In the present study of postmenopausal women, greater intake of total fiber, soluble fiber and insoluble fiber was related to lower plasma concentrations of IL-6 and TNF-α-R2, but not hs-CRP. Results suggest that IL-6 and TNF-α-R levels may be more sensitive to dietary fiber intake than hs-CRP levels in postmenopausal women. A growing body of evidence connects inflammation with increased risk for atherosclerosis [1
], type 2 diabetes [11
], and cancer [14
], but much less is known about the role of diet in inflammation. Most studies to date have focused on the relationship between hs-CRP and diet as well as other lifestyle variables, however, two previous studies have found that IL-6 and TNF-α levels may be stronger predictors of incident cardiovascular events than hs-CRP level [43
]. There is an emerging distinct role of TNF-α-R2 signaling in chronic inflammatory conditions [25
], including diabetes [13
]. The current study focuses on the effect of diet on the inflammation markers IL-6 and TNF-α-R2, which suggests that further interventional studies are needed.
It has been proposed [45
] that dietary fiber may inhibit inflammation through its effects on lowering glycemia [24
]. In a small clinical trial, Gonzalez and colleagues demonstrated that hyperglycemia increases TNF-a release from mononuclear cells in women with polycystic ovary syndrome [47
]. In a laboratory study, monocytic cells were cultured in the presence of 5.5 mmol/l (normal) or 15 mmol/l (high) glucose and mannitol. Secreted IL-6, intracellular IL-6, and IL-6 mRNA were found to be significantly increased with hyperglycemia (P < 0.001) [48
]. In addition, Qi and colleagues found that diets high in fiber may increase plasma adiponectin concentrations in diabetic patients [49
] and adiponectin has been found to have profound anti-inflammatory effects [50
We did not find an association between dietary fiber intake and hs-CRP in the current study, which is in contrast to other studies that examined this association in mixed gender samples [20
]. In an analysis of 1999–2000 NHANES data from both men and women, with 67% of the study population <56 years, King and colleagues [21
] found that subjects in the highest quartile of total fiber consumption had a lower risk of elevated hs-CRP than did subjects in the lowest quartile (OR: 0.58; 95% CI: 0.38, 0.88). Our group previously reported an inverse association between hs-CRP and total fiber, soluble, and insoluble fiber intake in a healthy adult sample that was largely Caucasian, 48% female, and had a mean age of 48 years [22
], with an average hs-CRP level of 1.8 mg/L. In a recent clinical trial of 28 women and 7 men (averages age 38 years old), increased fiber intake, either through a diet naturally high in fiber or through fiber supplementation, was associated with significant decreases in hs-CRP levels [23
].The study population in the present study was older (mean age = 62 years) and exclusively female, with an average hs-CRP of 2.0 mg/L which may account for discrepant findings. Additionally, Hs-CRP may differ by menopausal status, however, a recent study did not support this hypothesis [51
]. Future studies should further examine gender, age, and ethnic differences in these associations.
Potential mechanisms for the found association between IL-6 and TNF-α-R2 with dietary fiber intake, in the absence of an association between dietary fiber and hs-CRP, could be that IL-6 and TNF-α are inflammatory cytokines that regulate inflammatory marker CRP [13
], therefore, any dietary influence would first influence IL-6 and TNF-α and affect CRP indirectly. It also could be that IL-6 and TNF-α-R2 are more sensitive to dietary fiber increase than hs-CRP.
The current study suggests that high fiber diet might be one way to reduce inflammation and therefore reduce diseases that are associated with increased inflammation. The identification of dietary factors that reduce inflammation could have significant public health implications for the prevention of diabetes mellitus, cardiovascular disease, and metabolic syndrome.
Our study had several strengths. First, the total sample size was large and from a national study recruited women across the United States. Second, few studies have examined the role of dietary fiber in relation to markers of inflammation, and especially data in postmenopausal women are lacking. Third, we analyzed the associations of dietary fiber with hs-CRP, IL-6 and TNF-α-R2 by ethnicity. Fourth, the FFQ used in this study was well validated and provides estimation of many nutrients including fiber. Finally, several covariates were controlled for in the analyses including energy and alcohol intake, BMI, arthritis status, smoking, and use of hormone therapy.
This study also had several limitations worth noting. First, the weaker associations observed between fiber and pro-inflammatory cytokines in ethnic minorities could be due to the smaller sample size available for Asian (n=153), African-American (n=570), and Hispanic (n=228) women. To confirm ethnic differences in the association, studies with larger samples of minority participants are needed. Second, presence of active infections would reduce the association of between dietary fiber and inflammatory markers, though we did exclude 205 women with hs-CRP values greater than 10 (indicating active infection). Although we controlled for arthritis status in analyses, other chronic infections could not be identified in this study, which could impact the levels of inflammatory markers. Third, direct TNF-α measurement was not possible using frozen WHI specimen, however, TNF-α signals through at least 2 known cell surface receptors, namely TNF-α-R1 and TNF-α-R2. One study demonstrated a strong positive correlation between TNF-α-R2 and TNF-α mRNA expression level in human adipose tissue and suggested that these two moieties may be regulated by the same signal [52
]. Thus, we used TNF-α-R2 as a measure of TNF-α. Fourth, role of other unmeasured factors not included in study and/or analyses such as the use of aspirin and lipid lowering medications, which are also associated with markers of inflammation, cannot be ruled out. However, women with prior history of cardiovascular disease and diabetes were excluded from study sample to minimize the impact of these factors on analysis. In addition, women with these chronic diseases are more likely to have changed their diet [53
], and this could bias the results toward null. Fifth, prevalence of smoking was low (only 5.7% smoking) and average minutes of exercise was high (over 150 minutes a week) in the study population. These characteristics may affect generalizability of the study. As we also excluded women with prior history of cardiovascular disease and diabetes, our results can only be generalizeable to apparently healthy postmenopausal women. Sixth, there is limitation on FFQ to measure diet with possible of under-reporting [55
]. We adjusted total energy intake in the analyses, Willett has demonstrated some of the underreporting bias could be corrected with energy adjusted model [57
]. Seventh, only 20% of the sample population reported hormone use and 80% were unknown, which limited our ability to control effect of hormone use when examining fiber-inflammation relationship. Finally, hs-CRP measures have been shown to be variable [58
], potentially underestimating the potential fiber-inflammation relationship. Longitudinal measures of hs-CRP, IL-6 and TNF-α-R2 may be needed to examine changes in these markers in relation to diet.