EFFECT OF BREASTFEEDING ON RISK OF DEVELOPING INFLAMMATORY BOWEL DISEASE

doi:10.21203/rs.3.rs-2341901/v1

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EFFECT OF BREASTFEEDING ON RISK OF DEVELOPING INFLAMMATORY BOWEL DISEASE

https://doi.org/10.21203/rs.3.rs-2341901/v1

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Purpose:This study aimed to investigate whether breastfeeding in early childhood affect the risk of devoloping IBD.

Methods:In order to investigate the effect of breast milk on the development of IBD and in order to reduce the effects of genetic and environmental factors, the patient data obtained from the survey were compared to the data of their non-IBD siblings as a control group.

Results: The data of 122 Crohn's disease patients were compared with the sibling group of 332 individuals, and the data of 182 ulcerative colitis patients with the sibling group of 508 individuals. Compared to the control group, it was determined that the proportion of those who never breastfed was statistically significantly higher in both the CD and UC groups (7.4% vs. 2.1% for CD, p=0.017 and 3.9% vs. 0.8% for UC, p=0.01), and the risk of disease increased significantly in those who wasn’t breastfed (OR= 3.70 [1.35-10.16] for CD, p=0.017 and OR= 5.07 for UC [1.47-17.53], p=0.010). It was determined that the protective effect increased against CD as the duration of breastfeeding increased, but that the protection increased with breastfeeding for up to 12 months for UC, and breastfeeding for more than 12 months did not provide additional protection. There was no relationship between breastfeeding and demographic and behavioral chracteristics of patients.

Conclusions: Not having been breastfed in infancy increases the risk of developing both UC and CD, and as the duration of breastfeeding increases, the protection against disease risk increases.

Crohn’s disease

ulcerative colitis

brestfeeding

disease risk

Although the etiology of Crohn’s disease (CD) and ulcerative colitis (UC), which are chronic inflammatory diseases of the gastrointestinal tract, is still not fully understood, genetic predisposition, environmental causes and abnormal immune response against intestinal flora are the main suggested causes.

Mutations in more than 200 genes that affect immune regulation functions in IBD have been identified [1]. However, in a study conducted with monozygotic twins, an association of up to 55% for CD and 17% for UC was found [2]. This indicates that genetic predisposition alone is not effective in the pathogenesis of the disease.

Many environmental factors that increase or decrease the risk of disease have been defined in patients with IBD, such as smoking, use of antibiotics and some other drugs, breast milk, excessive hygiene, past infections, deficiencies of some vitamins, and physical activity [3]. In patients with genetic predisposition, chronic inflammation develops in the intestines as a result of an excessive immune response to abnormal intestinal flora triggered by environmental factors [4]. It is known that the decrease in species such as Bifidobacterium, Clostridium, Lachnospiraceae and the increase in species such as Proteobacteria, E. Coli, Fusobacterium in the intestinal flora play a role in the development of IBD by changing the innate immune response [5]. Breastfeeding not only provides protection against infections in infants, but also has important effects on the microbiome composition of the intestines and immune tolerance, and plays a protective role against atopic, allergic and autoimmune diseases [6, 7, 8]. It has been reported that human milk oligosaccharides (HMOs), which are abundant in breast milk, act as a prebiotic to increase the beneficial species, especially Bifidobacterium, in the intestinal flora, and to reduce harmful bacteria such as Acinetobacter and streptococcus with its antibacterial effect [9, 10].

Studies investigating the effect of breast milk on the risk of IBD so far are quite heterogeneous. While breastfeeding was found to be protective against IBD in some of them, it was found to have no effect in others [11, 12, 13]. Identifying and eliminating the modifiable factors in the etiology of diseases is important for the prevention of diseases. In this study, we compared the breastfeeding status of IBD patients and their healthy siblings in order to minimize the effects of genetic and environmental factors.

Patients diagnosed with inflammatory bowel disease monitored in the Gastroenterology clinic of our hospital were included in the study. After obtaining approval from the ethics committee of our hospital (No: E1-22-2744), the patients’ gender, age at diagnosis, place of residence (village, town, city), disease subgroup (UC, CD), disease localization according to the Montreal Classification [14] and CD behavior (inflammatory, stricture, fistulization, perianal disease), medications used, steroid refractoriness or dependence, and history of surgery related to IBD were recorded. The data on the duration of breastfeeding of patients were obtained by face-to-face questionnaire, and, for their siblings, by contacting them and their mothers. Patients who were not known for how long they were breastfed and their siblings were excluded from the study. Only those who were known for how long they were breastfed were included in the study.

Statistical Analysis:

IBM SPSS Statisticsfor Windows, Version 25.0 software (IBM Corp., Armonk, NY, USA) was used to perform the statistical analysis. Descriptive statistics (frequency, mean and SD, median and minimum-maximum) were calculated. Categorical variables were summarized as percentages. Normality analysis of the data was evaluated via Kolmogorov-Smirnov and Shapiro-Wilk tests. In group comparisons, a parametric test (Student's t-test) was used for normally distributed continuous variables, where as a non-parametric test (Mann-Whitney U and Kruskal-Wallis) was used for non-normally distributed variables. A chi-squared test or Fisher’s exact test (when chi-squared test assumptions do not hold due to low expected cell count) was used to compare categorical variables in different groups. In estimating the risk ratio of the duration of breastfeeding on the disease state; It was tested by calculating odds ratios adjusted with 95% confidence intervals. Spearman correlation coefficient was used to evaluate the relationship between breastfeeding and disease. Statistical significance was considered p ≤ 0.05 with a confidence interval (CI) of 95%.

304 IBD patients were included in the study. Mean age was 44.53 ± 12.26 years, 173 (56.9%) of the patients were male. 182 (59.9%) of the patients were diagnosed with UC, and 122 (40.1%) with CD. Demographic and clinical characteristics of patients CD and UC are shown in Table 1. The data of a total of 840 siblings of these patients (508 siblings of UC patients and 332 siblings of CD patients) were analyzed. The data of 122 CD patients included in the study were compared to the CD siblings group of 332, and the data of UC patients with the UC siblings group of 508.

Table 1

Demographic and clinical characteristics of patients with Chron’s disease and ulcerative colitis.
Demographic and clinical characteristics	CD (n = 122)	UC (n = 182)
Age	41.16 ± 11.26 (17–82)	46.89 ± 12.44 (18–76)
Gender Female Male	56 (45.9%) 66 (54.1%)	75 (41.2%) 107 (58.8%)
Age at Diagnosis* A1 (0–16 years) A2 (17–40 years old) A3 (> 40 years)	17–62 (34.08 ± 9.97) 0 (0.0%) 93 (76.2) 29 (23.8)	12–66 (38.22 ± 12.07) 7 (3.9%) 97 (53.6%) 78 (42.5%)
UC localization* Proctitis (E1) Left Type (E2) Extensive (E3)	-	41 (22.5%) 106 (58.3%) 35 (19.2%)
CD localization* Ileal (L1) Column (L2) ileocolon (L3) Isolated upper GIS (L4)	51 (41.8%) 16 (13.1%) 55 (45.1%) 0 (0.0%)	-
CD behavior* Inflammatory (B1) Stricturan (B2) Penetrating (B3) Perianal disease (p)	68 (55.7%) 34 (27.9%) 20 (16.4%) 21 (17.2%)	-
IBD-related operation Yes No	42 (34.4%) 80 (55.6%)	13 (7.1%) 169 (92.9%)
Steroid refractory/dependent No Refractory dependant	83 (68.0%) 26 (21.3%) 13 (10.7%)	168 (92.3%) 9(4.9%) 5 (2.8%)
Family history of İBD Yes No	11 (9.0%) 111 (91.0)	33 (18.1%) 149 (81.9%)
Place of residence Village Town City	7 (5.7%) 36 (29.5%) 79 (64.8%)	24 (13.2%) 43 (23.7%) 115 (38.1%)
Patients’ mean breastfeeding duration	12.92 ± 9.47 (0–48 ay)	14.83 ± 8.63 (0–36 ay)
Patients who have never been breastfed	9 (7.4%)	7 (3.9%)
Number of siblings	332 (Median:4 [0–9])	508 (Median:4 [0–18])
Siblings' mean duration of breastfeeding	15.51 ± 7.87 (0–48 ay)	14.67 ± 7.06 (0–54 ay)
Siblings who have never been breastfed	7 (2.1%)	4 (0.8%)
*CH: Crohn’s disease, UC: ulcerative colitis, IBD: inflammatory bowel disease, Montreal Classification**

Comparing the 122 CD patients to 332 siblings, it was found that the rate of those who were not breastfed in the CD group was statistically significantly higher than the sibling group (7.4% and 2.1%, p = 0.017) and the risk of disease increased significantly in those who were not breastfed (p = 0.01, OR = 3.70 [1.35–10.16]). In addition, when the breastfed group was analyzed separately as > 3 months, > 6 months and > 12 months, it was found that the protective effect increased as the duration increased (Table 2).

Table 2

Comparison of patients with Crohn's disease and their siblings in terms of duration of breast milk intake.
Breast milk intake	Patients n (%)	Sibling n (%)	p	Odds Ratio	95% Confidence Interval
No Yes	9 113	7 325	0,017	3.7	1.346–10.159
≤ 3 month > 3 month	19 103	20 312	0,001	2.88	1.478–5.602
≤ 6 month > 6 month	38 84	46 286	0,000	2.81	1.717–4.608
≤ 12 month > 12	77 45	161 171	0,006	1.87	1.187–2.283

Comparing the 182 UC patients to 508 siblings, the proportion of those with UC who were not breastfed was significantly higher than the sibling group (3.9% vs. 0.8%, p = 0.010), and the risk of disease was found to be significantly increased in those who were not breastfed (OR = 5.07 [1.47–17.53]). In addition, when the breastfed group was analyzed separately as > 3 months, > 6 months and > 12 months, it was found that the protective effect increased as the duration increased (p < 0.05), but there was no additional protection after 12 months (p > 0.05) (Table 3).

Table 3

Comparison of patients with ulcerative colitis and their siblings in terms of duration of breast milk intake.
Breast milk intake	Patients n (%)	Sibling n (%)	p	Odds Ratio	95% Confidence Interval
No Yes	7 175	4 504	0.01	5.07	1.466–17.525
≤ 3 month > 3 month	15 167	21 487	0.03	2.1	1.056–4.160
≤ 6 month > 6 month	36 146	63 445	0.01	1.75	1.118–2.751
≤ 12 month > 12	102 80	298 210	0.59	0.9	0.64–1.282

There was no relationship between the status and duration of breastfeeding and gender, age at diagnosis, place of residence, UC localization, operation history, medications used, and steroid refractoriness or steroid dependence in patients with UC.

Again, no relationship was found between the status and duration of breastfeeding and gender, age at diagnosis, place of residence, CD localization, CD behavior, perianal disease, operation history, medications used, and steroid addiction and refractoriness in patients with CD.

Many environmental factors along with genetic predisposition are blamed in the etiology of IBD, and the immune response against abnormal intestinal flora is mostly emphasized [5]. It has been reported that breast milk intake in the first period of life contributes to the formation of favorable intestinal flora and immunity [9].

In a study conducted by the Asia-Pacific Crohn’s and Colitis Epidemiology Study (ACCESS) Group, they showed that breast milk is protective against IBD [15]. Similarly, in a meta-analysis of 35 studies by Xu et al., it was found that the risk of both UC and CD was lower in those who received any amount of breast milk compared to those who did not receive any breast milk, and this effect was clearer in Asian populations than in European populations. [12]. In another meta-analysis, breast milk was found to be associated with a lower risk of CD and UC, while this relationship was found to be strong in studies with high methodological quality [16]. Contrary to these studies, it was reported that no relationship was found between breast milk and the risk of UC and CD in a prospective study including 146,681 women in the National Health Survey I and II cohorts published in 2013 [13]. Again, in different studies investigating the protectiveness of breast milk in patients with CD and UC, the effectiveness of breast milk could not be demonstrated [17, 18, 19, 20]. Interestingly, Baron et al. found that breast milk intake increased the risk of CD in their study in pediatric population [21]. In our study, however, we found that having never been breastfed significantly increased the risk of developing both UC and CD, and even when the duration of breastfeeding was compared, the highest risk increase was seen in those who were never breastfed. Since siblings of the patients were taken as the control group in our study, the effect of genetic and environmental factors was minimized, and the effectiveness of breast milk was demonstrated. Considering the previous studies on colostrum, which is the milk secreted in the first days after birth, which reported that colostrum increases immunity, provides protection against harmful pathogens, and helps the development of the newborn immune system, this was thought to be no surprise [22, 23, 24]. We think that the reason why only less than 5% of the patients in our study were not breastfed, and that the rate of not receiving breast milk at all in studies in other countries was more than 20% [17, 18, 19, 20] is due to the different patient populations studied, environmental factors and differences in local nutritional behaviors.

In addition to the protective effect of breast milk in CD and UC, the protective effect of the duration of breastfeeding against the disease has been investigated in different studies. In a meta-analysis, it was reported that the protective effect increased as the duration of breastfeeding increased [12]. Similarly, in another study, it was reported that the protective effect was clearer in those who were breastfed for longer than 12 months [15]. Ko et al. analyzed separately the immigrants from the Middle East to Australia and the native Caucasian race and reported that having been breastfed for more than 3 months reduces the probability of developing CD, and that having been breastfed for more than 6 months reduces the likelihood of developing UC [25]. In other studies, it has been reported that having been breastfed for more than 6 months reduces the risk of CD and UC [26, 27, 28]. Gearry et al., on the other hand, reported that it is necessary to have been breastfed for at least 3 months for a protective effect [29]. Differently, Sonntag et al. found no significant difference in terms of breastfeeding duration in both CD and UC groups [17], while Striscioglio et al. claimed that having been breastfed for longer than 3 months increases the risk of CD in their study on pediatric patients [30]. In our study, we found that the protective effect of breast milk starts from the first months and the protective effect increases in parallel with long-term breastfeeding, however, having been breastfed for more than 12 months does not provide additional protection in UC patients. We think that different results may be caused by diet, medications used in childhood, immunization, environmental factors and variability in different populations in the etiology of the disease.

Siblings of the patients were taken as the control group in order to reduce environmental and genetic effects, and the main limitations of this study are that it is a study conducted with the questionnaire and where the information was questioned retrospectively, and that the smoking status of the patients and their siblings, the time of supplementary food initiation, diet, childhood infections, vaccination, and hygiene conditions that may be associated with the risk of disease are not known.

Not having been breastfed in infancy increases the risk of developing both CD and UC, the protective effect of breast milk starts from the first months and the protective effectiveness increases in parallel with long-term breastfeeding.

Author’s Contributions

İlyas Tenlik and Ömer Öztürk contributed to the conception and design of the research, acquisiton of the data and drafing the manuscript; Orhan Coşkun contributed to the analysis and interpretation of the data; Derya Arı, Ferhat Bacaksız, Mahmut Yüksel, Bayram Yeşil, Muhammed Bahaddin Durak contributed to the acquisiton of the data. All authors critically revised the manuscript, agree to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the fnal manuscript.

Declarations

Conflict Interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical considerations: This study was approved by the ethics committee of our hospital (Date: 29/06/2022, No: E1-22-2744) and conducted ethically in line with the principles of the World Medical Association Declaration of Helsinki.

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No competing interests reported.

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EFFECT OF BREASTFEEDING ON RISK OF DEVELOPING INFLAMMATORY BOWEL DISEASE

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Abstract

Introduction

Materials And Methods

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Results

Discussion

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