Obesity-associated cancer risk: The role of intestinal microbiota in in the etiology of the host pro-inflammatory state

Abstract

Obesity increases the risks of many cancers. One important mechanism behind this association is the obesity-associated pro-inflammatory state. Although the composition of the intestinal microbiome undoubtedly can contribute to the pro-inflammatory state, perhaps the most important aspect of host-microbiome interactions is host exposure to components of intestinal bacteria that stimulate the inflammatory reactions. Systemic exposures to intestinal bacteria can be modulated by dietary factors by altering both the composition of the intestinal microbiota as well as absorption of bacterial products from the intestinal lumen. In particular, high fat and high energy diets have been shown to facilitate absorption of bacterial lipopolysaccharide (LPS) from intestinal bacteria. Biomarkers of bacterial exposures that have been measured in blood include LPS-binding protein, sCD14, fatty acids characteristic of intestinal bacteria and immunoglobulins specific for bacterial LPS and flagellin. The optimal strategies to reduce these pro-inflammatory exposures, whether by altering diet composition, avoiding a positive energy balance or reducing adipose stores, likely differ in each individual. Biomarkers that assess systemic bacterial exposures therefore should be useful to optimize and personalize preventive approaches for individuals and groups with specific characteristics, and to gain insight into the possible mechanisms involved with different preventive approaches.

PRO-INFLAMMATORY PATHWAYS ASSOCIATED WITH OBESITY INCREASE RISK OF CANCER

Obesity is one of the factors that increase the risk of many cancers. The data is especially compelling for cancers of the endometrium, kidney, colorectum, esophagus, pancreas and postmenopausal breast cancer (1). More recently, gall bladder, liver, thyroid and ovarian cancers have been identified to be among those cancers strongly affected by obesity (2, 3). Obesity-related cancer risks do vary by factors such as ethnicity, sex and menopausal status, but nonetheless substantial increases in risk have been observed with body mass index (BMI) increases above the normal weight range (2). For colorectal cancer, risk increases with obesity in a dose-dependent fashion, with a risk that is elevated by 32–41% in obese versus normal weight individuals (4, 5).

Several mechanistic pathways are identified to be operative in this link between obesity and cancer. These include hormonal alterations (e.g. leptin, estrogen), induction of insulin-signaling pathways and activation of pro-inflammatory pathways (6). More and more research is turning to the role of activated pro-inflammatory pathways in mediating obesity-associated risks of not only cardiovascular diseases and diabetes, but also of cancer. Indeed, experimental data supports the role of inflammation in the development of many cancers (7). Although immune surveillance does have a role in eliminating tumor cells, chronic, low-level activation of immune pathways also can alter the homeostatic state to stimulate tumor growth.

Cytokines, acute phase proteins and cancer risk

Excess body fat accumulation results in polarization of immune cells, resulting in generation of pro-inflammatory cytokines and chemokines (8). This activated immune state has been characterized by presence of “classically activated”, termed M1, macrophage-secreted factors, increased pro-inflammatory T-helper cell type 1 (Th1) cytokines, and decreased Th2, immune-regulatory cytokines (9–13). Among the many functions of cytokines, they signal production of acute-phase proteins secreted by the liver during injury or infection, including C-reactive protein (CRP), serum amyloid SAA. Interestingly, one of the functions of CRP is to bind to components of microorganisms to assist in their removal by immune cells (14, 15).

Elevated serum CRP is associated with elevated risks of several cancers, including that of the colon and breast (16–19). In the prospective European Prospective Investigation Into Cancer (EPIC) study, elevated CRP was associated with elevated risk of colorectal cancer (20). A pro-inflammatory state also plays an important role in survival from cancer, and an elevated pro-inflammatory state is a risk factor for breast cancer recurrence and survival (21–29). In a meta-analysis of ten studies, relatively high levels of CRP were associated with reduced overall survival, disease free survival and breast cancer specific survival (23). CRP also was predictive of cancer survival when measured at diagnosis or 2–3 years post diagnosis (21, 25, 28). Unlike CRP, cytokines such as IL-6 have not been as consistently associated with cancer risk (18, 19, 30, 31).

Eicosanoids and cancer risk

In addition to cytokines, eicosanoid production may be of interest as a more rapidly-responsive biomarker of the pro-inflammatory state of tissues since cytokines can take weeks to be fully manifest via induction of T cells (10). Eicosanoids are bioactive molecules formed from the metabolism of arachidonic acid. Eicosanoid formation is inextricably linked with activation and de-activation of immune cells. For example, inhibition of cyclooxygenases that produce eicosanoids using indomethacin decreased the pro-inflammatory cytokines interferon γ and tumor necrosis factor α, and increased the immuno-regulatory cytokine interleukin (IL) 10 (32).

One of the most widely studied eicosanoids with regard to carcinogenic processes is prostaglandin E₂ (PGE₂). Increased PGE₂ concentrations have been linked with increased risk of many cancers, including that of the colon, breast and skin (33–35). Eicosanoids, and especially PGE_2, have critical roles in the initiation and progression of cancer (36–38). Eicosanoids can also indirectly affect cancer growth. For example, PGE₂ induces aromatase expression, which is relevant to survival from postmenopausal breast cancer (39), in addition to the more direct effects of PGE₂ on driving breast cancer growth and metastases (33, 40, 41). Eicosanoids can be measured in tissues, but in epidemiological studies stable metabolites have more often been measured in urine. Increased concentration of the prostaglandin E₂ (PGE₂) metabolite in urine was positively predictive of increased breast cancer risk and of breast cancer metastases (42–45). Non-steroidal anti-inflammatory agents, that inhibit cyclooxygenases and PGE₂ formation, decreased breast cancer recurrence in overweight and obese women (46).

In the colon, pro-inflammatory changes characterized by increased colonic production of PGE₂ also have been shown to increase risk of cancer (47–49). PGE₂ has an important repair role for resolving frank inflammatory conditions such as colitis, but in normal tissue, low-level, chronic elevated PGE₂ promotes carcinogenic processes (50, 51). PGE₂ mediates colonic crypt cellular expansion that can subsequently result in adenoma formation (52–56).

Data in human colon tissue is more sparse than in animal models, but one study of subjects with a history of polyps showed that PGE₂ in the rectal mucosa was significantly increased with increasing BMI (57). In another study, expression of cyclooxygenase-2, and inducible form of the enzyme, was higher in the colonic mucosa adjacent to tumor of obese versus normal weight subjects (58).

Beneficial effects of weight loss on reversing obesity-associated inflammation

This obesity-associated, pro-inflammatory state likely is sensitive to the energy balance that drives metabolic processes towards either lipid synthesis or lipid oxidation. This could be one reason why pro-inflammatory states are not always associated with obesity; conversely, a pro-inflammatory state can occur in lean individuals (59, 60). A modest weight loss, in which case many obese individuals will remain in the obese state, appears sufficient for reducing inflammation. A weight loss of at least 5–10% of initial weight has been shown to be clinically significant and effective for eliciting beneficial effects on circulating adipokines and cytokines (61–63). Furthermore, 10% weight loss (of baseline weight) reduced cytokine concentrations 25–57% and down-regulated proteins involved in PGE₂ synthesis in rectal biopsies from 10 obese women (64).

The trajectory of weight change may therefore be important in governing the inflammatory state. Weight loss decreases systemic inflammation, and multiple studies have shown that serum CRP is linearly associated with weight change (61, 65, 66). In rodent models of cancer, diet-induced obesity increased and calorie restriction decreased colon tumorigenesis with analogous effects on systemic inflammation (67).

Perspective on the etiology of the obesity-associated pro-inflammatory state

In summary, the relationships between weight change, obesity and pro-inflammatory states are well described in the literature, but little is known about the etiology of the pro-inflammatory changes. One important factor may be increased systemic exposure to intestinal bacteria stemming from either the nature of the obesity-associated microbiome and/or to increased intestinal permeability. Biomarkers of bacterial exposure would be useful in gauging to what extent the intestinal microbiome plays in the obesity-associated pro-inflammatory state. If weight loss and/or avoiding a positive energy balance decreases bacterial exposures, this has implications not only for risk of colorectal cancers but also for risk of other cancers that are affected by obesity.

OBESITY INCREASES SYSTEMIC EXPOSURES TO INTESTINAL BACTERIA

Role of intestinal microbial composition

A number of studies have evaluated the effects of obesity on the composition of the intestinal microbiota. These studies have failed to reach a consensus on the effects that obesity has on the intestinal microbiome. An initial observation that obesity affects the relative abundance of Firmicutes (Gram-positive) and Bacteroidetes (Gram-negative) taxa has not been replicated, but many of these studies were limited in sample size and often failed to separate the effects of obesity and diet composition (68–83). For example, taxa in the Bacteroidetes phylum utilize fiber for growth and therefore would be expected to be decreased with high fat, low fiber diets (84, 85).

A re-analysis of data across published studies indicates that the relative abundance at the phylum level of Firmicutes and Bacteroidetes is more highly dependent on the study methodology rather than on true differences by the presence of obesity (86). A recent study found that the ratio of Firmicutes to Bacteroidetes was elevated in obese persons with metabolic syndrome relative to those without metabolic syndrome, suggesting that it may be important to look beyond BMI values (87). There has also been variability in findings of obesity-associated differences between animal models, and between humans and mice (81, 88, 89).

Lipopolysaccharide exposures

Although the composition of the intestinal microbiome is undoubtedly important, perhaps the most important aspect of host-microbiome interactions is host exposure to bacterial components that stimulate the immune system. Many components of bacteria are potentially immunogenic and this has been known for quite some time (90). Newer findings indicate that metabolites of bacteria should be considered. For example, microbial vitamin B metabolites are immunogenic (91).

Both Gram negative and Gram positive bacteria can induce an immune response, but the immunological response is greater with Gram negative bacteria (92). The cell wall of Gram negative bacteria contains lipopolysaccharide (LPS) that is an endotoxin. LPS absorption from he gastrointestinal tract likely is a critical etiological agent in obesity-associated inflammation and has been studied more extensively than other bacterial antigens (93–96). Endotoxin has been detected in human serum and is associated with metabolic syndrome (97). The inflammatory response to LPS includes production of cytokines and chemokines, and this is likely mediated by production of eicosanoids such as prostaglandin E₂ (98, 99).

Of relevance to colon cancer, LPS promotes colon cancer cell invasion into the extracellular matrix through the TLR4 pathway (100). This response in the colon appears to be mediated via initial interaction of LPS with soluble CD14 and LPS binding protein (LBP) that concentrate LPS at the cell surface. LPS exposure also induces production of LBP (101). This is followed by activation of toll-like receptor 4, TLR4 (102, 103). Both TLR4 and CD14 are needed for initiating the inflammatory response to LPS since knockout of either gene in mice resulted in resistance to the adverse effects of a high fat diet on induction of obesity and inflammation (104, 105). Effectors of TLR4 activation are MyD88 and subsequently NFκB, which is a key signaling molecule for the inflammatory response and cytokine production (100, 106–110). The LPS/TLR4/NFκB pathway has been suggested to be a target for colon cancer prevention because of the central role of NFκB in cell proliferation, transformation and tumor progression (107–109).

Flagellin absorption

As compared with LPS, there is much less known about the relationships of obesity with exposures to flagellin, another marker of bacterial exposures. Flagellin in serum was identified to be elevated in patients with Crohn’s disease (111). Bacterial flagellin is a structural protein in flagellated bacteria, which include both Gram negative and Gram positive species. Flagellin is recognized by both TLR-5 and the NLRC4 inflammasome, which subsequently activate of NF-κB and caspase-1, respectively, to result in production of inflammatory cytokines (112, 113).

DIET MODULATES ABSORPTION OF BACTERIAL COMPONENTS

Dietary factors potentially could alter both the composition of the intestinal microbiota as well as absorption of bacterial products from the intestinal lumen. Ingested foods can directly alter the intestinal environment not only in the small intestine but also in the colon where the majority of intestinal microbiota reside. Undigested fiber that reaches the colon can be digested, in part, by colonic bacteria to produce short-chain fatty acids, which have beneficial effects on colon health (114). In addition, although most nutrients are absorbed in the small intestine, some fat does reach the colon. About 5% of dietary fats are excreted in feces, and increased dietary saturated fat or dietary fiber increases fat excretion (115, 116). Colon does have nutrient absorptive capacity (117, 118), and it is possible that diet affects absorption of bacterial products in the colon as well as in the small intestine.

High fat, high energy diets

High fat and high energy diets facilitate absorption of bacterial LPS from intestinal bacteria (93–96, 119, 120). A high fat diet results in increased intestinal permeability and decreased antimicrobial peptides in the protective mucin layer (121). Studies have been conflicting as to whether or not high fat diets favor growth of Gram negative bacteria (121, 122). Interestingly, even a single high-fat meal increases postprandial endotoxemia (119, 123, 124). It is often difficult to separate the effects of a high fat diet from the effects of obesity discussed previously since energy dense diets tend to result in a positive energy balance and weight gain. Accordingly, it is not clear if increased LPS levels are due to a high fat diet per se or to a positive energy balance that results in weight gain. In one study of healthy men, circulating LPS was increased with increased dietary energy, but not independently with other macronutrients (93). Interestingly, there is rodent data that males may be more susceptible to the pro-inflammatory effects of a high fat diet than females (125).

Once exposure to LPS occurs, this can exacerbate the effects of an obesogenic diet. A low dose of LPS in animals can mimic the effects of a high fat diet on inducing obesity (104). The microflora also can alter energy harvest from the intestinal contents to help propagate the obese state (75, 126, 127). This makes the relationship between the microbiome and obesity bidirectional.

Types of dietary fat

In addition to the obesogenic effects of a high-fat diet, specific types of dietary fat can have disparate effects on exposure to intestinal bacteria. In mice, a high-fat saturated fat diet, but not a high omega-6 fatty acid diet, increased colonic permeability and mesenteric fat inflammation (128). The high saturated-fat diet was associated with decreased hydrogen-sulfide producing bacteria, and a large portion of the variability in intestinal variability could be accounted for by hydrogen-sulfide producing bacteria (128). Fish oil reduced the inflammation elicited by the high saturated fat diet (128). Fish oils have also been shown to counteract the dysbiotic effects of high omega-6 fatty acid diets under normal conditions, but in the case of frank sepsis fish oils impair the detoxification of LPS (129).

Production of cytokines and chemokines stimulated by bacterial exposures also is magnified by saturated fatty acids, and each fatty acid appears to affect distinct mechanisms (130). Further, LPS exposure induced cyclooxygenases and production of PGE2 both in vitro and in vivo (131, 132). Conversely, high fiber diets are expected to reduce LPS exposures via alteration of microbial composition, improvement in the mucosal barrier function through facilitating tight junction assembly and reduction in epithelial permeability through production of short chain fatty acids (133–136). Likewise, dietary antioxidants can counteract the adverse effects of LPS exposure in colon smooth muscle cells (137).

Dietary patterns

The interactions of obesity and certain types of dietary patterns are known to increase inflammation. Many studies have suggested that a Western diet (high n6 fats, low plant foods, low fiber) is pro-inflammatory and conversely that a Mediterranean diet (high MUFA, high n3/n6 ratios, high fruit, vegetables and whole grains) has anti-inflammatory effects (138). Importantly, a Mediterranean diet also appears to prevent weight gain (139, 140). In our studies, a Mediterranean diet accompanied by a very small weight loss resulted in reduced serum CRP (141). Whether or not this is mediated by changes in the microbiome is not known. More information on the role of diet composition with and without weight loss would be especially important for long term recommendations since a negative energy balance cannot be sustained indefinitely.

MUCIN PRODUCTION CAN MODULATE EPITHELIAL EXPOSURES TO INTESTINAL BACTERIA

In most studies, microbiota are typically quantified in excreted stool, or in the ceca of rodents. The microbiota, however, differ along the length of the intestine (142, 143). The taxa present in the lumen also may differ from those adhering to the mucin layer. Mucin in the intestine provides an epithelial barrier, but it is also a niche for bacterial growth (144, 145).

The bacterial species present in the mucin layer lining the luminal epithelium differ from those in the stool and were suggested to be present in horizontal layers (146). Other studies have suggested that species such as Bacteroides thetaiotaomicron can shift from degrading dietary fiber in the lumen to degrading mucin when dietary fiber is low (147–150). A higher prevalence of oxygen-tolerant species (vs. strict anaerobes) has been noted in the intestinal mucosa versus that in the lumen (151, 152). Finally, colonic mucin does appear to change in malignancy (153), but changes in mucin also may precede malignancy. In mice, a defective intestinal barrier function facilitates absorption of bacterial products, triggering and inflammatory environment that promotes colon tumors (154).

The amount of mucin produced can be greater in obese than lean subjects but the balance of mucin production to mucin degradation is what ultimately determines the integrity of the intestinal barrier. Receptors for the obesity associated hormone leptin are present in the colon, and activation of this receptor increases mucin and cytokine production (155–158). Pro-inflammatory stimuli such as cytokines also increase mucin production initially, likely as a defense mechanism (155, 159–162). Expression of mucin-encoding genes increases early in infection (163). This then would provide a niche for growth of mucin-degrading microbiota near the luminal, epithelial surface (144, 164), and eventually might lead to depleted mucin and an impaired mucosal barrier.

Interestingly, secretion of mucus is the initial colonic response to both low-level LPS and increased leptin, an obesity-associated hormone (155–158, 165–167). Increased mucin in turn should favor growth of mucin-degrading microbiota in close proximity to the epithelial cells. Elevated LPS in obesity therefore is not necessarily due to a compromised mucin layer such as that seen in frank inflammation, and it provocatively may result from increased mucin production and/or changes in the microbiota within the mucin. Notably, the mucin contains peptides such as resistin like molecule-β (RELMβ) that can further stimulate the pro-inflammatory response in response to the presence of bacteria (168–172).

Although some Gram negative Enterobacteriaceae have been found to be increased in obesity, one Gram-negative species that is a mucin-degrading bacterium in the human colon, Akkermansia muciniphila, is decreased in obesity (173, 174). Akkermansia appears to normalize changes in the mucin glycoproteins as well as in antimicrobial peptides that are altered by a high fat diet (174). Akkermansia also was shown to induce expression of regulatory (Th2-like) immune cells (175). In a small study of 16 adults, the relative abundance of Akkermansia was increased in individuals with successful weight loss and weight loss maintenance over two years (87). It should be noted, however, that although the beneficial effects of Akkermansia appear consistent, the studies generally have been small and require confirmation.

BIOMARKERS OF SYSTEMIC BACTERIAL EXPOSURES

LBP and sCD14

There is direct evidence of systemic exposures to intestinal bacteria from animal models. For example, bacteria trans-located into mesenteric fat as determined by presence of the 16S bacterial gene, and this correlated positively with changes in intestinal permeability (128). In order to identify factors that affect systemic exposures to intestinal bacteria in clinical trials, biomarkers of exposures are needed.

LPS is unfortunately difficult to measure in biological samples. The limulus amebocyte lysate (LAL) reactivity assay can be used to measure bacterial LPS, but this assay has been fraught with technical problems when applied to analyses of serum or plasma due to interfering compounds (176, 177). Many studies have therefore quantified LPS-binding protein (LBP). LBP is synthesized not only by the liver but also by adipose and intestinal epithelial cells, and in the intestinal cells LBP production is induced by cytokines (178, 179). Thus LBP represents both LPS load and obesity-related changes in the intestinal barrier and pro-inflammatory pathways.

LBP is the major LPS transporter in blood, and sCD14 serves to buffer the effects of LPS. In the colon, LBP and sCD14 function to concentrate LPS at the membrane toll-like receptor 4 (TLR4). LBP or the LBP/sCD14 ratio therefore has been used as a more reliable marker of LPS exposure in blood than the LAL assay, and this also has advantages over measuring LPS directly due to the short half-life of LPS (180–184). Most studies have utilized measures of LBP alone. LBP binds constituents of both Gram positive and Gram negative bacteria, making it a more general marker of bacterial exposures than the LPS that stems only from Gram negative bacteria (183).

LBP is increased in infection (185), but more subtle inflammatory states such as obesity also increase LBP. Glucose and saturated fatty acids can acutely increase plasma LBP, showing a dietary relationship (123, 180). Elevated LBP is tightly associated with obesity (178, 181, 186). In a Mediterranean dietary intervention, serum LBP was affected by obesity and modest weight loss, but not by 6 months of dietary change per se (187). The interpretation of LBP concentrations, however, can be a complicated and caution is advisable. LBP has a role in detoxifying LPS via an HDL-mediated pathway, and LBP has been shown to protect animals from septic shock (188, 189).

Fatty acids unique to bacteria

Bacteria contain fatty acids with odd numbers of carbon chains, branched chains and hydroxyl groups (190–192). These can be measured at low levels by gas chromatography with mass spectral detection. Accordingly, presence of bacterial 3-hydroxy fatty acids in environmental samples has been useful as an indication of endotoxin contamination (193). Quantitation of these fatty acids in serum would represent total bacterial exposures while the LAL reactivity assay represents only free LPS that is dissociated from the bacterial cell wall (194). A principal advantage of measuring bacterial fatty acids in serum is that this likely is more quantitative than the LAL assay or measures of antibodies to bacterial products.

The most conserved portion of LPS from Gram negative bacteria is lipid A. The lipid A fatty acids do differ by bacterial species, but 3-hydroxy fatty acids are widely distributed in Gram negative bacteria (195, 196). For example, 3-hydroxy 16:0, 3-hydroxy 14:0 and 3-hydroxy i17:0 (15-methyl hexadecanoic acid) are common in several species of Bacteroides fragilis (191, 192). B. fragilis associates with the colonic mucin, which would facilitate absorption, and has been implicated in risk of colon cancer (197–199). Of relevance to their use as biomarkers of bacterial exposures, blood measures of bacterial fatty acids have been shown to reflect the microbes present in the intestinal tract (200).

Quantitation of 3-hydroxy fatty acids also has been useful in clinical studies of infection: bronchial lavage fluid of patients with lung diseases (201); salivary 3-hydroxy fatty acids in periodontitis (202); and serum 3-hydroxy fatty acids in cardiac patients with endotoxemia (203). Importantly, the 3-hydroxy fatty acids in LPS appear to be active in stimulating the immune system (204, 205).

Unlike the 3-hydroxy fatty acids, branched chain (iso-methyl) fatty acids, namely 13-methylmyristic acid (i15:0),14-methylpentadecanoic acid (i16:0), and 15-methylpalmitic acid (i17:0), are common in both Gram negative and Gram positive bacteria (192). In addition to commensal bacteria, another source of iso-methyl fatty acids is endogenous synthesis in the skin, but this does not appear to be operative in other organs (206). Branched chain bacterial fatty acids also are known to be present in the meat and milk of ruminants: beef and dairy constitutes the majority of U.S. intakes of iso-methyl bacterial fatty acids (207). This raises the interesting possibility that iso-methyl bacterial fatty acids could be markers of both intestinal permeability and meat intake, while 3-hydroxy fatty acids are more specific for bacterial LPS.

Antibodies to LPS and flagellin

Flagellins are antigens present on the surface of flagellated bacteria, and flagellins are a major antigenic target of the immune system. Enzyme-linked immunoassays have been developed to quantify specific serum IgG and IgA that are formed in response to flagellin exposures (208, 209). For example, serum flagellin, LPS, or both were detected in most patients with short bowel syndrome, but not in normal control sera, using an ELISA for immunoglobulins specific for flagellin and LPS (210). In patients with colon adenomas, IgA antibodies to bacterial LPS from Escherichia coli and flagellin from Salmonella typhimurium were both increased by obesity, and antibody concentrations were higher in men than women (211).

EVIDENCE THAT SYSTEMIC EXPOSURES TO INTESTINAL BACTERIA INCREASE CANCER RISK

One large study evaluated systemic exposures to intestinal bacteria and colon cancer risk. In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, systemic exposures to LPS from Escherichia coli and flagellin from Salmonella typhimurium, were assessed in prospectively-collected serum using quantitation of immunoglobulins against those antigens (212). There were positive associations of these specific immunoglobulin biomarkers with risk of colorectal cancer in men, but not in women, pointing to sex-based differences in the immune response and/or in the nature of the microbiota (212). The associations in men between immunoglobulins and cancer risk were stronger in those subjects with either obesity, higher CRP concentrations or higher alcohol intakes (212). In another study using the same biomarkers of bacterial exposures, men were identified to have higher intestinal permeability and concentrations of bacterial immunoglobulin biomarkers than women, and in both sexes higher CRP and higher BMI was associated with higher biomarker concentrations (211). In two population-based case-control studies, higher serum antibodies to flagellin were associated with increased colorectal cancer risk (213).

Data is sparse for biomarkers of bacterial exposures in the risks of other cancers, although one might expect that similar pro-inflammatory responses elicited by chronic, low-level exposures to bacteria would increase risks of other cancer as well. In the liver, endotoxin exposure was shown to prevent apoptosis and promote tumorigenesis in rodents (214). In infection-associated cancers the association of cancer and inflammation is more obvious, although it is less likely to be modulated by obesity. The microbiome has a major role in liver cirrhosis and hepatocellular carcinoma (215). Increases in markers of microbial translocation likewise increased risk of AIDS-related lymphoma (216).

SUMMARY AND OUTLOOK

Both diet and the physiological changes resulting from obesity can work together to increase absorption of bacterial products from the intestine. Biomarkers of bacterial exposures have been detected in the blood. These exposures in turn result in a pro-inflammatory response that is evident systemically (Figure 1). The optimal strategy to reduce the pro-inflammatory stimuli, whether by diet composition, attaining energy balance or reducing adipose stores, however, may differ in each individual. Biomarkers that assess pro-inflammatory exposures therefore should be useful tools to optimize and personalize preventive approaches for individuals and groups with specific characteristics, and to gain insight into the possible mechanisms involved with different preventive approaches designed to reduce the inflammatory state.

FIGURE 1.

Overview of processes contributing to pro-inflammatory states and increased cancer risk. Western diets low in plant-based foods and high in saturated fats favor excess energy intakes and obesity. This results in increased absorption of bacterial products that contribute to a chronic, pro-inflammatory state that in turn increases risks of cancer, cardiovascular diseases and diabetes.

Abbreviations

BMI

Body mass index

CRP

C-reactive protein

LAL

limulus amebocyte lysate

LPS

lipopolysaccharide

LBP

lipopolysaccharide binding protein

PGE₂

prostaglandin E₂

Th1

T-helper cell type 1