Dietary Nut and Legume Intake and Risk of Crohn’s Disease and Ulcerative Colitis

Abstract

Background

We investigated the relationship between nut and legume intake and risk of Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

We conducted a prospective cohort study of 223 283 adults from the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (1986-2017), excluding those with inflammatory bowel disease (IBD) at baseline. Food frequency questionnaires were used to calculate nut and legume intake. Inflammatory bowel disease was self-reported on questionnaires and confirmed via blinded record review. Using Cox proportional hazards models, we calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CD and UC according to categories of nut and legume intake.

Results

In over 5 460 315 person-years of follow-up (CD = 371, UC = 481), neither nut nor legume intake was associated with CD or UC risk. Compared to those who never consumed nuts, those who consumed nuts ≥2 times/week had an aHR = 0.96 (95% CI, 0.63-1.47; P_trend = 0.57) for CD and 1.30 (95% CI, 0.92-1.84; P_trend = 0.36) for UC. Compared to those who consumed legumes 0-3 times/month, those who consumed legumes ≥4 times/week had an aHR of 1.26 (95% CI, 0.78-2.04; P_trend = 0.59) for CD and 0.72 (95% CI, 0.44-1.18; P_trend = 0.20) for UC. Baseline BMI modified the relationship between nut intake and CD risk (P_int = 0.03). In those with BMI ≥25, the aHR for CD was 0.14 (95% CI, 0.03-0.56; P = .006) per additional serving/day of nuts compared with 0.88 (95% CI, 0.45-1.74; P = .72) for those with BMI <25.

Conclusions

Nut and legume intake were not associated with CD or UC risk. However, higher nut intake decreased CD risk in overweight or obese individuals. Thus, personalized-risk stratification, rather than generalized dietary recommendations, may be important for IBD prevention strategies.

Key Messages.

What is already known? Nuts and legumes possess anti-inflammatory effects, positively affect intestinal microbiota, and are part of the Mediterranean diet. We investigated the relationship between nut and legume intake and risk of inflammatory bowel disease (IBD).

What is new here? Overall nut and legume intake was not associated with risk for development of IBD. However, higher nut intake decreased Crohn’s disease risk in those with elevated body mass index.

How can this study help patient care? Personalized dietary interventions, rather than generalized dietary recommendations, may be important in future strategies to prevent IBD, though further studies are needed.

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively known as inflammatory bowel disease (IBD), are chronic inflammatory diseases of the gastrointestinal tract with rising global burden. Inflammatory bowel disease develops as a sequence of events, whereby environmental and microbial factors contribute to impaired mucosal integrity, expansion of a disordered host immune response, and ultimately overt intestinal inflammation.¹ Numerous dietary risk factors have been identified for IBD, including fruit, vegetable, meat, and sugar intake.² Additionally, dietary patterns such as the Mediterranean diet have been associated with reduced risk of CD.³ In unaffected first-degree relatives of those with CD, a Mediterranean-like dietary pattern is associated with lower levels of subclinical inflammation and distinct gut microbial composition.⁴

Nuts and legumes are a central component of the Mediterranean diet and are recommended as part of a healthy diet by the American Heart Association (AHA) and the US Department of Agriculture and Department of Health and Human Services (USDA/USDHHA).^5,6 Nuts and legumes are high in dietary fiber and n-3 polyunsaturated fatty acids (PUFAs), which have been linked with decreased risk for IBD,⁷ and have been associated with lower systemic inflammatory markers such as C-reactive protein (CRP) and interleukin (IL)-6.⁸ Nut intake also affects gut microbial composition by promoting short-chain fatty acid–producing species,⁹ and in a mouse-model of colitis, walnut supplementation protected against colonic mucosal injury.¹⁰

Despite evidence of the anti-inflammatory effects of nuts and legumes, to date, no large prospective observational study has investigated the relationship between nut and legume intake and risk of IBD. Thus, in this study, we explored the relationship between dietary nut and legume intake and risk of incident CD and UC in individuals from the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-up Study (HPFS).

Materials and Methods

Study Population

We conducted a prospective cohort study of participants from the prospective NHS, NHSII, and HPFS, which have been previously described.¹¹ The NHS, established in 1976, enrolled 121 700 female registered nurses ages 30-55 years across 11 states, while NHSII, established in 1989, enrolled a younger cohort of 116 429 registered nurses ages 25-42 years from 14 states. The HPFS was established in 1986 and enrolled 51 529 male health professionals ages 40-75 from all 50 US states. All participants completed baseline and biennial questionnaires regarding demographics, anthropometric data, medical history, family history, and lifestyle habits; they were also asked to complete semiquantitative food frequency questionnaires (SFFQs) every 4 years. Follow-up for these cohorts exceeds 85%.^12,13

We included participants who completed a baseline SFFQ in 1986 (NHS/HPFS) and 1991 (NHSII). These participants have been shown to be similar to the original cohort.¹⁴ We excluded participants who had IBD at baseline (n = 141), missing or implausible body mass index (BMI <10 kg/m²; n = 1,484), and implausible total caloric intake (females: <600 or >3500 kcal/day; males: < 800 or >4200 kcal/day). Participants were followed from baseline to development of IBD, death, loss to follow-up, or end of follow-up (NHS: June 1, 2016; HPFS: January 1, 2016; NHSII: June 1, 2017), whichever occurred first.

The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, which considered participants’ completion of questionnaires as implied consent.

Ascertainment of Exposure and Covariate Data

Our primary exposures were cumulative average daily servings of dietary nut and legume intake. We chose to summarize intake data using servings (rather than ounces, cups, or grams) to facilitate clinical interpretability of our results. To obtain these, first, participants reported frequency of intake of servings of individual food items on SFFQs, ranging from “never or less than once per month” to “6 or more times per day.” These frequencies were converted to daily servings for each food item and then summed across categories to reach daily servings of total nut and legume intake. Nut intake included walnuts, peanuts, and other nuts, with a serving size defined as 1 oz or 1 small packet. Legume intake included beans, lentils, peas, lima beans, tofu or soy protein, with a serving size defined as a ½ cup of legumes in baked, dried, or soup form or 1 whole tofu or soy burger. Peanut butter was specifically excluded from nut exposure given the previously reported increased risk of CD with emulsifiers, such as that in peanut butter,¹⁵ which we hypothesized a priori may have the opposite effect of that for nuts alone. Other nut butters were not specifically queried on SFFQs. Food intake from SFFQs has previously been validated against 7-day dietary recall, with moderate correlation for legume intake (eg, Pearson correlation coefficient for beans and peas: 0.34-0.51).¹⁶ Finally, cumulative average of daily intake was calculated at each 4-year SFFQ interval to reduce measurement error and represent long-term dietary patterns.

We used biennial questionnaires to ascertain additional covariates, including body mass index (BMI), nonsteroidal anti-inflammatory drug use (NSAIDs), history of appendectomy, smoking status, physical activity, family history of IBD, alternate healthy eating index (AHEI), and total daily caloric intake using previously described methods (summarized in Supplementary Methods). The AHEI has previously been shown to predict chronic disease,¹⁷ with a high AHEI reflecting a diet rich in fruit, vegetables, and whole grains, and low AHEI reflecting a more “Western” dietary pattern, which has been linked with IBD risk.⁷

Ascertainment of IBD Outcome

Our methods for ascertaining CD or UC have previously been described.¹⁸ Briefly, CD and UC were first inquired on biannual surveys. Participants who reported a diagnosis were then sent additional follow-up questionnaires and were asked for permission to obtain and review medical records. Inflammatory bowel disease was then confirmed via review of medical records by 2 gastroenterologists blinded to exposure information and accepted clinical criteria.^19,20

Statistical Analysis

We used Cox proportional hazards models to calculate unadjusted and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for CD and UC according to categories of cumulative average servings of daily nut and legume intake. These categories were defined based on the distribution of the exposures (nut and legume intake) across the pooled cohort, such that an adequate number of participants and therefore cases would be present in each category. For nuts, these categories were never, 1-3 times per month, once per week, and 2 or more times per week. As legume intake was higher than nut intake across all cohorts, we defined categories for legumes as 3 times per month or less, once per week, 2-3 times per week, and 4 or more times per week. All models were stratified by time period (year), age (months), and cohort (NHS, NHSII, HPFS); and multivariable-adjusted models were adjusted for BMI (<25, 25-30, ≥30 kg/m²), regular NSAID use (yes/no), history of appendectomy (yes/no), smoking status (never, past, current), physical activity (quintiles), family history of IBD (yes/no), AHEI (quintiles), and total daily calories (quintiles). All covariates were modeled as time-varying except for family history of IBD and history of appendectomy. We also tested the validity of the proportional hazards assumption as described in the Supplementary Methods (all P > 0.39).

We performed several sensitivity analyses. First, we repeated our primary analyses using baseline (NHS/HPFS: 1986, NHSII: 1991) and simple updated (most recent) nut and legume intake as exposures, as well as nut and legume intake as continuous exposures. We also repeated our primary analysis according to high vs low nut and legume intake (dichotomized based on cohort-specific median), as well as healthy vs nonhealthy nut (≥3.5 or <3.5 servings/week) and legume (≥1.5 or <1.5 servings/week) intake, dichotomized based on AHA and USDA/USDHHA guidelines. Finally, we repeated our primary analysis including an additional term for vegetarianism in the final models. Further details are provided in the Supplementary Methods.

We also explored the relationship of nut and legume intake and risk of IBD according to strata of other known risk factors for IBD, including cohort mean age (<45 or ≥45 years), BMI (<25 or ≥25 kg/m²), smoking status, and family history of IBD and tested for effect modification by including an interaction term between these covariates and nut and legume intake in the models. In stratified models, we used continuous (over categorical) exposures given the low case numbers in some categories upon stratifying and to increase power. Finally, to explore for the possibility of reverse causation and delayed-exposure effect, we performed 4- and 8-year lagged analyses.

All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). Statistical significance was defined as P < .05 using 2-tailed tests.

Results

After exclusions, the final pooled cohort was composed of 223 283 individuals (NHS: 86 804, NHSII: 93 709, HPFS: 42 770). After studying over 5 460 315 person-years of follow-up, we ascertained 371 cases of CD and 481 cases of UC. Those in the highest category of nut intake were older. Those in the highest categories of both nut and legume intake were more likely to be male and had higher physical activity, AHEI scores, and caloric intake per day (Table 1). Characteristics were otherwise similar across categories of nut and legume intake.

Table 1.

Characteristics of pooled study population (n = 223 283) according to frequency of nut (A) and legume (B) intake.

A. Nuts	Never (21.0%)	1-3x/month (35.7%)	Once/week (27.0%)	2 or more/week (16.3%)
Baseline n	90 443	53 998	53 363	25 479
Person-years	1 154 587	1 957 649	1 469 556	878 523
Servings nuts per day (definition)	0	0.01-0.10	0.11-0.28	≥0.29
Servings nuts per day (mean)	0 (0)	0.05 (0.02)	0.16 (0.05)	0.57 (0.40)
Age (years)	50.5 (12.5)	58.1 (12.3)	59.1 (12.3)	62.7 (11.3)
Sex (% male)	15	14	21	31
Race (% White)	97	97	96	96
BMI (kg/m2)	26.5 (5.6)	26.7 (5.6)	26.4 (5.4)	25.7 (4.9)
Physical activity (METs/week)	18.1 (20.5)	19.3 (19.8)	22.0 (21.4)	25.5 (24.1)
Smoking status
Never (%)	52	55	55	55
Past (%)	36	36	37	38
Current (%)	12	9	9	8
Regular NSAID use (%)	16	20	20	19
History of appendectomy (%)	21	21	20	18
Family history of IBD (%)	4	4	4	4
AHEI score	47.7 (10.7)	48.3 (10.4)	50.4 (10.5)	54.6 (11.3)
Oral contraceptive use (%)a	62	68	70	70
Postmenopausal hormone usea
Never (%)	24	18	16	14
Past (%)	9	6	6	5
Current (%)	9	9	9	9
Premenopausal (%)	58	66	69	72
Vegetarian diet (%)	2	2	3	5
Calories per day	1623 (468)	1736 (450)	1911 (481)	2088 (512)
B. Legumes	0-3x/month (21.0%)	Once/week (49.3%)	2-3x/week (22.8%)	4 or more/week (6.9%)
Baseline n	59 512	112 878	32 082	18 811
Person-years	1 151 704	2 690 557	1 244 021	374 033
Servings legumes per day (definition)	0-0.10	0.11-0.28	0.29-0.57	≥0.58
Servings legumes per day (mean)	0.05 (0.03)	0.18 (0.05)	0.39 (0.08)	0.80 (0.32)
Age (years)	55.0 (12.9)	57.9 (12.8)	59.3 (12.3)	56.4 (13.0)
Sex (% male)	16	17	23	32
Race (% White)	97	97	96	94
BMI (kg/m2)	26.6 (5.6)	26.4 (5.4)	26.3 (5.4)	25.8 (5.2)
Physical activity (METs/week)	18.3 (19.5)	19.8 (20.1)	23.5 (22.5)	28.6 (26.7)
Smoking status
Never (%)	52	54	57	59
Past (%)	38	37	35	34
Current (%)	10	10	8	7
Regular NSAID use (%)	19	19	20	17
History of appendectomy (%)	20	21	20	18
Family history of IBD (%)	4	4	4	4
AHEI score	48.1 (10.9)	48.9 (10.4)	51.2 (10.9)	56.7 (11.5)
Oral contraceptive use (%)a	67	68	69	69
Postmenopausal hormone use a
Never (%)	18	18	16	16
Past (%)	6	7	6	6
Current (%)	9	10	9	10
Premenopausal (%)	67	66	69	69
Vegetarian diet (%)	1	2	4	14
Calories per day	1597 (451)	1777 (456)	1987 (477)	2174 (538)

Abbreviations: AHEI, alternate healthy eating index; BMI, body mass index; IBD, inflammatory bowel disease; MET, metabolic equivalent of a task; NSAIDs, nonsteroidal anti-inflammatory drugs.

All values are means (SD) for continuous variables and percentages for categorical variables over follow-up. Variables (except age) are standardized to the age distribution of the study population. Values of polytomous variables may not sum to 100% due to rounding. ^aFor female participants only.

In our primary analysis, nut intake was not associated with risk of CD or UC (P_trend = 0.57 and 0.36, respectively; Tables 2 and 3). Compared to those who never consumed nuts (mean = 0 servings/day), those who consumed nuts 2 or more times per week (mean = 0.57 servings/day) had an aHR of 0.96 (95% CI, 0.63-1.47) for CD and 1.30 (95% CI, 0.92-1.84) for UC. Similarly, legume intake was not associated with risk of CD or UC (P_trend = 0.59 and 0.20, respectively; Tables 2 and 3). Compared to those who consumed legumes 3 times per month or less (mean = 0.05 servings/day), those who consumed legumes 4 or more times per week (mean = 0.80 servings/day) had an aHR of 1.26 (95% CI, 0.78-2.04) for CD and 0.72 (95% CI, 0.44-1.18) for UC.

Table 2.

Nut and legume intake and risk of Crohn’s disease in the pooled (NHS, NHS2, HPFS) cohort.

Crohn’s Disease (n = 371)
Nut Intake	Never	1-3x/month	Once/week	2 or more/week	Ptrend
Cumulative Avg
Cases	81	160	88	42
Person-years	1 154 587	1 957 649	1 469 556	878 523
HR (95% CI)	1.00 (ref)	1.20 (0.90-1.58)	0.97 (0.70-1.32)	0.90 (0.61-1.34)	0.33
aHR (95% CI)a	1.00 (ref)	1.19 (0.89-1.58)	0.98 (0.70-1.36)	0.96 (0.63-1.47)	0.57
+ Vegetarianism term	1.00 (ref)	1.19 (0.89-1.58)	0.98 (0.70-1.36)	0.96 (0.63-1.47)	0.57
Simple Updated b
Cases	166	67	86	52
Person-years	2 058 907	972 068	1 405 217	1 024 123
HR (95% CI)	1.00 (ref)	0.90 (0.68-1.20)	0.85 (0.65-1.11)	0.83 (0.60-1.16)	0.18
aHR (95% CI)a	1.00 (ref)	0.90 (0.68-1.21)	0.87 (0.66-1.14)	0.89 (0.62-1.26)	0.34
Baseline c
Cases	162	105	76	28
Person-years	2 175 657	1 333 544	1 322 633	628 480
HR (95% CI)	1.00 (ref)	1.04 (0.81-1.34)	0.79 (0.60-1.04)	0.70 (0.46-1.06)	0.03
aHR (95% CI)a	1.00 (ref)	1.05 (0.81-1.36)	0.79 (0.59-1.05)	0.71 (0.46-1.10)	0.05
Legume Intake	0-3x/month	Once/week	2-3x/week	4 or more/week	P trend
Cumulative Avg
Cases	82	186	78	25
Person-years	1 151 704	2 690 557	1 244 021	374 033
HR (95% CI)	1.00 (ref)	0.99 (0.76-1.28)	0.92 (0.67-1.26)	1.08 (0.69-1.69)	0.88
aHR (95% CI)a	1.00 (ref)	1.02 (0.78-1.33)	1.00 (0.72-1.39)	1.26 (0.78-2.04)	0.59
+ Vegetarianism term	1.00 (ref)	1.02 (0.78-1.33)	1.00 (0.71-1.38)	1.25 (0.77-2.03)	0.62
Simple Updated b
Cases	108	182	33	48
Person-years	1 516 334	2 637 945	632 833	673 203
HR (95% CI)	1.00 (ref)	0.95 (0.75-1.21)	0.83 (0.56-1.23)	1.05 (0.75-1.49)	0.95
aHR (95% CI)a	1.00 (ref)	0.98 (0.77-1.25)	0.88 (0.59-1.32)	1.18 (0.82-1.69)	0.60
Baseline c
Cases	92	195	52	32
Person-years	1 447 581	2 773 152	784 034	455 548
HR (95% CI)	1.00 (ref)	1.10 (0.85-1.41)	1.09 (0.77-1.54)	1.23 (0.82-1.84)	0.34
aHR (95% CI)a	1.00 (ref)	1.14 (0.88-1.47)	1.18 (0.83-1.68)	1.41 (0.92-2.15)	0.11

Abbreviations: CI, confidence interval; HR hazard ratio. Models stratified by time period (year), age (months), and cohort (NHS, NHS2, HPFS). ^aAdjusted for BMI (<25, 25-30, ≥30 kg/m2), regular use of NSAIDs (yes/no), history of appendectomy (yes/no), smoking status (never, past, current), physical activity (quintiles), AHEI (quintiles), family history of IBD (yes/no), and total daily calories (quintiles). ^bNut or Legume intake updated every 4 years. ^cNut or Legume intake at baseline (NHS: 1986, NHS2: 1991, HPFS: 1986).

Table 3.

Nut and legume intake and risk of ulcerative colitis in the pooled (NHS, NHS2, HPFS) cohort.

Ulcerative colitis (n = 481)
Nut Intake	Never	1-3x/month	Once/week	2 or more/week	Ptrend
Cumulative Avg
Cases	115	180	112	74
Person-years	1 154 587	1 957 649	1 469 556	878 523
HR (95% CI)	1.00 (ref)	1.06 (0.83-1.37)	0.94 (0.72-1.24)	1.21 (0.88-1.66)	0.57
aHR (95% CI)a	1.00 (ref)	1.08 (0.84-1.38)	0.97 (0.73-1.29)	1.30 (0.92-1.84)	0.36
+Vegetarianism term	1.00 (ref)	1.08 (0.84-1.38)	0.97 (0.73-1.29)	1.31 (0.93-1.85)	0.35
Simple Updated b
Cases	193	90	127	71
Person-years	2 058 907	972 068	1 405 217	1 024 123
HR (95% CI)	1.00 (ref)	1.06 (0.82-1.37)	1.11 (0.88-1.39)	0.99 (0.74-1.32)	0.73
aHR (95% CI)a	1.00 (ref)	1.07 (0.83-1.38)	1.12 (0.89-1.42)	1.03 (0.76-1.41)	0.55
Baseline c
Cases	202	119	105	55
Person-years	2 175 657	1 333 544	1 322 633	628 480
HR (95% CI)	1.00 (ref)	1.04 (0.82-1.31)	0.94 (0.74-1.19)	1.23 (0.89-1.69)	0.61
aHR (95% CI)a	1.00 (ref)	1.05 (0.83-1.32)	0.96 (0.74-1.23)	1.27 (0.91-1.78)	0.49
Legume Intake	0-3x/month	Once/week	2-3x/week	4 or more/week	P trend
Cumulative Avg
Cases	103	265	92	21
Person-years	1 151 704	2 690 557	1 244 021	374 033
HR (95% CI)	1.00 (ref)	1.16 (0.92-1.46)	0.91 (0.68-1.21)	0.68 (0.42-1.08)	0.08
aHR (95% CI)a	1.00 (ref)	1.18 (0.93-1.48)	0.93 (0.69-1.25)	0.72 (0.44-1.18)	0.20
+Vegetarianism term	1.00 (ref)	1.18 (0.93-1.49)	0.93 (0.69-1.26)	0.74 (0.45-1.21)	0.24
Simple Updated b
Cases	142	250	48	41
Person-years	1 516 334	2 637 945	632 833	673 203
HR (95% CI)	1.00 (ref)	1.01 (0.82-1.25)	0.89 (0.64-1.24)	0.67 (0.48-0.96)	0.03
aHR (95% CI)a	1.00 (ref)	1.03 (0.83-1.27)	0.91 (0.65-1.28)	0.71 (0.49-1.02)	0.08
Baseline c
Cases	149	241	54	37
Person-years	1 447 581	2 773 152	784 034	455 548
HR (95% CI)	1.00 (ref)	0.87 (0.71-1.07)	0.75 (0.55-1.03)	0.86 (0.60-1.23)	0.12
aHR (95% CI)a	1.00 (ref)	0.88 (0.71-1.09)	0.78 (0.56-1.08)	0.92 (0.63-1.34)	0.27

Stratification and adjustment as per Table 2.

In sensitivity analyses, continuous nut and legume intake were not associated with CD or UC. The aHRs of CD were 0.64 (95% CI, 0.33-1.23; P = .18) and 1.29 (95% CI, 0.77-2.18; P = .33) for each additional daily serving of nut and legume intake, respectively. Similarly, the aHRs for UC were 1.19 (95% CI, 0.84-1.69; P = .34) and 0.77 (95% CI, 0.46-1.29; P = .32) for each additional daily serving of nut and legume intake, respectively.

Our findings were similar when using simple updated nut and legume intake (Tables 2 and 3). However, baseline nut intake was associated with a significantly lower risk of CD (P_trend = 0.05). At baseline, compared to those who never consumed nuts, those who consumed nuts 2 or more times per week had an aHR of 0.71 (95% CI, 0.46-1.10). There was no association between baseline legume intake and risk of CD (P_trend = .11) or between baseline nut or legume intake and risk of UC (P_trend = .49 and 0.27, respectively). Our findings were unchanged when additionally adjusting for vegetarianism in the final models (Tables 2 and 3).

When comparing high vs low nut and legume intake, we saw no relationship between high nut intake and risk of CD (aHR, 0.88; 95% CI, 0.71-1.10; P = .27) or UC (aHR, 1.01; 95% CI, 0.83-1.22; P = .92) nor between high legume intake and risk of CD (aHR, 0.98; 95% CI, 0.79-1.22; P = .88) or UC (aHR, 0.88; 95% CI, 0.72-1.06; P = .18) when compared to low values (Supplementary Table 1). Similarly, we observed no relationship between healthy nut intake and risk of CD (aHR, 0.72; 95% CI, 0.41-1.28; P = .27) or UC (aHR, 1.10; 95% CI, 0.73-1.67; P = .66) nor between healthy legume intake and risk of CD (aHR, 0.93; 95% CI, 0.74-1.17; P = .54) or UC (aHR, 0.90; 95% CI, 0.74-1.10; P = .31) when compared to nonhealthy intake (Supplementary Table 1).

In stratified analysis, baseline BMI modified the relationship between nut intake and risk of CD (P_interaction = 0.03; Figure 1). Amongst those with BMI <25, the aHR for CD was 0.88 (95% CI, 0.45-1.74; P = .72) per increase in each daily serving of nut intake. In contrast, amongst those with BMI ≥25, the aHR for CD was 0.14 (95% CI, 0.03-0.56; P = .006) per each increase in daily serving of nut intake. No interaction was seen between BMI and legume intake and risk of CD (P_interaction = 0.12). Baseline age, smoking status, and family history did not modify the relationship between nut or legume intake and CD (all P_interaction >0.10). Similarly, baseline age, BMI, smoking status, and family history did not modify the relationship between nut or legume intake and risk of UC (all P_interaction > 0.11).

Figure 1.

Nut and legume intake and risk of Crohn’s disease (A) and ulcerative colitis (B) according to strata of baseline age, baseline body mass index (BMI), updated smoking status, and family history of inflammatory bowel disease (IBD). Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval. Models for interaction analyses stratified by time period (year), age (months), and cohort (NHS, NHS2, HPFS). Models adjusted for same variables as Table 2, minus the strata variable.

Finally, in 4 and 8 years of lagged-analyses, we observed no relationship between nut and legume intake and risk of CD or UC (all P_trend > 0.21, Supplementary Table 2).

Discussion

In a large prospective cohort study of US adults, we did not detect an association between long-term intake of nuts and legumes and risk of incident CD or UC. However, secondary analyses revealed that higher nut intake was associated with lower risk for CD when examining baseline nut intake (P_trend = 0.05) and long-term nut intake in those with elevated, but not normal, BMI (P_interaction = 0.03). To the best of our knowledge, our study is the first prospective study to examine the relationship between dietary nut and legume intake and risk of developing IBD.

The health benefits of nuts and legumes have been studied in several other chronic diseases. Cross-sectional studies have shown that those with rheumatoid arthritis (RA) have lower legume intake, and those with psoriasis have lower nut intake as compared with healthy controls.^21,22 Nut and legume intake, as well as diets high in nuts and legumes like the Mediterranean diet, have also been associated with lower risk for cardiovascular disease (CVD), diabetes, metabolic syndrome, systemic lupus erythematosus (SLE), and colorectal cancer in prospective cohort studies.^23–27 Specific components such as n-3 PUFAs, tocopherol, and fiber may mediate protection against chronic inflammation by modulating postprandial oxidative stress and insulin response,²⁸ lipid metabolism,⁸ and both microvascular²⁸ and systemic inflammation.²⁹

The Mediterranean diet has also been associated with lower risk for IBD, particularly CD.³ In a study of unaffected first-degree relatives of those with Crohn’s disease, those who adhered to a Mediterranean-like diet had lower fecal calprotectin levels, a marker of subclinical inflammation, and distinct gut microbial abundance of fiber-degrading Ruminococcus, as well as Faecalibacterium taxa.⁴ In those with established IBD, adherence to a Mediterranean-like diet has been shown to decrease BMI, liver steatosis, IBD disease activity, and circulating inflammatory markers.³⁰ Accordingly, the Mediterranean diet has been used as therapy for IBD³¹ and is currently the recommended dietary goal for those with IBD.³² While baseline nut intake was associated with lower risk for CD, our remaining analyses showed no association between nuts and legumes and IBD risk. That the Mediterranean diet, but not nuts or legumes, reduces risk of IBD may speak to the importance of dietary patterns rather than specific components in modulating IBD risk. Alternatively, other dietary constituents of the Mediterranean diet, such as fruit, total fiber or n3:n6 PUFA from other sources (eg, oils or fish), may instead mediate the observed anti-inflammatory effects that lower IBD risk and disease activity.^33,34

Interestingly, we saw that increased nut intake conferred lower risk for CD in those with elevated (≥25 kg/m²), but not normal, BMI. Obesity is associated with altered abundance of gut Bacteroidetes and Firmicutes,³⁵ adipokine-mediated systemic inflammatory markers such as CRP, IL-6, and tumor necrosis factor (TNF)-α,³⁶ and increased risk for CD but not UC.^37,38 Nuts have been shown to lower markers of systemic inflammation, including IL-6 and CRP,²⁹ in overweight or obese individuals at risk for other chronic inflammatory conditions such as CVD.³⁹ Thus, dietary nut intake may reduce CD risk in those with obesity-induced pro-inflammatory states but not in those with normal BMI, whose disease may be driven by alternative pathways. Alternatively, because BMI does not necessarily capture body composition, this finding may also reflect associations between health patterns in those with elevated BMI with elevated lean body mass and risk for CD, such as physical activity. However, our models adjusted for important confounders such as physical activity and overall dietary pattern, making this less likely.

We note several strengths of our study, including our large cohort size, 30-year length of follow-up, and low loss to follow-up. Further, dietary information was prospectively collected, minimizing the possibility of recall bias, and conducted using validated SFFQs, with moderate correlation between legume intake via SFFQ and 7-day dietary recall.¹⁶ Inflammatory bowel disease ascertainment was also conducted through blinded review of medical records, minimizing the chance of outcome misclassification. We also note several limitations. First, SFFQs may not capture all dietary constituents such as those included as ingredients of larger meals, and few participants reported vegetarian diets. Information regarding correlation for dietary nut intake between SFFQ and 7-day dietary recall is also limited.¹⁶ Further, we were unable to examine for the association between specific nut- and legume-based oils and IBD, which may be important contributors to disease risk and are an important component of the Mediterranean diet. Additionally, mean age of our pooled cohort is approximately 45 years, which is higher than the average age of IBD onset, and thus younger-onset IBD may be underrepresented. Finally, we note the possibility of false-positive error in our exploratory analyses that may stem from multiple comparisons.

Together, our findings suggest that dietary nut and legume intake is not broadly associated with risk of IBD. However, this risk may differ according to specific subgroups defined by BMI. Thus, while dietary nuts and legumes remain an important part of a well-balanced diet, personalized risk-assessments according to individualized risk factors, rather than generalized dietary recommendations, may be important in future strategies to prevent IBD, specifically. Future studies are needed to better characterize which populations may benefit from personalized dietary prevention strategies.

Author Contributions

E.W.L., Z.Y., A.T.C., and H.K. were involved in the study concept and design. E.W.L., A.N.A., J.M.R., K.E.B., A.T.C., K.C., and H.K. participated in acquisition of data. E.W.L., Z.Y., S.E.W., K.C., and H.K. were involved in statistical analysis. E.W.L. and H.K. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in interpretation of data. E.W.L., Z.Y., and S.E.W. performed initial drafting of the manuscript. All authors participated in critical revision of the manuscript.

Funding

Funded by National Institutes of Health UM1 CA186107 NHS cohort infrastructure grant, U01 CA176726 NHSII cohort infrastructure grant, and U01 CA167552 HPFS cohort infrastructure grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was funded by a senior research award from the Crohn’s and Colitis Foundation to H.K. and a senior research award from the Crohn’s and Colitis Foundation to A.T.C. E.L. is funded from NIH 1K23DK136977-01A1. Funding sources did not participate in study design, analysis, interpretation, drafting of manuscript, or submission process.

Conflicts of Interest

H.K. is supported by the American College of Gastroenterology Senior Research Award and the Beker Foundation; H.K. has received consulting fees from Abbvie and Takeda; H.K. has also received grant funding from Pfizer and Takeda; A.T.C. is the Stuart and Suzanne MGH Research Scholar; A.T.C. has received consulting fees from Bayer Pharma AG, Pfizer Inc., and Boehringer Ingelheim for work unrelated to this manuscript. There are no other relationships or activities that could appear to have influenced the submitted work.

Data Availability

Further information including the procedures to obtain and access data from the Nurses’ Health Studies and Health Professionals Follow-up Study is described at https://www.nurseshealthstudy.org/researchers (email: nhsaccess@channing.harvard.edu) and https://hsph.harvard.edu/research/health-professionals/resources/for-external-collaborators/.