Environmental risk factors for inflammatory bowel diseases: Evidence based literature review

Table 1 Commonly studied environmental factors in inflammatory bowel diseases

Environmental factor
Lifestyle
Smoking
Sleep
Stress
Diet
Breastfeeding
Pharmacologic agents
Non-steroidal anti-inflammatory drugs
Antibiotics
Oral contraceptives
Vaccination
Gut Microbiome
Dysbiosis
Ecological factors
Air Pollution
Water Pollution
Low Vitamin D
Surgery
Appendectomy

Table 2 Oxford Centre for Evidence-Based Medicine evidence levels of evidence scale

Level	Study questions on therapy/prevention, etiology/harm
1a	Systematic review (with homogeneity of RCTs)
1b	Individual RCT (with narrow confidence intervals)
1c	All or none studies
2a	Systematic review (with homogeneity) of cohort studies
2b	Individual cohort study (including low quality RCT, e.g., < 80% follow-up)
2c	Outcomes research: ecological studies
3a	Systematic review (with homogeneity) of case control studies)
3b	Individual case control study
4	Case-series (and poor quality cohort an case control studies ++)
5	Expert opinion without explicit critical appraisal or based on physiology, bench research or first principles

Users can add a minus-sign “-” to denote the level of evidence that fails to provide a conclusive answer because: either a single result with a wide confidence interval, or a systematic review with troublesome heterogeneity. Provided by Ref. [7].

Table 3 Effect of environmental factors in Crohn’s disease and impact of interventional studies to modify specific environmental factors

Ref.	Disease onset (Incident CD)	Disease progression	Study populationand design	Intervention and comparison group	Outcome
Lifestyle
Smoking[11,13] (LOE 2b, 2a)	↑	↑	Cohort study current smokers with CD (n = 474)[17] (LOE 2b)	Smoking cessation counselling	Decreased risk of flares, need for surgery and immunosuppressive therapy[17]
			Cohort study current smokers with CD (n = 408)[18] (LOE 2b)	Quitters vs non-quitters	Continuing smokers had more disease relapses, and patients who quit smoking had similar relapse incidence compared with non-smokers[18]
Sleep[177,178] (LOE 2b)	No data	↑	None	None	No data
Stress[158,159] (LOE 2b)	No data	↑?	Adult and adolescent patients with IBD Systematic review of RCTs and quasi-RCTs (n = 1745)[162] (LOE 1a)	Multi-modality psychotherapy	No evidence for efficacy of psychological therapy in adult patients with IBD In adolescents, psychological interventions may be beneficial, but the evidence is limited
Diet
Dietary fat[118] (LOE 3a)	n-6 PUFA↑	↓	CD in remission Systematic review of RCTs (n = 1039)[201] (LOE 1a)	Fish oil n-3 (PUFA) or placebo	Non-significant trend towards lower risk of relapse at 1 yr in fish oil group compared with placebo
	n-3 PUFA↓
Dietary protein[118,120] (LOE 3a, 2b)	Animal protein( meat and fish)↑	↔?	Mild- moderate CD	Restricted diet ( red meat + spelt bread) or control diet (low-fiber, low-fat, and high-carbohydrate )	Radiologic and endoscopic improvement in restricted diet group (interpret with caution; small study with limited generalizability)
	Vegetable and diary↓		RCT (n = 18)[197] (LOE 2b)
Dietary fiber[118,120] (LOE 3a, 2b)	Fruit and vegetable fiber↓	↓	Inactive or mildly active CD, RCT (n = 352)[207] (LOE 1b)	High fiber diet vs low fiber	No difference in disease activity, surgery or hospitalizations
Food additives [Microparticles (MP)[130,131] (LOE 5)]	High MP-diet↑	High-MP diet↑	Active CD RCT (n = 20)[203] (LOE 1b) RCT(n = 83)[202] (LOE 1b)	Low -MP-diet vs control diet	Decrease in CDAI in smaller trial[203]
					No difference in larger trial[202]
Fruits and vegetables[118] (LOE 3a)	↓	↓?	CD in remission	Semi-vegetarian diet or omnivorous diet	Maintenance of remission rates higher on semi-vegetarian diet compared to omnivorous diet
			RCT (n = 22)[198] (LOE 1b)
Food antigens[128] (LOE 4)	No data	↑	Active and inactive CD RCT (n = 40)[129] (LOE 2b) Active CD Systematic review RCTs (n = 334)[210] (LOE 1a)	Elimination diet based on IgG positivity to cheese and yeast or sham diet	Daily stool frequency significantly decreased by 11% during a specific diet compared with a sham diet. Abdominal pain reduced and general well-being improved[129]
				Elemental vs non-elemental diet	No difference in the efficacy between elemental and non-elemental diet[210]
Enteral nutrition	No data	↔	Active CD Systematic review (n = 192)[210] (LOE 1a)	Enteral nutrition vs corticosteroids	Enteral nutrition less effective than corticosteroids for induction of remission
Breastfeeding[187-189] (LOE 3a, 3b, 2b)	↔	No data	None	None	No data
Pharmacologic agents
Nsaids[139-140] (LOE2b)	↑?	↑	Inactive IBD with arthralgia.	Rofecoxib 25 mg or 12.5 mg x 20 d	41% responded with reduction in arthralgia scores. P < 0.05. No IBD flares
			Open label trial (n = 32)[144] (LOE 2b)		9% developed GI side effects
Oral contraceptives[150,151,153,155] (LOE 3a, 2b)	↔	↔	None	None	No data
Antibiotics[145-147] (LOE 3b, 3a)	Early exposure↑	↓	Active CD Systematic review of RCTs (n = 1160)[71] (LOE 1a-)	Antibiotic or placebo	Antibiotics superior to placebo at inducing remission
Vaccination[183] (LOE 3a)	No effect	No effect	None	None	None
Gut microbiome
Dysbiosis[80-82] (LOE 4)	↑	↑	Mild-moderate CD Systematic review of RCTs (n = 746)[199] (LOE 1a)	Probiotics, prebiotics and synbiotics or placebo	Insufficient data to recommend probiotics for use in CD
Ecological (Abiotic)
Air pollution[33,34] (LOE 2c, 3b)	↑	↑?	None	None	No data
Water pollution[36-38] (LOE 5)	↑?	↑?	None	None	No data
Low Vitamin D[42,44,57,59] (LOE 2b, 3a, 2b)	↑	↑	CD in remission RCT (n = 94)[51] (LOE 1a)	Vitamin D3 or placebo	Lower relapse rates in patients randomized to vitamin D3 1200 IU/d[51]
			Mild-moderate CD Cohort study (n = 18)[60] (LOE 2b)	No comparison group	24 wk of vitamin D3 (up to 5000 IU/d) reduced mean CDAI scores by 112 ± 81 points from 230 ± 74 to 118 ± 66 (P < 0.0001). Quality-of-life scores also improved following vitamin D supplementation[60]
Surgery
Appendectomy[192,193] (LOE 3b, 3a)	↔	No data	None	None	No data

↑ : Increased risk; ↔ : Equivocal risk; ↓ : Decreased risk; ? : Questionable risk. LoE: Levels of Evidence; CD: Crohn's disease; IBD: Inflammatory bowel diseases; PUFA: Polyunsaturated fatty acid.

Table 4 Effect of environmental factors on ulcerative colitis and impact of interventional studies to modify specific environmental factors

Ref.	Disease onset (incident UC)	Disease Activity	Study population and design	Intervention and comparison group	Outcome
Lifestyle
Smoking[11,20,24] (LOE 2b, 3b, 2a)	Current smoking ↓	↓	Mild-moderate UC Systematic review (n = 233)[205] (LOE 1a) (n = 81)[205] (LOE 1a)	Nicotine or placebo	No evidence for efficacy for nicotine preparations in inducing remission in UC
	Smoking cessation ↑			Nicotine or corticosteroids
Sleep[176,179] (LOE 2b)	No data	↑	None	None	No data
Stress[158,159] (LOE 5, 2b)	No data	↑?	Adult and adolescent patients with IBD	Multi-modality psychotherapy	No evidence for efficacy of psychological therapy in adult patients with IBD
			Systematic review of RCTs and quasi-RCTs (n = 1745)[162] (LOE 1a)		In adolescents, psychological interventions may be beneficial, but the evidence is limited
Diet
Dietary fat[118] (LOE 3a)	n-3 PUFA ↓	n-3 PUFA ↓	UC in remission Systematic review of RCTs (n = 148)[208] (LOE 1a)	fish oil (n-3 PUFA) or placebo	No difference in risk of relapse between n-3 PUFA compared with placebo
	n-6 PUFA ↑
Dietary milk[116,117] (LOE 5)	↑	No data	Active UC	Milk-free diet or sham diet	Fewer relapses on milk-free diet than on sham diet
			RCT (n = 77)[209] (LOE 2b)
Dietary protein[118] (LOE 3a)	↑	↑	None	None	No data
Dietary fiber[118,120] (LOE 2b)	↔	↔	UC in remission Open label RCT (n = 59)[200](LOE 2b)	Germinated barley food stuff (GBF) + conventional therapy or conventional therapy	Prolonged maintenance of remission in GBF group[200]
			UC in remission Open label RCT (n = 105)[122] (LOE 2b)	Plantago ovata or Mesalamine	Plantago ovata as effective as Mesalamine in maintenance of remission[122]
Food antigens[128] (LOE 4)	↑?	No data	None	None	No data
Food additives[131,132] (LOE 5)	↑?	No data	None	None	No data
Breastfeeding[187,189] (LOE 3a, 3b, 2b)	↔	No data	None	None	No data
Medication
Nsaids[139,140] (LOE 2b)	↑?	↑	Quiescent to mild	Rofecoxib 25 mg or 12.5 mg × 20 d	41% responded with reduction in arthralgia scores. P < 0.05. No IBD flares 9% developed GI side effects
			UC and CD with arthralgia
			Prospective Open label trial (n = 32)
Oral contraceptives[150,151,153,155] (LOE 3a, 2b)	↑	↔	None	None	No data
Antibiotics[145,147] (LOE 3b, 3a)	Early exposure ↔	↓	Active UC Systematic review of RCTs (n = 9 studies)[71] (LOE 1a)	Antibiotic or placebo	Antibiotics superior to placebo at inducing remission
Vaccination[183] (LOE 3a)	No effect	No data	None	None	No data
Gut microbiome
Dysbiosis[80,83,84] (LOE 4)	↑	↑	Mild-moderate UC Systematic review of RCTs (n = 650)[199] (LOE 1a)	Probiotics + conventional treatment or placebo	Probiotics effective for induction and maintenance of remission in UC and pouchitis[199]
			Active UC RCT (n = 70)[204] (LOE 1b)	Fecal microbiota transplant (FMT) or Placebo	FMT induced remission in a significantly greater percentage of patients with active UC than placebo (24% vs 5%)[204]
			Active UC, RCT (n = 100)[206] (LOE1b)	Ciprofloxacin + E-coli Nissle or placebo + E-coli Nissle	No benefit in the use of E. coli Nissle as an add-on treatment to conventional therapies for active UC
Ecological (Abiotic)
Air pollution[33,34] (LOE 2c, 3b)	↑	↑	None	None	No data
Water pollution[36-38] (LOE 5)	↑	↑	None	None	No data
Low Vitamin D[44,57] (LOE 2a, 2b)	↑	↑	Active UC Cohort study (n = 368)[59] (LOE 2b)	Vitamin D3 or No treatment	Reduction in health-care utilization in the vitamin D treatment group
Surgery
Appendectomy[195-196] (LOE 2b, 3b)	↓	No data	None	None	No data

↑ : Increased risk; ↔ : Equivocal risk; ↓ : Decreased risk; ? : Questionable risk. LoE: Levels of Evidence; CD: Crohn's disease; IBD: Inflammatory bowel diseases; PUFA: Polyunsaturated fatty acid; UC: Ulcerative colitis.