Gastrointestinal System - Inflammatory Bowel Disease

Summary of Recommendations and Evidence


 
This Summary of Recommendations and Evidence synthesizes the Key Practice Point(s) for each Practice Question (PQ) in this Knowledge Pathway. It is organized by the Nutrition Care Process and contains statements or recommendations that have been graded using either the PEN or GRADE approaches to critical appraisal. For additional information on the evidence and references, see the PQs in this Knowledge Pathway.

Content
ASSESSMENT 
  1. Nutrient Requirements 
    1. Energy Requirements
    2. Protein Requirements
    3. Vitamin and Mineral Requirements
  2. Bone Loss Screening  and Supplements
  3. Dietary Factors and IBD Development Risk 
    1. Fat
    2. Carbohydrates  
    3. Protein  
    4. Fruit and Vegetables
    5. Alcohol  
    6. Vitamins and Minerals
    7. Breastfeeding
    8. Antigens and Food Additives

INTERVENTION 

  1. Iron-Deficiency Anemia 
    1. Anemia
    2. Iron Supplementation
  2. Ulcerative Colitis
  3. Crohn’s Disease Management

MONITORING/EVALUATION

  1. Nutrition Concerns and Pregnancy 
    1. Remission
    2. Flare-ups 

  1. Nutrient Requirements
Energy Requirements
Recommendation
Until more research is available, standard predictive equations for REE are recommended for adults and children for ulcerative colitis (UC) and Crohn's disease (CD) and for active disease and remission states.

Malnutrition Risk
Individuals with IBD may be at an increased risk of malnutrition. In situations where individuals experience unexplained weight loss, poor absorption and decreased dietary intake should be considered as alternative explanations for increased energy requirements.

During periods of remission, individuals should be encouraged to adjust their energy intake in order to achieve and/or maintain a healthy weight.

Evidence Summary
A review of energy requirements for individuals with IBD concluded there are no consistent results based on IBD type, disease status or patient age. Based on these results and clinical experience, clinical practice guidelines suggest that energy requirements for individuals with IBD are similar to those of healthy populations and that standard predictive equations can be used to estimate TEEs. Observational studies in both children with active CD and adults with CD in remission reported no differences in resting energy expenditures (REEs) between patients and controls, although one very small case-control study reported a 7.6 kcal/kg fat-free mass increase in REE in children and adolescents with active CD compared to controls.

Observational studies have indicated that levels of moderate or severe malnutrition risk in IBD populations vary between 6.4% to 35.5% depending on the IBD population and anthropometric measure. A pediatric study described significantly decreased BMI z-scores for children with CD compared to both healthy controls and those with UC. In this study, children with active CD had significantly decreased BMIs compared to those with CD in remission, but the same was not true for children with UC. Finally, an analysis of secondary causes of death in individuals whose primary source of death was IBD reported higher than expected rates of protein-energy malnutrition and marasmus compared to the general population.

A narrative review described rates of obesity in populations with IBD as similar to those in non-IBD populations. Currently, the effect of overall obesity on IBD outcomes is poorly understood and evidence is conflicting as to whether there is a positive or negative effect or no effect. There is some evidence that visceral adiposity specifically has been associated with negative IBD outcomes. Intervention research on the effect of weight loss on IBD outcomes has not been completed.
Grade of Evidence C
 
Remarks
IBD has been associated with an increased prevalence of malnutrition and has been estimated to affect 65-75% of individuals with CD and 18-62% of individuals with UC (9). The main determinants of malnutrition include decreased oral intake, malabsorption due to inflammation, nutrient loss due to epithelial alteration and disease activity and increased energy expenditure. More recently, IBD has also been associated with an increased risk of sarcopenia (up to 12% of individuals with CD) (9). Dietitians should be cognizant of the increased risk of both malnutrition and sarcopenia when assessing and treating individuals with IBD.
 
Protein Requirements
Recommendation
Individuals with IBD in remission should aim for 1.0 g protein/kg body weight/day and those with active IBD should aim for 1.2 to 1.5 g protein/kg body weight/day.

Evidence Summary
Expert consensus recommends 1.0 g protein/kg body weight/day for individuals with IBD in remission and 1.2 to 1.5 g protein/kg body weight/day for individuals with active UC or CD. In a mortality study, individuals whose primary cause of death was UC or CD were significantly more likely than the general population to have protein-energy malnutrition listed as a secondary cause of death.
Grade of Evidence C
 
Remarks
Individuals with IBD may be more likely to experience protein loss due to decreased intake, increased turnover and nutrient losses and as a result of IBD treatments.
 
Vitamin and Mineral Requirements
Recommendation
Individuals with IBD should be assessed regularly for deficiencies with particular attention to iron, vitamin D and zinc, which may require specific supplementation even if taken with a daily general multimineral and multivitamin. Additional deficiencies have been described for:
  • children – vitamins A, B12, E and K, folate, calcium and magnesium
  • adults – vitamins C and K, niacin, folate, selenium and copper. 

 

Individuals with Crohn's disease (CD) who have more than 20 cm of distal ileum resected should be screened yearly for vitamin B12 deficiency and, if deficient, be given intramuscular vitamin B12 injections (1000 IU, every other day for one week followed by monthly injections).

Individuals treated with sulphasalazine or methotrexate should take a folic acid supplement. For methotrexate, the recommended dose of folic acid is 5 mg, administered as one dose 24 to 72 hours after the methotrexate or as five daily consecutive 1 mg daily doses.

Evidence Summary

Evidence-based clinical practice guidelines concluded there was strong evidence of an increased risk of vitamin B12 deficiency in individuals with CD who have had >20 cm of distal ileum resected. They recommended that these individuals be screened annually and treated for deficiency via intramuscular vitamin B12 injections.
Grade of Evidence A

The clinical practice guidelines further concluded that individuals who take sulphasalazine or methotrexate require a folic acid supplement because the drugs contribute to folate deficiency via inhibition of the enzyme that creates tetrahydrofolic acid and decreased folate absorption, respectively.
Grade of Evidence B

Based on clinical experience, the clinical practice guidelines recommended regular checking for and correction of micronutrient deficiencies for individuals with IBD, while citing the usefulness of a daily multivitamin and the likely need for additional iron, zinc and vitamin D supplements.
Grade of Evidence C

The clinical practice guidelines did not make specific recommendations for micronutrient supplementation but noted that several deficiencies had been reported in the literature including deficiencies in the fat-soluble vitamins (A, D, E, K), folate, vitamin B12, calcium, iron, magnesium and zinc. In related research, four observational studies reported decreased bone mineral density in pediatric populations with IBD and one case-control study reported that children with CD had significantly lower dietary intakes of riboflavin, vitamin B6, folate and calcium.
Grade of Evidence C

For adults, a heterogeneous meta-analysis of observational studies suggested that individuals with IBD had significantly lower serum folate concentrations than controls by an average of 0.46 ng/mL (95%CI, -0.64 to -0.27 ng/mL). When broken down by disease type, the difference remained significant for individuals with ulcerative colitis (UC) but not CD. The same study found no difference between groups in serum vitamin B12 concentrations, although there was evidence of publication bias. A case-control study also reported evidence of significantly lower serum selenium levels in individuals with IBD, and more so in individuals with CD than UC. A cross-sectional analysis of secondary causes of death in individuals whose primary cause of death was IBD reported higher than expected numbers of unspecified anemia (UC and CD), iron-deficiency anemia (CD) and unspecified nutritional deficiencies (CD). A narrative review suggested that iron, zinc and vitamin K deficiencies are more prevalent in active IBD, although they have also been reported in remission. Finally, a case-control study of individuals with CD indicated that more than 50% of individuals had low plasma concentrations of vitamin C, copper, niacin and zinc.
Grade of Evidence C
 
Remarks
Individuals with IBD may be prone to micronutrient deficiencies and undernutrition for a variety of reasons including:
  • decreased oral intake due to anorexia associated with disease activity, medications or dietary restrictions intended to control disease symptoms
  • malabsorption of nutrients
  • increased gastrointestinal losses, and drug-nutrient interactions (1).

Many of the contributing factors to micronutrient deficiencies in IBD are associated with disease activity and are therefore more common when individuals have disease flare-ups than in states of remission A notable exception is when large portions of the gastrointestinal tract have been resected, which can permanently affect nutrient absorption (1).

In IBD, during periods of active disease, micronutrient deficiencies can be challenging to diagnose because the serum levels for many vitamins and minerals are positively or negatively affected during the body’s inflammatory response. Inflammation has been shown to influence the plasma concentrations of vitamin A (retinol), vitamin B6 (pyridoxal phosphate), vitamin C, vitamin D (25-hydroxy cholecalciferol), vitamin E (α-tocopherol), iron (ferritin, transferrin), zinc and selenium.

The micronutrient assessment strategy should be carefully selected as blood values for some micronutrients are not reflective of total body stores due to homeostatic regulation within the body. Additionally, the accurate interpretation of laboratory test results can be confounded by method-related limitations (e.g. sensitivity, specificity), sampling difficulties, subject-related factors (e.g. age, sex, lifestyle, physiological state) and health-related factors (e.g. disease state, medication use).
 
2. Bone Loss Screening and Supplements
Evidence Summary
Based on consistent evidence from several case-control and cohort studies, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommends monitoring serum calcium and 25(OH) vitamin D levels in individuals with active IBD or those using corticosteroids and supplementing as needed.
Grade of Evidence B

Based on very low quality evidence, the American College of Gastroenterology suggests screening individuals with conventional risk factors for low bone mineral density (e.g. advanced age, family history of low bone density, female sex, history of previous fracture and conditions that decrease estrogen levels) upon diagnosis with IBD and periodically thereafter.
Grade of Evidence C
 
Remarks
For individuals with IBD, prevalence rates of osteopenia between 20% and 50% have been reported and rates of osteoporosis have ranged from 2% to 30%. Prevalence rates appear similar for children and adults. There is a moderately increased risk of fractures in individuals with IBD (RR=1.41; 95%CI, 1.27 to 1.56) that is most evident in older adults. In these studies there was no difference in relative fracture risk between those with ulcerative colitis and Crohn's disease and between males and females.

Conventional risk factors for low bone mineral density include age, family history, previous fracture, female sex, family history, Caucasian and Asian ethnicity, hysterectomy, long-term glucocorticoid therapy, and hormonal deficiencies (menopause in women and hypogonadism in men).

The etiology of IBD-related bone loss is multifactorial and incompletely understood.  Risk factors for low bone mineral density in adults with IBD include low serum 25(OH) vitamin D, male sex, Asian, low BMI, corticosteroid use and Crohn’s disease. There is not yet a consensus on the effect of age or age at diagnosis. For pediatric populations, risk factors include corticosteroid use, low BMI and low height-for-age.  
 
3. Dietary Factors and IBD Development Risk
Fat
Recommendation 
The relationship between fat intake and IBD risk is unclear. There may be an increased risk with high omega-6 fatty acid intake, particularly when omega-3 fatty acid intake is low, but this result has not been reproduced reliably and many studies have failed to find any significant association between fat intake and IBD risk.

Until more research is available, individuals should follow their national recommendations for dietary fat intake. See Additional Content: International Dietary Guideline Collection.

Evidence Summary
A systematic review of 19 studies suggests an increased risk of IBD with high PUFA and high omega-6 fatty acid intake, an increased risk of ulcerative colitis (UC) with high total fat intake and an increased risk of Crohn's disease (CD) with high saturated fat intake. However, most case-control and cohort studies published after this review have failed to reliably reproduce these results.
Grade of Evidence C
 
Carbohydrates
Recommendation 
Sucrose may slightly increase ulcerative colitis (UC) risk and adequate fibre intake may decrease IBD risk. There are no known associations between IBD and total carbohydrate or other sugar intakes. Individuals should be counselled in line with dietary recommendations for carbohydrate, sugar and fibre intake. See Additional Content: International Dietary Guideline Collection.

Evidence Summary
A systematic review and meta-analysis of observational studies reported no evidence of an association between carbohydrates, sugar, monosaccharides, disaccharides, mono- and disaccharides, fructose or starch and UC risk. There was a small but significant increase in UC risk associated with sucrose intake (RR=1.10 per 10 g increment/day; 95%CI, 1.02 to 1.18, I2=0). Similarly, the systematic review that informed the ESPEN clinical practice guidelines found no consistent association between carbohydrate intake and IBD risk.

A heterogeneous meta-analysis of seven studies reported a protective effect of fibre intake on risk of CD (RR=0.44; 95%CI, 0.29 to 0.69; I2=56%), with a demonstrated dose-response relationship (13% reduced risk per 10 g fibre). The pooled results of eight studies suggested a possible protective effect of fibre intake on risk of UC (RR=0.8; 95%CI, 0.64 to 1.0; I2=48).
Grade of Evidence C
 
Protein
Recommendation 
Until more research is available, individuals should be counselled to meet their national dietary recommendations for protein intake. See Additional Content: International Dietary Guideline Collection.

Evidence Summary
A systematic review and meta-analysis of observational studies does not suggest that total protein intake is associated with an increased risk of ulcerative colitis (UC).

Evidence from a systematic review and a meta-analysis suggest that high intakes of meat, particularly unprocessed red meat, may increase IBD risk. However, there were significant inconsistencies in the studies that informed the meta-analyses and, as yet, there is no information regarding the level of meat intake or the
component(s) of meat that are associated with IBD risk.
Grade of Evidence C
 
Remarks
Although some studies have linked meat intake to IBD, a mechanism that might explain the association is not clear. Some have suggested that diets high in meat also tend to be high in saturated fat, which may change the intestinal microenvironment. Others have proposed that chemical by-products created by cooking meat at high temperatures may play a role or that processed meats contain nitrites that react in the intestine. 
 
Fruit and Vegetables
Recommendation
Fruit and, to a lesser extent, vegetables may be associated with a decreased risk of IBD, although the literature is inconsistent. Individuals should be counselled to meet their national dietary recommendations for vegetable and fruit intake. See Additional Content: International Dietary Guideline Collection.

Evidence Summary
With respect to vegetable intake, evidence from a heterogeneous meta-analysis suggested that high intakes were not associated with Crohn's disease (CD) but decreased one’s risk of ulcerative colitis (UC). Evidence from a prospective cohort reported the opposite; high vegetable intakes were associated with a decreased risk of CD but not UC.
Grade of Evidence C

With respect to fruit intake, a systematic review, heterogeneous meta-analysis and prospective cohort study reported that those with high intakes were less at risk for CD than those with low intakes. Fruit intakes were not associated with UC in the systematic review and prospective cohort but were protective in the meta-analysis.
Grade of Evidence B

Fruit and vegetable intakes during adolescence were not associated with CD or UC risk in adulthood.
Grade of Evidence C
 
Remarks
It is not yet clear how fruit and vegetable intake decreases IBD risk but it may be due to a corresponding increase in fibre intake or a decrease in fat and meat intake as other foods are displaced.

Alcohol
Recommendation 
Light or moderate alcohol consumption that falls within national recommendations does not appear to increase one’s risk of IBD, but alcohol abuse, both chronic and episodic, may increase ulcerative colitis (UC) and Crohn's disease (CD) risk. More research is needed to confirm this result.  See Additional Content: International Alcohol Guideline Collection.

Evidence Summary
An observational study reported decreased odds of UC in those who drink alcohol compared to those who do not (OR=0.56; 95%CI, 0.37 to 0.86), but a second observational study found no association between UC risk and alcohol consumption that could not be accounted for by other risk factors, such as smoking.

A large European, prospective cohort study also found no increased risk of IBD associated with any level of drinking, but a large Asian, retrospective cohort study reported an increased risk of IBD in individuals who abused alcohol compared to those who did not (HR=3.17; 95%CI, 2.19 to 4.58).
Grade of Evidence C
 
Remarks
There are several proposed mechanisms by which alcohol may be related to IBD. In terms of protective effects, some alcohols contain powerful antioxidants such as phenols and isoflavones that can inhibit inflammatory cytokines. However, ethanol can cause injury to the intestinal wall and has been associated with increased biomarkers for relapse in individuals with IBD.
 
Vitamins and Minerals
Recommendation
Until more research is available, individuals should be counselled to meet national dietary recommendations for vitamin and mineral intakes. See Additional Content: International Dietary Guideline Collection.

Evidence Summary
Longitudinal data suggests that women with higher vitamin D status as a result of lifestyle or dietary factors have a lower Crohn's disease (CD) risk, and a lower CD and ulcerative colitis (UC) risk with higher vitamin D status as a result of geographic factors. Women with adequate zinc intakes are less at risk for CD but not UC than women with zinc intakes <8 mg/day. Intakes of total iron and heme iron during adolescence do not appear to influence risk of CD or UC during adulthood.
Grade of Evidence C
 
Remarks
Micronutrients including vitamin D and zinc have been suggested as important nutrients in the pathophysiology of IBD because of their roles in immunity and GI tract maintenance. It has been proposed that iron, specifically iron from animal sources, is involved in IBD because it is known to promote the formation of compounds that impact cell division in the intestine. 
 
Breastfeeding
Recommendation
Breastfeeding may reduce an infant’s risk of IBD; the research is conflicting.

Regardless of IBD risk, breastmilk provides optimal nutrition for infants. Exclusive breastfeeding is recommended for about the first six months of life and can be continued alongside complementary feeding for up to two years and beyond. See Additional Content: International Dietary Guideline Collection.

Evidence Summary
Clinical practice guidelines based on expert panel discussion of a systematic review of case-control and cohort studies concluded that breastfeeding reduced the risk of children later developing IBD, but also described conflicting results with some studies reporting a protective effect and others reporting no association. Two studies not included in the systematic review also reported conflicting results; a prospective cohort analysis of adult-onset IBD reported no association with breastfeeding whereas a case-control analysis of childhood-onset IBD reported a protective effect for IBD and UC.
Grade of Evidence C
 
Remarks
While the specifics of IBD etiology remain unknown, the mechanism is thought to involve genetic susceptibility, an inappropriate immune response and the intestinal microbiome. As breastfeeding has been shown to positively influence both immune system development and the composition of bacterial populations in the gut, it has been proposed as a protective factor for IBD.  In an animal study, breastmilk feeding was shown to limit the development of colitis in mice deficient in interleukin 10. This was explained by the change of intestinal flora of the developing mice from pathogenic bacteria to nonadherent bacteria as a result of oligosaccharides found in the milk that stimulate Bifidobacterium and Lactobacillus growth. 
 
Antigens and Food Additives
Recommendation
As yet, there is no research to confirm or deny theories that food antigens and additives increase IBD risk or that probiotics decrease IBD risk.

However, children with a cow’s milk allergy diagnosed before the age of two may be at an increased risk of developing IBD.

Evidence Summary
A large prospective cohort study suggests that children who are diagnosed with a cow’s milk allergy before the age of two are at an increased risk of IBD (IR=2.6; 95%CI, 1.7 to 3.8), particularly UC (IR=2.9; 95%CI, 1.8 to 4.7).
Grade of Evidence C

Food antigens and additives (e.g. micro/nanoparticles) have been suggested as theoretical risk factors for IBD, but no research has been completed in humans to support these claims.
Grade of Evidence D

The relationship between probiotic use and IBD risk has not been examined in the literature.
Grade of Evidence D

4. Iron-Deficiency Anemia
Anemia
Evidence Summary
Anemia and iron-deficiency anemia are prevalent in individuals with IBD. Based on expert opinion, the European Crohn’s and Colitis Organisation recommends regular anemia screening for all individuals with IBD, every six to 12 months for those with inactive or mild disease and at least every three months for those with active disease.
Grade of Evidence C

Iron Supplementation
Evidence Summary
When iron-deficiency anemia is identified, individuals with IBD should receive iron supplementation.
  • Intravenous (IV) iron is recommended for individuals with:
    • active disease
    • hemoglobin levels <100 g/L
    • previously identified oral iron intolerance
    • a need for erythropoiesis-stimulating agents.
  • Oral iron is recommended for individuals with:
    • inactive disease
    • mild anemia (i.e. hemoglobin levels 110-129 g/L [men], 110-119 g/L [non-pregnant women])
    • no previous adverse effects from oral iron.

Grade of Evidence A

According to meta-analyses of RCTs, IV iron is more effective than oral iron at increasing hemoglobin levels by ≥2 g/dL and is associated with fewer adverse events than oral iron.
Grade of Evidence A

A systematic review and network meta-analysis published in 2017 compared the efficacy and tolerability of different IV iron formulas. Although all evaluated IV iron treatments were effective and there were no significant differences between them, ferric carboxymaltose was ranked as the best treatment according to the rank probability matrix, followed by iron isomaltoside, iron sucrose, and then oral iron. Ferric carboxymaltose (along with iron dextrose) also had the lowest rate of adverse events (12%).
Grade of Evidence B

Remarks

In the literature, prevalence rates of anemia among individuals with IBD range from six to 74% and anemia is especially common in children and individuals with CD. Most often, the anemia arises from a combination of iron deficiency and anemia of chronic disease and it is associated with increased risks of morbidity, hospitalization and mortality as well as increased medical costs.  
 
Additional Remarks
Intestinal bleeding, malabsorption, inadequate intakes from loss of appetite, increased macrophage iron re-utilization have been described as contributing factors to iron deficiency and iron-deficiency anemia with inflammatory bowel disease. The concerns with oral iron therapy for those with IBD are that unabsorbed ferrous iron can aggravate intestinal inflammation and thereby worsen IBD symptoms. Additionally, the iron may not be well absorbed due to intestinal damage from IBD.
 
5. Ulcerative Colitis 
Prebiotic Supplementation
GRADE Recommendation
prebiotic supplements (7-20 g/day psyllium/ispaghula fibre) to adults with ulcerative colitis as a way to help manage the disease.
Conditional recommendation |  Low quality evidence ⊕⊕⊝⊝

Remarks
The suggestion for a prebiotic supplement is based on low quality evidence that suggested individuals with disease in remission who took psyllium fibre (also known as ispaghula fibre) experienced an improvement in bowel symptoms and a decreased risk of relapse compared to those who took nothing or a placebo. Doses and treatment durations were 7 g/day for 12 months, 20 g/day for 12 months and a two-month treatment with an unreported dose. However, disease state may be an important consideration. A single low quality study in individuals with active disease showed no benefit of oligofructose (12 g/day for two weeks) compared to placebo on disease activity or remission rates. Harms were not reported. The decision to take psyllium fibre supplements should be discussed with individuals, with consideration given to personal preferences, possible side-effects (i.e. flatulence and bloating) and supplement cost. Psyllium fibre is available as whole husks, powdered or in capsules. Serving sizes and preparation instructions vary by product and region. Individuals should start with a small dose and increase gradually while being monitored for tolerance. Each dose should be taken with liquid. Additional research with larger numbers of participants, a lower risk of bias, emphasis on the effect of disease status (active, in remission or in remission with ongoing functional or IBS-like symptoms) and optimal treatment dose and duration is needed.

Probiotic Effectiveness in Inducing Remission
Recommendation
There is insufficient evidence to suggest that probiotics are superior to standard therapy (i.e. aminosalicylic acid (5-ASA)) for the induction of remission in mild to moderately active ulcerative colitis (UC). However, limited evidence from one RCT suggests that probiotics combined with 5-ASA may improve the induction of clinical remission compared to 5-ASA alone. Results from several RCTs suggest that probiotics may be more effective at inducing remission compared to no treatment. Minor adverse effects were reported but were not found to be different between treatment and placebo groups. 
 
Recommendations from clinical practice guidelines differ. The American Gastroenterological Association (AGA) recommends probiotics only be used in the context of a clinical trial. ESPEN recommends Lactobacillus reuteri or VSL#3 (based on two older RCTs) for inducing remission for individuals with mild to moderate UC. The World Gastroenterology Organisation (WGO) recommends (based on older trials) VSL#3 (see Remarks) for adults and VSL#3 and Escherichia coli Nissle 1917 for inducing remission in children with mild to moderate UC. 
 
More research is needed to determine if probiotics are effective in inducing remission in severe active UC.

Evidence Summary
The results of a 2020 Cochrane systematic review of 14 RCTs (two pediatrics, 12 in adults), 11 of which were included in the meta-analysis, indicated that when compared to placebo (n=9 RCTs) or combined with 5-ASA and compared to 5-ASA alone (n=1 RCT), probiotics may improve induction of clinical remission in individuals with mild to moderate active UC. However, when compared to 5-ASA based on one RCT, it is uncertain whether probiotics lead to a difference in the number of individuals who attain remission. Subgroup analysis found no difference when comparing studies using a single strain to those using multiple strains. However, due to small study numbers, this should be interpreted with caution. Overall, results were found to be low certainty evidence due to small numbers, imprecision, inconsistency, indirectness, publication bias and high/unclear risk of bias.
The 2020 AGA guidelines recommend that due to a knowledge gap, probiotics should only be used in the context of a clinical trial for adults and children with UC. This recommendation was based on 11 RCTs and used an earlier 2007 Cochrane review rather than the 2020 review.

Clinical practice guidelines based on small numbers of older RCTs generally recommend that probiotics can be used as treatment to induce remission in individuals with mild to moderate UC. ESPEN specifically recommends the probiotic strain Lactobacillus reuteri or VSL#3 (see Remarks), based on two RCTs in 60 children. The WGO recommends VSL#3 (see Remarks) for adults, which was based on one uncontrolled trial of 32 participants. For children, the WGO recommend Escherichia coli (E. coli) Nissle 1917 based on one open-labelled pilot study of 34 children and VSL#3 (see Remarks) based on one open-labelled pilot study of 13 children and one RCT of 29 children.
Grade of Evidence C

Remarks
The most studied probiotic strain was VSL#3 with a dose of around 900 billion (n=6 of the studies below). All other studies used different single or multiple strains at different doses. Subgroup analysis in the most recent Cochrane review found no different in outcomes when comparing studies using single strain to those using multiple strains. 
 
The VSL#3 probiotic formulation used in the literature cited in this practice question is no longer available under the same brand VSL#3. 

Additional Remarks
Probiotics appear to be well tolerated and have limited side-effects in individuals with mild to moderate UC. Side-effects may include: an unpleasant taste in the mouth, dizziness, flu-like symptoms, acne, alopecia, dyspepsia, abdominal pain, nausea, headache, flatulence, bloating, changes in stool, incontinence and mouth ulcers. A systematic review of nine RCTs including 82 participants in adults with IBD (n=6 RCTs in UC) found there may be an increased risk of side-effects when taking probiotics compared to placebo in adults with IBD (RR 1.35, 95%CI 0.93 to 1.94). As well as the above side-effects, three individuals reported fever and/or respiratory side-effects. Side-effects were not classified or graded in all studies. There was heterogeneity in study design, probiotics used and duration of treatment. Participants included those with UC and Crohn’s disease.

Although there has been an increase in research studies in this area (14 RCTs identified in the updated Cochrane review and only four in the previous review (3), research evaluating strains, dose and treatment length remains sparse. Future research that includes larger participant numbers, builds on previous studies and consistently reports side-effects is needed.

UC is a relapsing and remitting chronic inflammatory disease with unknown etiology. Current treatments include dietary management and loperamide, 5-aminosalicylic acid (5-ASA), corticosteroids, antimetabolites and sometimes surgery (7), fail to induce remission in 20-30% of those with UC. The side-effects from these treatments include headache, rash, nausea, pancreatitis, agranulocytosis, dizziness and arthralgia. Therefore, alternative treatment options are being sought, one of which includes probiotics. Probiotics may offer benefit to individuals with UC by improving the intestinal immune response, enhancing the gut barrier function and improving the intestinal microbial balance. Immunologic, neurologic and biochemical effects of probiotics are likely to be dose and strain specific. Some effects are also dependent on interactions between different strains and many different strains may provide similar benefits.
 
Probiotic Effectiveness in Maintenance of Remission
Recommendation
Limited evidence conducted predominantly in adults suggests that probiotics are not superior to standard therapy (i.e. aminosalicylic acid (5-ASA)) alone in relapse incidence or the maintenance of clinical remission in ulcerative colitis (UC). When compared to standard therapy combined with probiotics, it is uncertain whether probiotics lead to a difference in the incidence of relapse. When compared to no treatment, probiotics are not superior in the incidence of clinical relapse. However, it is uncertain whether probiotics lead to a difference in maintenance of remission. Probiotics do not appear to be associated with serious adverse effects. 
 
Recommendations from clinical practice guidelines differ. The American Gastroenterological Association (AGA) recommends probiotics only be used in the context of a clinical trial. The ESPEN recommends Escherichia coli Nissle 1917 and VSL#3 (based on three older RCTs) for the maintenance of clinical remission in individuals with mild to moderate UC when compared to standard treatment. The World Gastroenterology Organisation (WGO) (based on two older RCTs) recommends Escherichia coli Nissle 1917 for the maintenance of clinical remission in adults only; no recommendations are provided for children.

Evidence Summary
The results of a 2020 Cochrane systematic review of 12 RCTs (relapse was an outcome in all and maintenance of remission an outcome in five trials) found no clear difference in the incidence of clinical relapse (n=2 RCTs) or maintenance of clinical remission (n=1 RCT) when probiotics were compared to 5-ASA alone. When probiotics were combined with 5-ASA and compared to 5-ASA alone, no clear difference in maintenance of remission (n=1 RCT) was found; however, it was uncertain whether there was a difference in clinical relapse (n=2 RCTs). When probiotics were compared to placebo, no clear difference was seen in the incidence of clinical relapse (n=4 RCTs) and it was uncertain whether probiotics led to a difference in maintenance of remission (n=2 RCTs). This is based on low to very low certainty of evidence due to a high risk of bias and imprecision due to the small number of events and wide confidence intervals.

The 2020 AGA guidelines recommend that due to a knowledge gap, probiotics should only be used in the context of a clinical trial for adults and children with UC. This was based on six RCTs and used an older 2011 Cochrane review rather than the 2020 review.

Clinical practice guidelines based on a small number of older RCTs recommend that probiotics should be considered as treatment for the maintenance of remission in individuals with mild to moderate UC. ESPEN suggests that the probiotic strains Escherichia coli (E. coli) Nissle 1917 and VSL#3 (see Remarks) are beneficial. This is based on one systematic review (n=2 RCTs specifically investigated the effect of E. coli Nissle on the maintenance of remission in UC) and one separate RCT (investigating the effect of VSL#3 on the maintenance of remission in UC). ESPEN also provided a cautionary note in relation to the probiotic stain Lactobacillus rhamnosus GG and cases of bacteraemia in individuals with acute severe colitis. The WGO guidelines recommend E. coli Nissle 1917 for adults only, based on two RCTs.
Grade of Evidence C

Remarks
The most studied probiotics strain was E. coli Nissle 1917 (n=5 of the studies below) with a dose of around 200 mg/day (100 mg contains 2.5-25×109 bacteria). All other studies used different single or multiple strains at different doses.
 
The VSL#3 probiotic formulation used in the literature cited in this practice question is no longer available under the same brand VSL#3. 
 
6. Crohn’s Disease Management
Prebiotic or Synbiotic Supplementation
GRADE Recommendation
not taking prebiotic supplements as a dietary modification to help manage Crohn’s disease.

not taking synbiotic supplements as a dietary modification to help manage Crohn’s disease.
Conditional recommendation |  Low quality evidence ⊕⊕⊝⊝

Remarks
The suggestion against a prebiotic supplement is based on low quality evidence that indicated the majority of studies reported no effect or a negative effect on disease activity, quality of life, remission and bowel symptoms. Inconsistency among trials was an issue for outcomes for which a positive effect was reported (disease activity and bowel symptoms). Prebiotic doses ranged from 10 g/day of ispaghula to 15-20 g/day of mixed inulin and oligofructose and treatments lasted one to three months. Participant populations included men and women with active disease or a mix of active disease and disease in remission.

The suggestion against synbiotic supplements (combination pre- and probiotics) is based on evidence that indicated no difference in disease relapse or bowel symptoms between those who received a synbiotic and those who received a placebo. Synbiotic doses ranged from 10 g/day of prebiotics (equal mix of β-glucans, inulin, pectin and resistant starch) with 4x10^10 CFU lactobacilli or four strains of probiotics (strains and doses not reported) to 12 g/day of inulin/oligofructose and 2x10^11 CFU Bifidobacterium longum. Treatment durations ranged from six to 24 months. Disease status may be an important consideration. A single, low quality study in individuals with active disease reported an improvement in disease activity compared to baseline after six months of treatment with 12 g/day inulin/oligofructose and 2x10^11 Bifidobacterium longum. There was no difference between groups for measures related to disease relapse and both groups experienced improvements in quality of life and bowel symptoms.

For both prebiotic and synbiotic supplements, additional research is recommended with larger numbers of participants that targets individuals in specific disease states (i.e. active, in remission and in remission with ongoing functional or IBS-like symptoms). No research on patient preferences for these supplements was identified.
 
Modified Dietary Fibre Intake and Crohn’s Disease 
GRADE Recommendation
a high fibre diet as a dietary modification to help manage Crohn’s disease (active or in remission).

a low fibre diet as a dietary modification to help manage Crohn’s disease (active or in remission).
Conditional recommendation |  Very low quality evidence ⊕⊝⊝⊝

Remarks
Consistent evidence showed no difference between high fibre (27-46 g/day) and moderate fibre (about 16 g/day) diets on disease activity scores and bowel symptoms. The suggestion against a high fibre diet for adults with Crohn’s disease (active or in remission) was made by placing a higher value on inconsistent evidence that reported high fibre increased risk of disease relapse than on inconsistent evidence that reported it increased quality of life. The overall quality of evidence was very low based on serious risk of bias, some inconsistency among research studies and small numbers of participants in studies. Additional research is required to support the conclusions.

The suggestion against a low fibre diet is based on a single very low quality trial that showed no difference between a low fibre (about 3 g/day) and a moderate fibre (about 13 g/day) diet on disease activity scores, steroid use or weight in individuals with Crohn’s disease (active or in remission). Additional research is required with larger samples sizes, lower risk of bias and subgroup analysis by disease state (active, in remission, in remission with ongoing functional or IBS-like symptoms).

After assessing current dietary fibre intake, targets should be discussed with individuals while taking into account individual preferences and the health benefits associated with fibre independent of Crohn’s disease. Some individuals may be reluctant to follow a more liberalized diet if it contradicts previous dietary counselling advice.

For individuals at risk of bowel obstruction or with stricturing CD, see Additional Content: Can a low fibre diet prevent bowel obstruction in individuals at risk of bowel obstruction?

Probiotic Supplementation
Recommendation
Based on very limited evidence, there appears to be no benefit of probiotics compared to placebo in inducing remission in mild to moderate Crohn’s Disease (CD). Probiotics were not associated with adverse effects in the studies. 

Evidence Summary
Results from a 2020 Cochrane review of two small RCTs found no difference in effect when probiotic supplements were given for the induction of remission in CD (Crohn’s Disease Activity Index 150-450) compared to placebo after six months. No serious adverse events were noted and no difference in adverse events were observed between probiotics and placebo. The certainty of evidence was assessed as being very low due to the risk of bias and imprecision.
Grade of Evidence C
 
Remarks
The probiotics strains investigated in the Cochrane review included: Lactobacillus rhamnosus GG and Bifidobacterium longu.
 
See Additional Content: 
 
7. Nutrition Concerns and Pregnancy 
Evidence Summary
Expert consensus (supported by studies in healthy pregnancies) recommends that women with IBD follow the nutrition guidelines set forth by the WHO for all pregnant women and that iron and folate levels should be monitored regularly to avoid deficiencies.
Grade of Evidence C

A prospective cohort study suggests that inadequate gestational weight gain is associated with a more than doubled risk of premature delivery in women with IBD, independent of disease activity.
Grade of Evidence C

Remission
Evidence Summary
An uncontrolled observational study reports that individualized restriction diets for remission maintenance in Crohn’s disease (CD) were not associated with an increased risk of adverse pregnancy outcomes compared to the general population.
Grade of Evidence D

Flare-ups 
Evidence Summary
An uncontrolled observational study and case reports indicate that treating disease flare-ups during pregnancy with an elemental diet has been associated with successful outcomes for both mother and infant.
Grade of Evidence C  
 
Remarks
Women with IBD who become pregnant, particularly while the disease is active, have a higher incidence of adverse pregnancy outcomes and should be treated as a potentially high risk group. Women with IBD should be encouraged to plan pregnancy during periods of stable remission and, like all women of reproductive age, should ensure adequate folate intake through diet or supplementation before conception.

Expert consensus recommends that iron and folate levels be checked regularly throughout the pregnancy and limited evidence suggests that inadequate gestational weight gain should be addressed early with nutrition interventions. If IBD flares up during pregnancy, limited evidence suggests that enteral feeding using an elemental diet can be used successfully with normal pregnancy outcomes for both mother and infant.
 
Additional Remarks
For women who take sulphasalazine as part of their treatment, folic acid supplementation before conception may be particularly important as sulphasalazine is a known folic acid antagonist that has been associated with folate deficiency.

Women with IBD who become pregnant, particularly while the disease is active, have a higher incidence of adverse pregnancy outcomes and should be treated as a potentially high risk group. Women with IBD should be encouraged to plan pregnancy during periods of stable remission and, like all women of reproductive age, should ensure adequate folate intake through diet or supplementation before conception.

Expert consensus recommends that iron and folate levels be checked regularly throughout the pregnancy and limited evidence suggests that inadequate gestational weight gain should be addressed early with nutrition interventions. If IBD flares up during pregnancy, limited evidence suggests that enteral feeding using an elemental diet can be used successfully with normal pregnancy outcomes for both mother and infant.

Target Group: All Adults
Knowledge Pathways: Gastrointestinal System - Inflammatory Bowel Disease
 Last Updated: 2022-04-05