antimicrobial molecules are therefore tightly related to the composition of the gut microbiota, in which the presence of specific bacteria stimulates the production of antimicrobial peptides, whereas other bacteria are directly killed by these peptides.
Indeed, these compounds specifically target either Gram-positive or Gram-negative bacteria in order to maintain bacterial niches and the symbiosis of the microbial ecosystem in the gut 79 , 80 , 81 , The high rate of epithelial cell renewal 3—5 days also serves as a protective mechanism to remove damaged cells 84 , in which some factors such as intectin a small intestine-specific glycosylphosphatidylinositol-anchored protein 85 might play a part. It has been shown that diet-induced obesity in mice was associated with a reduced expression of this factor, whereas treating mice with a high-fat diet enriched with prebiotics abolished metabolic endotoxaemia and inflammation and was associated with a higher expression of intectin and a reinforcement of the gut barrier The paracellular permeability of the gut is under the control of protein complexes known as tight junction proteins that reside near the apical surface of adjacent epithelial cells 44 , Several studies show that the localization and the distribution of these tight junction proteins are also strongly influenced by gut microbiota composition and are crucial in regulating the efficiency of the gut barrier Fig.
During both genetic or diet-induced obesity and diabetes in mice, data show that altered expression and localization of tight junction proteins eventually contribute to the leakage of LPS into the circulation 44 , 63 , 67 , 73 Fig. Although we and others found that a high-fat diet induces changes in the gut microbiota and gut permeability and increases low-grade inflammation, an analysis in of randomized controlled trials from to found that most diet interventions showed either no or minor effects of dietary fat intake on inflammatory markers in patients with overweight and obesity The authors conclude that it is important to consider mechanistic studies, such as those that characterize obese phenotypes at a molecular level using omics data and gut microbiota composition This assumption is indeed important when considering the link between obesity, diet, gut barrier and inflammation.
Thus, besides diet and the physical factors contributing to the gut barrier mucus, epithelial cell renewal and tight junction proteins , the immune system of the gut must be clearly considered. Indeed, the gut immune system relies on a precise organization of immune cells in the different layers of the intestinal mucosa; for example, T cells reside throughout the mucosa, whereas B cells and innate immune cells are mostly found in lymphoid structures and the lamina propria By using dietary intervention or genetic deletion of intestinal immune cells, Luck et al.
For instance, upon high-fat diet feeding, the authors found a reduction in regulatory T T reg cells in the gut, a pro-inflammatory shift in some adaptive and innate T cell populations and translocation of LPS. More importantly, they found a similar observation in a cohort of seven patients with obesity compared with seven lean individuals Interestingly, although gut inflammation and loss of immune tolerance have been associated with severe bowel inflammation, tissue damage and colon cancer 92 , data also confirm an accumulation of T cell densities in the intestines of patients with obesity consuming a high-fat, low-carbohydrate diet, a phenomenon that also correlates with comorbidities of cardiovascular risk, such as systemic inflammation, hyperglycaemia and insulin resistance Conversely, another type of immune cell, mucosal-associated invariant T MAIT cells innate-like T cells , is dramatically decreased in the blood of patients with obesity and T2DM, but these cells display an activated phenotype with elevated T helper 1 T H 1 cell-like and T H 17 cell-like cytokine production It is worth noting that studies have suggested that these cells also have an effect beneficial or deleterious on gut barrier immunity and tumour immunity, therefore revealing the dichotomous nature of the T H 17 cells in cancer 95 , Altogether, these findings strongly suggest that both diet and immune cell abundance and function must be taken into account when investigating gut barrier function and gut permeability.
Similar to obesity and metabolic disorders, inflammation is recognized as an enabling characteristic of cancer development, providing support for multiple hallmark capabilities of tumours, including the supply of bioactive molecules, such as growth, survival and pro-angiogenic factors, to the tumour microenvironment, and inducing signals leading to epithelial-to-mesenchymal transition activation and the expression of tissue remodelling enzymes 97 Fig.
In addition, inflammation is also responsible for the production of reactive oxygen species ROS and reactive nitrogen species that are mutagenic and can drive mutations within oncogenes and tumour suppressor genes, a feature that is not restricted to gastrointestinal cancer and is also valid for other types of cancer 9 , 98 , 99 , Indeed, increased ROS generation by polymorphonuclear neutrophils PMNs at the site of inflammation causes endothelial dysfunction and tissue injury. Under inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier Interestingly, the presence of adaptive immune cells within the tumour has been shown to be a good predictor of tumour progression in colorectal carcinoma Consequently, tumour-infiltrating inflammatory cells have been shown to induce and help sustain tumour angiogenesis, stimulate cancer cell proliferation, facilitate tissue invasion and support the metastatic dissemination and seeding of cancer cells Direct links exist between the gut microbiota and gastrointestinal cancer development via the modulation of inflammation and immune function.
TLRs, the key regulators of inflammatory signalling, mediated by MYDdependent and MYDindependent pathways, might promote carcinogenesis by mediating pro-inflammatory, anti-apoptotic, proliferative and pro-fibrogenic signals in either the tumour microenvironment or tumour cells themselves Fig. An association between positive TLR gene expression and increased TLR protein levels in blood cells was observed in human colon carcinogenesis Similarly, Lu et al. It is important to note, however, that TLRs exert a dichotomous role in cancer : the magnitude and duration of receptor activation might have a critical effect on outcome, whereby chronic low-grade TLR activation might favour a tumour-promoting pro-inflammatory state, whereas high-level TLR activation might promote an antitumour response.
Indeed, the high expression of TLRs by antigen-presenting cells, including dendritic cells, and their ability to induce antitumour mediators such as type I interferon are the reasons why TLR antagonists are considered in tumour therapy in order to convert the often-tolerant immune response towards an antitumour response. Conversely, TLRs are also increasingly recognized as regulators of tumour-promoting inflammation and promoters of tumour survival signals For example, TLR4 or MYD88 deletion reduces colon cancer development in mice , , , , whereas overexpression of TLR4 increases colitis-associated neoplasia Activation of MYD88 has also been shown to promote colorectal cancer development in spontaneous and carcinogen-induced models of intestinal tumorigenesis by signalling through the IL receptor One study showed opposite results regarding TLR4 overexpression by finding a reduction in colorectal cancer tumour load via increased tumour cell apoptosis The data also favour a tumour-promoting role of TLR4 in the liver and pancreas , , Others showed that TLR4 was required for hepatocellular carcinoma HCC promotion, where it mediates increased cell proliferation and prevents apoptosis Tumour-promoting effects of TLR4 in pancreatic cancer have been described to be mediated by bone marrow-derived cells Interestingly, it has been demonstrated that mice lacking TLR4 signalling were protected against diet-induced obesity, and mice lacking MYD88 specifically in the intestinal epithelial cells were partially protected against diet-induced obesity, inflammation, gut barrier dysfunction and eventually inflammation 52 , In the latter study, the gut microbiota from mice lacking intestinal epithelial MYD88 protected germ-free recipient mice against fat-induced metabolic disorders and inflammation, suggesting a major role for the gut microbiota in diet-induced obesity Deletion of NOD1 or NOD2 in mice resulted in an upregulation of inflammatory cytokines and intestinal tumour formation , Interestingly, data also suggest that during diet-induced obesity, peptidoglycan sensing by NOD2 is key for maintaining gut barrier function More precisely, it has been shown that NOD deletion increases gut mucosal bacterial colonization, metabolic inflammation and insulin resistance Taken together, these data again suggest the strong similarities between gut microbiota signalling pathways in both obesity-related inflammation and cancer development.
The most common association is in ulcerative colitis leading to colorectal cancer , , in which the gut barrier alteration and the different inflammatory and immune factors contribute to cancer development. In addition to the close relationship among microbial factors in inflammatory pathways, the gut microbiota exerts effects at distant anatomical sites, such as the liver, which receives nutrients but also microbial components coming from the gastrointestinal tract discussed later directly via blood from the portal venous system.
Indeed, the translocation of bacterial components such as LPS has also been linked with liver cancer , , , thereby explaining why an organ that does not contain a known microbiota might also be affected by the gut microbiota For instance, although also associated with LPS, pancreatic cancer seems to be mostly linked with LPS coming from the oral cavity , , strongly suggesting that the role of the microbiota in carcinogenesis is organ-specific but linked to similar triggers, such as LPS Fig.
However, all these findings must also be put into the larger context of bacterial metabolites. Thus, the next part of this Review focuses on mechanisms other than LPS or TLRs, particularly the mechanisms by which specific metabolites produced by the gut microbiota might affect gastrointestinal cancers. Whether microorganisms play a direct or indirect part in colon cancer development has been debated Researchers developed a model for colon carcinogenesis that highlighted the role of some bacteria as drivers and others as passengers in colon cancer carcinogenesis , , , Pathogenic driver bacteria with pro-carcinogenic capabilities , such as enterotoxigenic Bacteroides fragilis, Shigella spp.
These opportunistic passenger bacteria, including Fusobacterium spp. With respect to the obesity-specific microbiota, the passenger F. Beyond the direct effect of the gut microbiota on carcinogenesis, mediated by activation of TLRs 11 , , a protective role of SCFAs produced by bacteria in the intestine has been described. SCFAs are suggested to be less present during obesity , Different studies have observed a lower abundance of several butyrate-producing bacteria in faecal samples from patients with T2DM than in samples from healthy individuals, suggesting a protective role of butyrate in obesity-related metabolic disorders , As mentioned, SCFAs are derived from bacterial fermentation and metabolism of undigested carbohydrates and dietary fibres 15 , The role of SCFAs, particularly butyrate, in colon cancer has been extensively studied, and its tumour suppressive functions are caused by intracellular actions, notably, inhibition of histone deacetylases One study showed that GPRA signalling promotes anti-inflammatory properties and decreases colorectal cancer development in an inflammation-associated colon carcinogenesis model by enabling colonic macrophages and dendritic cells to induce differentiation of T reg cells and ILproducing T cells , T reg cells have indeed been shown to increase IL expression, which in turn suppresses intestinal inflammation Interestingly, GPRA is shown to be highly expressed in healthy human colon tissues but silenced in human colon carcinoma cells Restoration of GPRA expression in colon cancer cells induces apoptosis in the presence of butyrate Fig.
A link in colon carcinogenesis with the gut microbiota has been suggested in antibiotic-treated mice that showed a modified gut microbiota concomitant with increased GPRA-dependent carcinogenesis Indeed, recurrent exposure to certain antibiotics might be associated with cancer risk at specific organ sites, including the colon, stomach and pancreas By contrast, other authors reported a decrease in colon tumour burden in an experimental model after exposure to vancomycin, metronidazole and streptomycin and hypothesized that the reduction in tumour burden observed in their study was due to the initial relative abundance of both the genus Lactobacillus and the family Enterobacteriaceae By studying the bacterial populations within the gut in the context of health and disease, researchers will continue to gain important insights into the possible roles of the microbiota in disease development However, only a butyrate-supplemented diet was shown to to increase T reg cell numbers in the colon , Interestingly, T reg cells have also been shown to be able to regulate obesity-associated inflammation and host metabolism , , ; therefore, it is tempting to speculate that the development of gastrointestinal cancers associated with obesity might also be linked with T reg cells and microorganisms.
Restoration of GPR43 expression in HCT8 human colonic adenocarcinoma cells induces G0—G1 cell cycle arrest and activates caspases, leading to increased apoptotic cell death after propionate or butyrate treatment It was also shown that GPR43 suppresses inflammation-associated colon carcinogenesis and plays a part in dietary fibre-mediated promotion of Bifidobacterium spp. Consequently, administration of Bifidobacterium spp. The therapeutic relevance of the modulation of the receptors for cancer therapy still needs to be established. Using experimental rodent models and case—control human studies, diets rich in fibre have been shown to be protective in the development of colorectal cancer As stated, butyrate is an important energy source for the colonic mucosa and has a role in the epigenetic control of gene expression while also functioning as a mediator of anti-inflammatory responses, in the maintenance of the intestinal barrier integrity and in the protection against oxidative stress 28 , Importantly, and despite the plethora of experimental data describing butyrate in cancer prevention, the published literature remains inconclusive on the role of butyrate in colon cancer versus healthy tissue ; this lack of consensus is probably explained by variations in the amounts of experimental butyrate used in different studies, differences in the type of fibre assessed and the fact that measurement of butyrate concentrations in the colon is indirect Although subsequent reports reveal a protective role of microbial-produced butyrate against colon cancer development, the data are still mostly correlative Butyrate has paradoxically been shown to stimulate proliferation in normal colonic epithelial cells in vitro , which raises concerns of its role in interacting with certain genetic backgrounds to influence colon cancer development.
Thus, it is important to consider not only the type of bacterially derived metabolite produced in the colon but also how this metabolite is interacting with host genetics The role of butyrate as a protector or promoter of colon cancer is therefore not simple to address. A large body of evidence has shown that HCC is associated with obesity The gut microbiota has been shown to contribute to NAFLD development and the dysbiosis that influences the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host immune system and other cell types , However, the gut microbiota has also been linked with the onset of inflammation, which is the major characteristic of NASH As described earlier, high-fat diet feeding increases intestinal permeability and systemic LPS levels 52 , Currently, the alteration of gut barrier function is considered the major cause of NASH and is also probably the main reason for the progression of liver diseases and eventual HCC , Fig.
It is also clear that LPS-induced carcinogenesis in the liver might occur by different mechanisms, such as via LPS—TLR4 signalling in the promotion of fibrosis but also via the regulation of specific mitogenic factors , The specific mechanisms by which bacteria and metabolites contribute to HCC have been extensively reviewed by Yu and Schwabe Of interest, it has been suggested that in the gut microbiota of both animals and humans with obesity, there is an increased ratio of the Gram-positive Firmicutes to Gram-negative bacteria , , Besides the direct role of inflammatory factors such as LPS, data suggest that the altered microbiota composition observed during obesity also largely influences the metabolization of specific bile acids for example, deoxycholic acid; reviewed elsewhere and eventually hepatocarcinogenesis.
Indeed, deoxycholic acid is known to cause DNA damage through ROS production , and DNA damage is a critical inducer of the senescence-associated secretory phenotype SASP , which in turn leads to the secretion of inflammatory and tumour-promoting factors in the liver Similarly, the hepatic translocation of obesity-induced lipoteichoic acid, a component of Gram-positive gut microorganisms, promotes HCC development by enhancing the SASP of hepatic stellate cells.
Interestingly, in mice, the link between microorganisms, obesity and HCC has also been proposed to be transmitted from generation to generation Fig. Poutahidis et al. They also found that transferring the gut microbiota from high-fat-diet-treated mice into female germ-free mice was associated with an increased rate of liver cancer in the offspring of these mice Obesity and T2DM are not only associated with low-grade inflammation of gut origin; evidence also suggests that periodontal diseases an inflammatory disease of the oral cavity owing to bacteria are also associated with the development of overweight and insulin resistance , , , , One hypothesis for these findings is that obesity-associated high plasma levels of TNF can lead to a hyperinflammatory state, increasing the risk of periodontal disease, meaning that adipocyte production of pro-inflammatory cytokines is a pathogenic factor linking obesity and periodontal infections , A positive association of periodontitis with pancreatic cancer has been observed in large cohort human studies , , , as reviewed by Michaud and Izard Antibodies to various oral pathogens were related to the risk of pancreatic cancer in a large prospective cohort study involving a 9-year follow-up the European Prospective Investigation into Cancer Cohort The authors observed a greater than twofold increase in the risk of pancreatic cancer when high levels of serum antibodies to a pathogenic strain of Porphyromonas gingivalis were observed at baseline In line with this finding, a prospective study identified that the presence of oral pathogens, P.
A high amount of Fusobacterium spp. Although those studies suggest that P. In animal models, P. One study has also assessed variations of the oral microbiota in patients with established pancreatic cancer versus that in healthy individuals However, an independent study did not confirm variations of these two bacteria and rather found a significantly higher ratio of Leptotrichia spp. In , a potential link between the gut microbiota and pancreatic cancer was suggested.
Ren et al. These features perfectly fit with the profile of metabolic alterations and the altered microbial ecosystem found during obesity , , Evidence suggests that obesity increases the risk of developing cancer.
Several studies have established a link between the development of adiposity and the creation of microenvironments that are favourable for tumorigenesis and metastatic progression. However, the development of obesity and gastrointestinal cancers is also characterized by a state of low-grade inflammation. The origin of this inflammation remains a matter of debate; nevertheless, data have linked the composition of the gut microbiota and its metabolic activity with the onset of gastrointestinal cancers.
Data also show that specific gut microorganisms that produce SCFAs or reinforce gut barrier function are key elements that constitute putative novel therapeutic targets. Indeed, the leakage of microbial components such as LPS constitutes a common mechanism linking obesity with gut microbiota composition and different types of gastrointestinal cancer. Moreover, studies point towards the metabolic activity of the gut microbiota producing butyrate or propionate or altering bile acids as a key mechanism leading to the progression of colon and liver cancer. Thus, the overall effect of the gut microbiota and its metabolic activity on the onset of obesity and cancer is still under the scrutiny of numerous research teams.
Nonetheless, in light of the advances made in this field, novel therapeutic approaches for either restoring the abundance of specific microorganisms or targeting specific receptors for microbial ligands such as GPRA or GPR43, mechanisms that both act on immune responses, might be designed and proposed. Finally, the gut microbiota is a seducing area of research to understand the mechanisms involved in the onset of obesity and gastrointestinal cancers; however, it is important to highlight that there is no one-size-fits-all solution to target such complex diseases.
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Editors view affiliations Andrew J. Dannenberg Nathan A. Front Matter Pages i-xiii. Obesity, Inflammation, and Insulin Resistance. Lesley G. Ellies, Andrew Johnson, Jerrold M. Pages Inflammasomes and Obesity. Lyon, Nan Zhang, Helen Y. Wang, Rong-fu Wang et al. Inflammation, Obesity, and Colon Cancer. Obesity, Inflammation, and Breast Cancer. Neil M. Iyengar, Patrick G. Morris, Clifford A.