Lactose Intolerance and Small Intestinal Bacterial Overgrowth (SIBO) in Paediatric Patients with Inflammatory Bowel Disease

Abstract

In recent years, an increase in the incidence of Inflammatory Bowel Disease has been observed, with particular emphasis on Crohn’s disease and ulcerative colitis in the paediatric population, also in the youngest age group. Underlying factors are genetic, environmental (including the microbiome) and immunological. Clinical manifestations are very often uncharacteristic, and the clinical picture is dominated by abdominal pain, weight/growth deficiency and/or diarrhoea. Similar symptoms occur in the course of lactose intolerance and small intestinal bacterial overgrowth (SIBO). On the other hand, Inflammatory Bowel Diseases (IBD) seem to favour the onset of SIBO and lactose intolerance. Only the diagnosis of these disease entities ensures appropriate therapeutic management. The manuscript analyses the latest literature on the co-occurrence of these disease entities in patients with IBD—especially Crohn’s disease and ulcerative colitis, clinical symptoms, and diagnostic and therapeutic procedures.

1. Introduction

In recent years, an increase in the incidence of Inflammatory Bowel Disease has been observed, with particular emphasis on Crohn’s disease (CD) and ulcerative colitis (UC) in the paediatric population, also in the youngest age group. Underlying factors are genetic, environmental (including the microbiome) and immunological.

Clinical manifestations are very often uncharacteristic, and the clinical picture is dominated by abdominal pain, weight/growth deficiency and/or diarrhoea. Similar symptoms occur in the course of lactose intolerance and SIBO. On the other hand, Inflammatory Bowel Diseases seem to favour the onset of SIBO and lactose intolerance. Only the diagnosis of these disease entities ensures appropriate therapeutic management [1, 2, 3, 4, 5, 6].

2. Lactose intolerance

Lactase is also known as Beta-galactosidase. Its maximum activity can be observed in the descending part of the duodenum and the initial section of the jejunum—on the upper surface of the villi. The activity of lactase can be observed as early as the 12th week of pregnancy, with its peak activity after birth when it is twice as high as in older children. A drop in the lactase activity can be seen from the 2nd-3rd year of life and varies according to ethnicity. Lactase activity is not diet-dependent—the amount of lactose in the diet. It has been stressed that lactose plays an important role in the human body:

• It is a source of energy (human milk contains around 7 g of lactose/100 ml and cow milk around 3.5 g/100 ml);

• It participates in the intestinal regenerative processes;

• It stimulates the growth of acidophiles

• It takes part in calcium metabolism and the absorption of iron

• It impacts the motor activity of the gastrointestinal tract

• It has a low glycaemic index [7, 8, 9, 10].

2.1 Epidemiology

The problem of lactose intolerance affects 50% of the adult population of South America and Africa. In the US, it concerns 15% of the white population, 53% of Mexican-Americans and 80% of the black population. In Sicily, lactose intolerance occurs in 70% of adults, in Scandinavia—in 2–5% of the population and in Poland in 20–35% of adults and 20% of school-age children. The meta-analysis on lactose intolerance rates does show a statistically significant increase in prevalence. Adult type-hypolactasia: Among Europeans, two single-nucleotide polymorphisms were described upstream of the LCT–gene: LCT-13910CC and LCT-22018GG. In Europe, the incidence of the LCT 13910CC or 22018GG genotype among healthy adults was 30–40%.

2.2 Clinical manifestations of lactose intolerance

The most common symptoms of lactose intolerance include osmotic diarrhoea, abdominal pain and bloating, rumbling and gurgling. At times, dyspeptic symptoms, nausea and vomiting may occur as well as symptoms of depression caused by the abnormal metabolism of tryptophane. In infants, high levels of acidic metabolites in faeces may irritate the skin of the buttocks [7, 8, 9, 10].

Types of lactose intolerance:

1. Congenital alactasia, characterised by a complete lack of lactase activity since birth. The condition is very rare, and only single cases have been reported in the relevant literature. The symptoms are very dramatic and the clinical manifestations are dominated by intense diarrhoea since early infancy—following the introduction of breast-feeding or lactose-containing modified formula—promptly leading to dehydration and a disturbance in the acid–base and electrolyte balance. Such infants will not tolerate even minute amounts of lactose in their diet. The histopathological examination of the small intestine comes back normal. Only an early diagnosis combined with a lactose-free diet would ensure the survival of such children. A lactose-free diet will have to be adhered to for life.

2. Adult-type hypolactasia—genetically determined—inherited as an autosomal recessive trait. The gene is located on chromosome 2. The activity of lactase is inter-subject variable but never amounts to zero. The activity of the enzyme reduces with age and the time it takes for symptoms to start depends on a number of factors, including the patient’s ethnicity. The most common type is a consequence of lactase depletion. The decrease of lactase production starts in the second year of life, although the first symptoms occur in adolescence or adulthood. The structure of the intestinal villi is normal, and organic diseases of the gastrointestinal tract are ruled out.

3. Secondary lactase deficiency. Most commonly observed as a result of damage to/atrophy of the small intestine villi or caused by toxic substances (chemotherapeutics, tetracycline, colchicine), in the course of coeliac disease, food allergy, Crohn’s disease, severe giardiasis, radiation-induced intestinal damage and/or post-resection syndromes [7, 8, 9, 10].

2.3 Lactose intolerance diagnosis

In most patients, lactose intolerance is diagnosed based on a thorough medical history and the elimination-provocation test using lactose containing products. The following are used additionally in the diagnostics of lactose intolerance:

• The assessment of faecal pH and reducing substances (>0.5%), increase in the amount of lactic acid in stools, increase in osmolity >140mOsmol/l

• Hydrogen breath test after a lactose load—positive test—increased concentration levels of hydrogen >20 ppm during 3-hour examination

• Capillary blood sampling of glucose after an oral lactose load

• The assessment of the activity of lactase in the small bowel mucosa specimen—the procedure is invasive, difficult to perform and not reflecting the full activity of the enzyme in the intestine

• Genetic testing—in the case of adult-type hypolactasia, it does not reflect the actual activity of lactase—it is a gene associated with hypolactasia but the condition may occur at any age. A positive result of the genetic testing does not equal adult-type hypolactasia. However, the test remains valuable in the diagnostics of congenital alactasia.

Some of the factors that affect lactose tolerance include:

1. Increasing tolerance: small amounts, young age, slow emptying of the stomach, high total intestinal lactase and normal intestinal microbiome

2. Reducing tolerance: large amounts, older age, fast emptying of the stomach, low total intestinal activity and abnormal intestinal microbiome [11, 12, 13, 14, 15, 16, 17].

2.4 Treatment of lactose intolerance

The primary treatment of lactose intolerance is a diet aimed at reducing the intake of this disaccharide. Some of the products rich in lactose include sweet milk, cream and ice-cream. Fermented products like kefir, yoghurt and probiotic-enriched foods are recommended in patients with diagnosed lactose intolerance. In the cases when it is impossible to exclude lactose-containing products, pharmacological supplementation with lactase is recommended. It is important to take into account that lactose is a component of certain medication and foodstuffs.

The amount of lactose varies in the different types of dairy products and there is a large content of “hidden” lactose in many products not derived from dairy. Table 1 presents the summary of safe and not-recommended foodstuffs in lactose intolerance [8, 9, 10, 18, 19].

Dairy products rich in lactose (g/100 g)	Products with average lactose content (g/100 g)	Dairy products containing a small amount of lactose	Products with “hidden” lactose
Whole milk (4.9 g); Fat-free milk (5.3 g); Buttermilk (4.7 g); Goat’s milk (4.7 g); Cream flavour, ice cream (4.4 g); Powdered milk (4.2 g); Kefir (4.2 g); Sweet cream (3.9 g); Ricotta (3.5 g); Sour cream (ok. 3.5 g); Cottage cheese (3.2 g)	Feta cheese (1.4 g); Butter (0.6–1.1 g)	Mozzarella (0.7 g); Cheddar (0.5 g); Emmentaler and other types of cheese, hard-type cheese, e.g. parmesan, blue cheese, e.g. brie, camembert, gorgonzola: <0.1 g	Sweets with powdered milk, including chocolate, chocolate bars, confectionary sweets; Ready cake mixes; Bread, rolls, crescent-shaped rolls (a full-butter croissant contains on average 48 g of butter so approx. 3 g of lactose); Sauces, including ready ones, soups, puree and margarine
	Yoghurts: similar to kefirs and depending on the production process (the fermentation, the addition of milk powder) may contain from 0.5 (very rarely) to 4.5 of lactose. The most common products available on the market on average contain 3.3 g/100 g

Table 1.

The content of lactose in differed foodstuffs.

Ultimately, whether the clinical symptoms occur or not after a lactose-containing meal depends not only on the amount of lactose but also on the content of the whole meal, so the amount of protein and fat.

3. Small intestinal bacterial overgrowth

This is an abnormal, excessive growth of commensal bacterial in the small intestine, leading to abnormalities in the digestion and absorption of mainly fats and vit. B12. The excessive growth mainly involves the following bacteria: Escherichia coli, Enterococcus spp., Klebsiella pneumoniae. Dysbiosis is an imbalance in the intestinal microbial community leading to the loss of probiotics and the appearance of pathogenic strains. The type and proportions of the bacteria (enterotypes) take shape with age and the lifestyle and ensure the homeostasis of the gastrointestinal tract. Bacteriocins produced by probiotic bacteria with their bacteriostatic or bactericidal properties against sensitive pathogens modify the composition of the intestinal microbiota. The growth of the pathogenic bacteria is linked to the increase in the concentration levels of toxic and genotoxic bacterial metabolites not only in the intestine but also in the general circulation. Toxins induce mutations and by doing so they impact the transduction of the intracellular signals. The deconjugation of bile acids contributes to the maldigestion of fats and the production of the lithocholic acid, which may be toxic for enterocytes. The damage to the intestinal barrier leads to the translocation of the bacteria from the intestinal lumen to the surrounding tissues, lymph glands and the circulatory system. The enterotoxins reaching the liver are strong activators of the T CD8 cytotoxic lymphocytes, which play a role in the fibrogenesis.

The first study by Faber describing the link between pernicious anaemia and intestinal narrowing was published in 1897. In 1939, Barker and Hummel put forward a hypothesis that there was a link between pernicious anaemia and small intestinal bacterial overgrowth. The microbiome plays a role not only in the pathogenesis of the disorders of the gastrointestinal tract but also of the respiratory tract, the circulatory system, the endocrine system, the urinary system and/or the osteoarticular system. It affects the functioning of the central nervous system; it impacts the mood and the processes of perception [17, 20, 21, 22, 23].

Non-pathogenic intestinal bacteria impact the development of the immune system, the morphology of the intestinal villi and the intestinal crypts and the motor activity.

In the clinical studies of healthy persons, SIBO is present in 0–20%.

Some of the mechanisms that protect from the development of small intestinal bacterial overgrowth include the following:

• Low-pH gastric juice

• The presence of pancreatic juice, which contains bactericidal enzymes (proteolytic and lipolytic)

• The normal motor activity of the small intestine

• The presence of mucosa lining the intestinal epithelium

• The gut mucosal immune system—secretory IgA, the Paneth cells

• Antibacterial property of bile

• Anatomical barrier between the colon and the small intestine—the ileocecal valve [17, 20, 21, 22, 23].

Factors contributing to the occurrence of small intestinal bacterial overgrowth are presented below (Table 2) [17, 20, 21, 22, 23, 24, 25, 26].

Factors influencing the risk of developing SIBO
Anatomical anomalies	The presence of intestinal diverticula, intestinal fistula, intestinal strictures
Post-surgical lesions	lleocecal valve resection, gastroenterostomy bypass, Roux-en-Y-type surgeries, post-operative adhesions
Medication affecting the motor activity of the gastrointestinal tract	opiodis, anticholinergics medication used in the treatment of diarrhoea/constipation
Reduced secretion of gastric juice	Conducted gastrectomy, autoimmune gastritis, chronic use of proton pump inhibitors
Insufficient digestive enzymes/bile acids	Cystic fibrosis, chronic pancreatitis, cirrhosis (PPC, PBC)
Disorders of the motor activity of the small intestine	Bowel inflammatory diseases, coeliac disease, radiation enteritis, diabetes, amyloidosis, scleroderma, intestinal pseudo-obstruction, gastroparesis drug-induced (opioids, anticholinergics)
Immunodeficiencies	HIV, congenital immunodeficiency (primary hypogammaglobulinaemia, immunosuppressive therapy)
Inflammatory	Non-specific inflammatory bowel diseases
Infections	Infections of the gastrointestinal tract
Metabolic	Diabetes
Dietary	High-fat, high-carbohydrate and low-fibre diet
Others	Irritable bowel syndrome

Table 2.

Factors contributing to the occurrence of small intestinal bacterial overgrowth.

It has to be remembered that the chronic use of proton pump inhibitors is an independent factor in the development of SIBO (decrease in the population of Bacteroides and increase in Firmicutes), which may lead to an increase in Clostridioides difficile.

Small intestinal bacterial overgrowth leads to many serious complications, some of which include the following:

1. Abnormalities in the metabolism of fatty acids—fat digestion disorders - > steatorrhea, and malabsorption of fat-soluble vitamins

2. B12-deficiency anaemia

3. Secondary malabsorption syndromes

4. Disaccharidase deficiency and as a result of the abnormalities in their digestion and absorption

5. Increased absorption of antigens through damaged mucosa (immune complexes).

3.1 Microbiome and other diseases

There are studies dedicated to the impact of the changes to the microbiome on the following comorbidities:

• obesity and metabolic syndrome

• diabetes mellitus

• dyslipidaemia

• food allergies

• autoimmune diseases

• coeliac disease

• inflammatory bowel diseases

• irritable bowel syndrome

3.1.1 Epidemiology of small intestinal bacterial overgrowth

Accurate data concerning the occurrence of SIBO in the European and global population is unknown. SIBO affects around 50% of the patients who underwent gastrojejunostomy and vagotomy, 5% of the patients after vagotomy and pyloroplasty and 2–10% of those with autonomic diabetic neuropathy. There is no data concerning the paediatric population.

3.1.2 Clinical manifestations of small intestinal bacterial overgrowth

Very often the clinical manifestations of SIBO are highly non-specific and of little use in the diagnostic process. The more proximal section of the small intestine is affected by SIBO, the more severe the course of the disease is.

The clinical picture is dominated by the following:

• abdominal bloating/feeling full/excessive flatulence

• abdominal pain

• diarrhoea/constipation

• nausea/vomiting

• dyspeptic symptoms

• heartburn, regurgitation

• tiredness

• insufficient body weight

• oedema (intestinal loss of protein)

• ataxia, peripheral neuropathy

There is a link between the occurrence of irritable bowel syndrome (IBS) and of small intestinal bacterial overgrowth. Undoubtedly, the population of the bacteria present in the intestinal lumen plays a role—through the metabolic processes; the population of the bacteria in the intestinal mucosa—through the activation of immunological interactions with the host and the induction of persistent moderate inflammation. A decrease in the number of Lactobacillus and Bifidobacterium and an increase in the numbers of Clostridium and Enterobacteriaceae are observed. The bacteria forming the intestinal ecosystem of patients with IBS show little stability and are susceptible to significant malfunctions in the case of even mildly intensive factors such as stress, a diet high in animal-based saturated fats and synthetic carbohydrates, surgical procedures, non-steroidal anti-inflammatory drugs, proton pump inhibitors, H2 blockers, prokinetics and antibiotics.

3.1.3 Diagnostics of small intestinal bacterial overgrowth

A hydrogen and methane breath test is commonly used in the diagnostics of the condition. The cells of the human body do not produce methane or hydrogen in their gas forms. Their presence in the exhaled air indicates an increased metabolism of carbohydrates in the intestinal lumen. The production of gas in the intestinal lumen in the course of SIBO varies and depends on the volume and the types of the bacterial colonising the small intestine as well as the amount of carbohydrates in the lumen of the intestine and the intestinal capability of their absorption. According to NASPGHAN, a heathy body contains between 30 and 100 ml of gas in the lumen of the intestine and it is mainly hydrogen, carbon dioxide, methane as well as smaller amounts of oxygen, nitrogen, hydrogen sulphide and ammonia. Enterobacteriaceae may also produce trace amounts of indole and its derivative—skatole, the so-called odorous gases. There are four main sources of intestinal gases. These are as follows: those swallowed with food, chemical reactions forming in the lumen of the intestine, blood diffusion and the metabolism of the intestinal bacteria. The last mechanism in the sole source of the origin of hydrogen and methane is used in the breath tests techniques. Anaerobic bacteria, which inhabit the large intestine in physiological conditions and the small intestine also in non-physiological conditions, cause the fermentation of undigested carbohydrates, and following the diffusion of thus resulting gases into the blood and their transport to the lungs—an increase in their concentration levels in the alveolar air [12, 13, 14, 16, 17, 26, 27, 28].

There is no single diagnostic test that would allow for the conclusive diagnosis of SIBO. Very often it is a good response to an empirical antibacterial treatment that acts as a confirmation.

1. Lactulose hydrogen breath test

   • 10 g of lactulose-disaccharide non-absorbable in the small intestine, water-soluble and subject to fermentation

   • Metabolised by gut microbiota ->hydrogen produced in the reaction

   • (+) test—increased concentration levels of hydrogen >20 ppm in the 90th minute after the oral administration of lactulose

2. Glucose hydrogen breath test—recommended. Following the oral administration of glucose and as a result of the fermentation processes, hydrogen is produced. An increase in the concentration levels of hydrogen >20 ppm after glucose load is considered a positive result.

3. Quantitative and qualitative culture of jejunal aspirates—the gold standard (important: technical challenges of sample collection, the risk of sample contamination, possibility of false-negative results). Quantitative and qualitative microbial investigation of duodenal or jejunal aspirates are considered the gold standard in the diagnostics of SIBO but techniques of aseptic sample collection are not standardised; during the endoscopy of the upper section of the gastrointestinal tract 3–5 ml of the content is aspirated and placed in aerobic and anaerobic conditions in a growth medium—SIBO is confirmed at the value of ≥10³ CFU/ml of the aspirate; the most common strains include Escherichia, Shigella, Aeromonas, Pseudomonas.

4. The PCR analysis of the contents of the jejunum.

Table 3 shows the doses of the substrates used in hydrogen breath tests.

Substrate	Aim of the diagnostics	ESNM—adults	ESNM—children	EPGHAN/NASPGHAN
		2021		2022
Glucose	SIBO	50 g in 250 ml of water	2 g/kg max. 50 g in 200–250 ml of water	50 g or 1 g/kg
Lactulose		10–20 g in 250 ml of water	10–20 g in 100–200 ml of water	10 g
Lactose	Lactose intolerance	25-50 g in the diagnostics of lactose malabsorption, 25 g in the diagnostics of lactose intolerance	0.5-2 mg/kg (max.25-50 g) in the volume corresponding to the 10–20% solution	50 g or 1 g/kg

Table 3.

Doses of the substrates used in breath tests.

There is a consensus in the diagnostics of SIBO that glucose seems to be more reliable than lactulose, which results from a greater probability of obtaining a false-positive result with lactulose because it accelerates the peristalsis.

As regards the assessment of the concentration of methane in the exhaled air this is recommended because around 1/3 of the European population is colonised with methane-producing microbiota such as Methanobrevibacter smithii. Its presence lowers the result of the hydrogen test because of the use of hydrogen as a substrate in the production of methane. Therefore, it is considered one of the reasons for a false-negative result. The colonisation of children with methanogenic bacteria is smaller; however, the incidence may be comparable to the adult population.

An increase of over 20 ppm in the concentration levels of hydrogen and of over 10 ppm of that of methane is considered a positive result. The starting—so before the load—concentration level of hydrogen in the exhaled air should be less than 10 ppm (according to ESPGHAN it is 7+/−5 ppm). If the obtained values are >10 ppm, the test should be stopped so the patient should not be given the tested disaccharide. ESNM recommends that if the result is ≥15 ppm on an empty stomach, the patient should be asked to rinse their mouth with water and the test can then be re-taken [12, 13, 14, 16, 17, 26, 27, 28]. Table 4 presents the causes of questionable results of breath tests.

Causes of questionable results of breath tests
Invalid collection on an empty stomach	False-positive results in intolerance testing	False-negative tests in intolerance testing
Diet rich in non-absorbable carbohydrates the day before the test	SIBO	Lack of hydrogen-generating microbiota (10% of the population)—may be determined with a lactulose test because lactulose is not absorbed in healthy people.; Medication—antibiotics and/or macrogol.; Lack of cooperation with the patient (if the test is performed in a standard way so without a valved mask)
Insufficient oral hygiene	Significantly accelerated OCTT	Significantly prolonged OCTT (if fermentation occurs once the measurements have been taken)

Table 4.

Causes of questionable results of breath tests.

The treatment of SIBO involves three stages:

1. Remission induction therapy—lasts between 5 days and 1 month—repetitive cycles (optimum 14 days)

2. Sustaining of remission

3. The treatment of/the modification of the factors underlying the bacterial growth

Rifaximin forms the basis of the treatment. It is an antibiotic and a eubiotic—it acts as a modulator of the intestinal microenvironment. Rifaximin has antibacterial, anti-inflammatory properties—it modulates the immune response of the host, lowers the IL-6 and alpha TNF and binds the pregnane X receptor—PXR. It also modulates the activity of the intestinal microbiome (the metabolism, the binding and the virulence). Additionally, it hinders the bacterial interaction with the body and the activation of its immune response. Rifaximin is used in the dose of 800–1650 mg/day for 10–14 days. The TARGET 1, TARGET 2 and TARGET 3 studies of patients with IBS have shown the disappearance of symptoms in 40.7% and a reduction in bloating in 40.2% (NNT-10.1). About 83–86% of patients had a negative result of the control hydrogen breath test. The eradication of the bacteria and the disappearance of symptoms were observed in 70% of patients. Rifaximin showed its antibacterial effects against E.coli, Klebsiella spp., Enterobacter spp. and Enterococcus faecalis [17, 20, 21, 22, 23].

The meta-analysis of 32 clinical studies involving a total of 1331 patients showed that the proportion of the eradication of SIBO following the administration of rifaximin and confirmed with breath test was 72.9%, and the withdrawal of symptoms was confirmed in 67.7% of patients with SIBO. The daily recommended dose of rifaximin for adults is 1600 mg/day for 14 days. In the case of the recurrence of SIBO, the treatment with rifaximin may be cyclical with 30-day intervals between the cycles [17, 20, 21, 22, 23].

SIBO is characterised as relapsing because after receiving the first successful dose of antibiotics, approximately 44% of patients suffer from the same symptoms again after 9 months. Based on the severity of the symptoms and their rapidity of return, patients usually need to follow a regimen of rotating different antibiotics [17, 20, 21, 22, 23].

OTHER ANTIBIOTICS used in the treatment of SIBO

• Ciprofloxacin

• Metronidazole

• Doxycycline

• Amoxicillin

• Neomycin

PROBIOTICS- even though the use of antibiotics in the treatment of SIBO may seem illogical, experiments conducted on rats indicate that probiotics may act as prokinetic agents. The meta-analysis investigating the use of probiotics in SIBO showed a decrease in the production of hydrogen (OR 1.61; 95% CI: 1.19–2.17). However, the studies included in the meta-analysis involved small groups of patients, different preparations of probiotics were used, and different final outcomes were assessed. In a recent randomised study, it has been shown that probiotics may cause SIBO and lactic acidosis, and may trigger excessive flatulence and bloating. These symptoms disappeared once the probiotic was stopped and an antibiotic was introduced.

Undoubtedly, probiotics have a beneficial effect on the intestinal microbiome, they modulate the balance between saprophytes and pathogenic bacteria, and they restore the microbiological homeostasis of the intestines. Some probiotics have the ability to stimulate the production of mucin by increasing the expression of the MUC2 genes. Probiotics may be identified based on their ability to colonise the intestinal mucosa, which, in the future, may facilitate targeted therapies, according to the clinical needs. Probiotics may increase the effectiveness of the antibiotic therapy, for example, Lactobacillus casei. There is some evidence suggesting that during a prolonged therapy with proton pump inhibitors the probiotic bacteria Bacillus subtilis and Enterococcus faecium may be effective in the therapy of SIBO. However, controlled, double-blind clinical studies are needed to confirm which probiotic strains are effective, their doses and the duration of therapy. Therefore, the ACG experts concluded that there is no data justifying the use of probiotics in the treatment of SIBO [17, 20, 21, 22, 23].

FAECAL TRANSPLANT The data concerning the effectiveness of faecal microbiota transplantation in patients with SIBO is scant and casuistical. Currently, it is not recommended in the treatment of SIBO. Additionally, recently there have been warnings about the risk of transferring multidrug-resistant bacteria during the procedure. There are no grounds for routine faecal microbiota transplantation when treating SIBO.

3.1.4 Diet and SIBO

The main dietary modification in SIBO is the reduction in the intake of fermentable foods and those low in fibre, polyols, and fermenting sweeteners such as sucralose. Also, prebiotics, for example inulin, should be avoided. The introduction of the FODMAP diet, so one with small amounts of fermentable oligo-, di- and monosaccharides, and polyols. However, this diet should only be used for a limited time—from 4 to 6 weeks.

Elemental diets may be a safe and effective alternative for antibiotics—for those patients not tolerating antibiotics or not responding to them. The nutrients are absorbed in the initial sections of the small intestine and do not reach the bacteria in the further sections of the intestine. Such therapy should last at least 2 weeks.

Undoubtedly, the following support the treatment:

• Regular meals

• Avoiding large volumes of meals

• Reducing the fat content in the diet

• Reducing the content of foods which cause bloating

The treatment of the primary disease is of paramount importance in the following:

• Inflammatory bowel Diseases

• Coeliac disease

• Diverticulosis

• Connective-tissue diseases—autoimmune disease (lupus, scleroderma)

• Diabetes mellitus

• Adhesive disease

SIBO complications—deconjugation of bile acids leading to impaired digestion of fats → steatorrhea and abnormal absorption of fat-soluble vitamins; intra-intestinal decomposition of proteins by the bacteria → abnormal absorption of amino acids; vitamin B₁₂ deficiency → megaloblastic anaemia; damage to the intestinal villi and defective digestion of disaccharides → the lowering of the pH of the intestinal contents, excessive concentration of gases and bloating; excessive breaking down of proteins and urea with the production of ammonia → conducive for the development of encephalopathy in patients with liver failure; increased absorption of bacterial antigens into the bloodstream.

SIBO prevention:

• avoiding prolonged therapy with proton pomp inhibitors

• concurrent administration of IPP and probiotics, e.g. Bacillus subtilis, Enterococcus faecium

• avoiding unnecessary antibiotic therapy

• the treatment of the primary disease [17, 18, 20, 21, 22, 23].

4. Small intestinal bacterial overgrowth and inflammatory bowel disease

The composition of the gastrointestinal microbiota has a strong impact on the homeostasis of the entire organism. Imbalances of this part of the body can lead to the occurrence of many conditions and diseases. The intestinal microbiota is an essential element with regard to IBD. The gut microbiota is different in patients with Crohn’s disease where the disease is manifested in the colon and ileum. Lactose consumption helps maintain the balance of gut microbiota composition. Moreover, lactose contributes to the development of Bifidobacterium and other lactic acid bacteria. The change in the microbial population of the gastrointestinal tract can lead to inflammation. SIBO in patients with IBD may have clinical significance as it may contribute to the pathogenesis, symptom development, malabsorption with consequent malnutrition, altered drug metabolism and poor response to therapy [4, 17, 29, 30, 31, 32].

According to various reports, the frequency of SIBO occurrence is between 18 and 30% for Crohn’s disease and 14 and 17.8% for ulcerative colitis when the hydrogen breath test is used as a diagnostic method. Andrei et al. showed the prevalence of SIBO in patients with Crohn’s disease—overall, of the entire group of patients screened, SIBO was present in 30.77% of patients with CD—in particular in the patients with strictures, extensive lesions and advanced perianal lesions. Prevalence of SIBO in patients with ulcerative colitis was 19.4%. Distribution according to the Montreal classification: 28.5% with extended colitis, 25% with left-sided colitis and no patient with ulcerative proctitis [24]. Ghoshal in his study showed that patients with IBD had a higher risk of SIBO than healthy controls. SIBO was commoner among Crohn’s disease than ulcerative colitis. The factors associated with the presence of SIBO among patients with IBD included female gender, low serum total protein, albumin and prior surgical treatment for IBD [4]. This data was confirmed by Ricci et al. who proved that SIBO is a highly prevalent condition in patients with Crohn’s disease [33]. Wanzl has shown that an increased amount of SIBO was found in IBD patients and was especially more frequent in patients with Crohn’s disease than in those with ulcerative colitis. In patients with ulcerative colitis, SIBO rates were not different to patients with other gastrointestinal diseases investigated. In active IBD positive SIBO was detected more often [31]. Shah has conducted a systematic review with meta-analysis—the dataset included 11 studies (1175 adult patients with IBD and 407 controls)—all using the breath test for the diagnosis of SIBO. The proportion of SIBO in IBD patients was 22.3% [32]. However, Wei believes that patients with SIBO had a 2.27-fold elevated risk of clinical relapse compared to those without SIBO [34].

The risk factors that were identified as associated with the presence of SIBO in IBD patients are as follows:

• extended ulcerative colitis

• perianal and ileocolonic involvement in Crohn’s disease

• fibrostenosing forms of Crohn’s disease

• post-operative condition—postoperative absence of the ileocecal valve

• dysfunctions of the motor activity of the gastrointestinal tract

• abdominal fistulas

• drugs used in treatment—immunosuppressants [34, 35].

However, Sanchez-Montes believes that immunosuppressants and/or biological drugs do not induce SIBO in inactive CD. Fistulising disease pattern and meteorism are associated with SIBO [36].

5. Lactose intolerance and inflammatory bowel disease

The clinical symptoms of non-specific inflammatory bowel diseases and lactose intolerance may very often be similar and manifest themselves as abdominal pain, stomach gurgling, bloating and increased flatulence and/or belching. Sometimes, the distinction between the two conditions may be very difficult if it is only based on the clinical manifestations. On the other hand, differentiating the symptoms of the inflammatory bowel disease from symptoms of food intolerance is important to avoid the overtreatment of IBD-related intestinal inflammation, given its associated adverse effects. It is a condition with an inability to digest and absorb lactose and may occur in IBD patients because of the resulting changes in the structure and function of the GI tract related to the chronic inflammatory state of IBD [1, 2, 3, 37, 38, 39, 40, 41].

The largest meta-analysis by Szilagyi et al. included 17 studies and 1935 IBD patients. The risk of lactose maldigestion was reported to be higher among IBD patients than the controls. In subgroup analysis, the risk of lactose maldigestion was only significant for Crohn disease but not ulcerative colitis patients compared another study [42]. Mishkin reported that lactose intolerance prevalence in ulcerative colitis patients was more likely to follow the normal population, whereas Crohn’s disease patients had prevalence beyond the ethnic risk [43]. The additional risk in Crohn’s disease and intolerance lactose:

• Ethnic risk

• Location of the disease—the small bowel having the highest risk

• Coexistence small intestinal bacterial overgrowth

• Surgical treatment

• Exacerbation/acute phase disease

• Increased small bowel transit time

• Immunosuppressive therapy

The significance of decreased duodenal lactase levels in some patients with inflammatory bowel disease remains controversial.

Eadala et al., in their examination of 165 IBD patients with CC13910 genotype, reported that sensitivity to lactose occurs in a high percentage of patients in remission. They highlighted the importance of a thorough consideration of lactose malabsorption in IBD patients because of their similar symptomatology [3].

Research by Jasielska et al. indicated that lactose intolerance occurred in 23.2% of children with ulcerative colitis and 22.6% of those with CD. Secondary lactose intolerance in IBD was diagnosed in 6.7% of patients and its occurrence was not dependent on such factors as location, activity and duration of the disease or the number of relapses in the past [5]. On the other hand, Pawłowska et al. reported that lactose intolerance affected about 30% of children with IBD. In terms of IBD about 40% of patients with active IBD and about 33% of those in remission avoided products with lactose [10]. In his study, Tirpitz reported lactose intolerance in 46.9% of the patients with Crohn’s disease compared to 16.6% of those from the control group. A very high incidence rate of lactose intolerance was observed in the patients with the active form of the disease (CDAI>150)—83.3% and a long duration of the disease. Unlike other scientists, he did not show a correlation with the scope of the lesions and the condition after bowel resection [44]. Kirschner et al. were not able to show any statistically significant difference in the prevalence of lactose intolerance in children and adolescents with ulcerative colitis and Crohn’s disease. Involvement of the terminal ileum, disease activity and previous surgery have been discussed as determinants of intolerance lactose. He believed that the pathomechanism of lactose intolerance in patients with Crohn’s disease is not fully understood. Lactose maldigestion may be influenced by bacterial overgrowth and increased small bowel transit time [38]. Park et al. performed enzyme assays on jejunal biopsies. He did not find any increased prevalence of lactose intolerance in patients with inflammatory bowel disease [39]. In contrast, Dunnee et al. observed a significant reduction of lactase and other disaccharidases in mucosal biopsies from the proximal jejunum in Crohn’s disease patients. In patients with ulcerative colitis patients did not differ from the healthy control group [12]. In our studies (Wiecek and al.) assessing the activity of disaccharidases in the small intestine biopsy in children with IBD, a decreased activity of lactase was found in 33% of patients with Crohn’s disease and in 20% children with ulcerative colitis [45]. On the other hand, Pfefferkorn et al. did not show an increased incidence of decreased lactase activity in the intestine biopsies of patients with IBD in relation to healthy control [40]. Also, Nardone concluded the prevalence of lactose intolerance in IBD patients did not differ from that of control. Despite presenting suggestive symptoms, about 1/3 of IBD patients are not lactose intolerant, thus not needing “a priori” elimination diet [37].

The role of dairy foods in inflammatory bowel disease has been controversial and confounded by the phenotypic divide of lactase status in the adult population. In several polish studies, the incidence of the LCT-13910CC genotype associated with ATH in healthy people was estimated at 30–31.5%. It is suggested that lactose intolerance in inflammatory bowel disease is determined by ethnicity in most cases of ulcerative colitis and Crohn’s disease. Buning et al. in Germany did not find differences in the incidence of LCT-22018GG and LCT-13910CC genotypes between patients with IBD, their first-degree relatives and healthy volunteers [2]. Nolan et al. demonstrated with a large group of patients that T-allele in locus LCT-13910, responsible for lactase persistence, occurs more often in patients with Crohn’s disease [29]. On the other hand, Elguezabal also did not prove any connection between the genotype LCT-13910CC and inflammatory bowel diseases [35].

It has to be remembered that unnecessary elimination of dairy products from the diet may aggravate these deficiencies. Many IBD patients are already undernourished, especially those with uncontrolled disease or in acute flares; restrictive diets can further worsen their malnutrition. Avoiding dairy products and its associated long-term effects on bone density contributes to the increasing rates of osteoporosis among IBD patients, who are already at an increased risk, particularly those on chronic steroid or immunosuppressants. It is important to evaluate IBD patients to lactose intolerance before subjecting them to a lactose-restricted diet, given its potential adverse effects.

6. Summary

When objective evidence of active inflammation does not correlate with the persistent symptoms in IBD patients, clinicians should consider other disease with alternative pathophysiological mechanisms presenting with functional gastrointestinal symptoms, small intestine bacterial overgrowth and/or food intolerance (e.g. lactose intolerance). Differentiating the symptoms of IBD-related inflammatory changes from symptoms of non-IBD diseases is important to avoid the overtreatment of IBD-related intestinal inflammation, given their associated adverse effects.

The comparison between the clinical picture of lactose intolerance, small intestinal bacterial overgrowth and inflammatory bowel disease is shown in Table 5.

Parameter	Lactose intolerance	Small intestinal bacterial overgrowth	Inflammatory bowel disease
Pathogenesis	Genetic background; Lactase deficiency Lactose maldigestion	Dysfunction of the intestinal microbiome; Dysfunction of the motor activity of the gastrointestinal tract	Genetic factors; Immunological factors; Environmental factors
Clinical symptoms	Diarrhoea/constipation; Bloating; Abdominal pain; Nausea	Diarrhoea/constipation; Bloating; Abdominal pain; Nausea; Loss of body weight/difficulty getting weight; Loss of appetite; Anaemia	Diarrhoea/constipation; Bloating; Abdominal pain; Nausea; Loss of body weight/difficulty getting weight; Loss of appetite; Gastrointestinal bleeding; Fever; Anaemia
Abnormalities in the laboratory tests	No	Anaemia; Hypoproteinaemia; B12 deficiency	Anaemia; Elevated parameters of inflammation; High concentration of calprotectin in stools
Diagnostics	Elimination and challenge lactose Hydrogen breath test; Lactose/methane breath test; The presence of faecal reducing substances; Genetic tests; The assessment of lactase activity in mucosal biopsies	Lactulose/glucose hydrogen/methane breath test; Quantitative/qualitative assessment of the intestinal flora	Colonoscopy/gastroscopy with the histopathological assessment of the samples; MRI enterography
Treatment	Elimination diet; Supplementation with lactase	Antibiotics-Rifaximin; Diet therapy-reduction of FOODMAP; Faecal transplantation	Diet therapy-Modulife IBD; Immunosuppressing treatment; mesalazine glucocorticoids biological treatment methotrexate azathioprine Surgical treatment
Complications	Worsening of the quality of life	Anaemia; Malnutrition	Anaemia; Malnutrition; Strictures,; Abdominal fistulas, enterocutaneous fistulas, perianal lesions
Prognosis	Life-long condition from the onset of symptoms	Very high risk of recurrence	Chronic, progressive disease with periods of remissions and relapses

Table 5.

The comparison between the clinical picture of lactose intolerance, small intestinal bacterial overgrowth and inflammatory bowel disease.