Life Extension

“Inflammatory bowel disease” describes a collection of conditions affecting the digestive tract. Crohn’s disease and ulcerative colitis are by far the most prevalent and thus are the focus of this protocol.

Inflammatory bowel disease is a result of immunologic imbalances at the interface of the intestinal lumen (the “hollow” part of the digestive tract through which food passes) and the intestinal epithelium (the inward-facing surface of the intestinal wall). Suppressing inflammation is the chief goal of both conventional and integrative treatment. However, potent immunosuppressive medications employed in inflammatory bowel disease, such as glucocorticoids, are laden with side effects; which greatly limits their long-term efficacy (Bernstein 2011; Cosnes 2009; Rutgeerts 1994).

On the other hand, several natural interventions such as omega-3 fatty acids, vitamin D, and probiotics modulate immune cell function without impairing infection-fighting ability, which is one of the many side effects of TNF-inhibitors, another class of drugs used in inflammatory bowel disease (Cosnes 2009).

Patients with inflammatory bowel disease are predisposed to colon cancer. Even between disease flares, low-level inflammation irritates and damages intestinal tissue, which can lead to malignancy. This sub-clinical inflammation also propagates systemically, which can increase cardiovascular risk (Ruffolo 2010; Henriksen 2008). Therefore, not only is it imperative that patients with inflammatory bowel disease have regular colon cancer screenings, but also that they monitor inflammatory markers in their blood such as C-reactive protein (CRP) and interleukin-6 (IL-6). In this protocol, you will learn how several natural ingredients powerfully regulate gut immunity and complement the action of conventional treatments to quench the fires of inflammatory bowel disease. You will also discover several convenient blood tests that can help identify nutritional deficiencies due to malabsorption – a common problem in inflammatory bowel disease. By integrating dietary strategies, evidence-based nutritional support, and pharmaceutical therapeutics one can develop a comprehensive program to help manage inflammatory bowel disease during both disease flares and periods of remission.

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The digestive tract consists of a single long tube that has many folds and convolutions and extends from the mouth to the anus. The tube is divided into distinct parts (such as the esophagus, stomach, small intestine, and large intestine), each with a specific structure and function. Solid organs such as the liver and pancreas are also considered portions of the digestive system.

The hollow parts are responsible for breaking down large portions of food into small molecules that can be readily absorbed into the circulation. The sterile bloodstream is separated from the mass of nutrients, toxins, and organisms in various parts of the hollow digestive tract by only a very thin layer of cells, collectively called the intestinal mucosa. This delicate and complex lining is responsible for secreting substances that aid in digestion and absorption of nutrients, and for defending the body against the toxins and other contaminants in the intestine itself.

The intestinal mucosa must selectively allow entry of beneficial molecules while excluding toxins and organisms that could be harmful. To do this, the mucosa is equipped with several kinds of cells including secretory cells that produce a layer of mucus to trap contaminants, immune cells that directly attack and destroy invading organisms (macrophages), and other inflammatory cells (neutrophils, killer T cells, and others) that respond to the presence of foreign molecules by producing proinflammatory cytokines (small cell-signaling protein molecules) (Abraham 2009).

During healthy conditions, the immune cells in the intestinal lining cope with invaders quickly and efficiently, without producing excessive amounts of localized inflammation. However, in inflammatory bowel disease, inflammation becomes uncontrolled. Cytokines released by inflammatory cells in the intestine attract additional immune cells that produce destructive chemicals and propagate inflammation (Neuman 2004). In particular, a subset of inflammatory immune cells called Th17 cells are principally responsible for driving inflammation in Crohn’s disease, while Th2 cells drive inflammation in ulcerative colitis. A number of factors cause Th17 and Th2 cells to produce excessive inflammation including penetration of the intestinal epithelium by gut microbes, composition of the intestinal microbiota, injury to the intestinal wall, insufficient mucus layer production, and allergies or sensitivities to foods. Genetics contribute to inflammatory bowel disease susceptibility, but the immune response as well as the intestinal microenvironment and diet can be modified to mitigate inflammatory propensity, even in genetically predisposed individuals.

Since the inflammatory reactions taking place in the gut can promote systemic inflammation people with IBD should monitor levels of inflammatory cytokines in their blood. Cytokine testing can be used as a measure of the effectiveness of anti-inflammatory therapies, and can also help determine risk for other conditions associated with inflammation, such as atherosclerosis. Cytokine blood profiles measure tumor necrosis factor-alpha (TNF-a), interleukin-1 (beta) (IL-1b), and interleukin-6 (IL-6).

Crohn’s disease can attack any portion of the digestive tract, although inflammation most commonly occurs in the lower portion of the small intestine, known as the ileum. The disease can cause ulcerations within the intestine that can erode into surrounding tissues such as the bladder (Sato 1999), vagina (Feller 2001), or even the surface of the skin (Tavarela 2004). Inflammation in Crohn’s disease is not limited to the intestine—some people who have Crohn’s disease have inflammation of the eyes and joints as well.

The most common symptoms of the disease include severe abdominal pain with or without diarrhea. Diarrheal stool may be mixed with blood, mucus and/or pus. Bowel movements are often painful. Cramping in the right lower side of the abdomen is common, especially after meals. People with Crohn’s disease often have chronic low-grade fever, poor appetite, fatigue, and weight loss. Skin rashes may also occur. People who have Crohn’s disease often have some degree of anemia, related to poor iron, folic acid, and/or vitamin B12 absorption and due to chronic blood loss. Those with mild Crohn’s can eat and function reasonably normally, while those with severe disease often fail to respond to conventional treatment and have persistent gastrointestinal symptoms, as well as fevers, and infections. Blood tests for ferritin, which measures iron storage, and vitamin B12 and folate can help detect deficiencies due to malabsorption.

Diagnosis of Crohn’s disease is usually based on a patient’s medical history and symptoms. Diagnostic tests may be used to confirm the disease and to distinguish it from ulcerative colitis. Such tests include x-rays (with contrast material such as barium), colonoscopy, and endoscopy.

No blood test can diagnose Crohn’s disease, but routine testing is usually done to detect anemia, infection, degree of inflammation, and determine liver function. Certain markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be used to follow a patient’s course over time. The anti-Saccharomyces cerevisiae antibody (ASCA) blood test is sometimes used to help differentiate Crohn’s disease from ulcerative colitis (Vermeire 2001).

There is a high prevalence of Celiac disease in people with Crohn’s disease (Tursi 2005). Celiac disease blood testing such as tissue transglutaminase and anti-gliadin antibodies should be considered in Crohn’s.

Ulcerative Colitis: Background and Diagnosis

Ulcerative colitis is characterized by inflammation of the large intestine (colon) that leads to episodes of bloody diarrhea, abdominal cramping, and even fever. Unlike Crohn’s disease, ulcerative colitis usually does not affect the full thickness of the intestine and rarely affects the small intestine. The disease usually begins in the rectum or sigmoid colon and spreads partially or completely through the large intestine.

Ulcerative colitis typically begins gradually, with abdominal pain and diarrhea that is sometimes bloody. In more serious cases, diarrhea is severe and frequent. Fever, loss of appetite, and weight loss occur. The severity of the disease depends on how much of the colon is involved. For many patients, there may be long periods with no symptoms at all, followed by flare-ups.

A definitive diagnosis can be made by direct examination of the colon by sigmoidoscopy (examination of the lower portion only) or colonoscopy (examination of the entire colon, the preferred approach). Both procedures can be used to take a biopsy of intestinal tissue, which can reveal important information about the degree and extent of inflammation and help rule out other causes of symptoms. A barium enema x-ray of the colon may also be required at some point in the course of colitis to determine the extent of involvement. Once diagnosed, ulcerative colitis can be categorized based on disease severity as follows:

  • Severe. Severe ulcerative colitis, which involves the whole colon, is the least common form of the disease. Symptoms consist of profuse bloody diarrhea (occurring six or more times per day), often with a sustained fever and tachycardia (rapid heart rate). Severe anemia, increased white blood cell count, and decreased serum albumin levels are also characteristic symptoms.
  • Moderate. Symptoms consist of recurrent diarrhea, small amounts of blood in the stool, possible low-grade fever, mild anemia, and minimal signs of inflammation. Moderate ulcerative colitis responds quickly to appropriate therapies. However, repeated attacks of equal or increased severity can occur, which can significantly increase the risk of developing colon cancer later.
  • Mild. Mild ulcerative colitis is the most common form of the disorder, occurring in about 50 percent of patients. In most cases, ulcerative colitis will be limited to the lower portion of the colon and the rectum. Systemic complications are uncommon and the primary symptom is rectal bleeding.

Conventional treatments for IBD depend on disease location and severity, complications, and response to prior treatments. The goals of therapy are to control inflammation, correct nutritional deficiencies, and relieve symptoms such as abdominal pain, diarrhea, and rectal bleeding. It is important to note that an early diagnosis is associated with greater efficacy of less-aggressive drug regimens and thus a less oppressive burden of side effects. Therefore, seeing a physician as soon as symptoms emerge is suggested. Therapy may include drugs, surgery, or a combination of approaches.

Drug Treatments

The following drugs can be used to treat IBD:

Anti-inflammatory drugs

  • Aminosalicylates are drugs that contain 5-aminosalicyclic acid (5-ASA) and help control local inflammation of the gut. These drugs are primarily used to treat mild to moderate IBD and help with remission maintenance (Bebb 2004). Adverse effects include nausea, vomiting, heartburn, diarrhea, and headache. 5-ASA agents such as olsalazine, mesalamine, and balsalazide have fewer adverse effects and may be used by people who cannot take sulfasalazine. Balsalazide is converted in the colon to mesalamine, and has been shown to reduce bowel inflammation, diarrhea, rectal bleeding, and stomach pain (Muijsers 2002). 5-ASA agents are given orally or rectally (through an enema or in a suppository), depending on the location of the inflammation. Sulfasalazine interferes with folate absorption, so those taking this drug should also supplement with folate (Jansen 2004). Use of aminosalicylate drugs or antibiotics may deplete vitamin K in IBD patients, and oral supplementation of this vitamin relieves this problem (Krasinski 1985).
  • Glucocorticoids or cortiocosteroids (such as prednisone and hydrocortisone) reduce inflammation. They are used to treat more severe cases of IBD and to end acute attacks. Glucocorticoids can be given orally, intravenously, or rectally (through an enema or in a suppository), depending on the location of the inflammation. These drugs can cause serious adverse effects, including increased risk of infection, diabetes, high blood pressure, bone loss, kidney suppression, and ulcers. Less serious adverse effects include weight gain, acne, facial hair, and mood swings. They are not recommended for long-term use and are typically replaced with 5-ASA drugs once remission has been induced. Calcium and vitamin D may help combat glucocorticoid-induced bone loss (Homik 2000).

Immune system suppressors

  • Antimetabolites such as azathioprine and mercaptopurine prevent replication of inflammatory T cell lines. They are used to treat people with IBD who have not responded to 5-ASAs or glucocorticoids, or who are dependent on glucocorticoids. However, antimetabolites are slower acting than other types of drugs. Anyone taking these drugs should be monitored for complications such as pancreatitis, hepatotoxicity, reduced white blood cell count, and an increased risk of infection. A genetic test known as thiopurine methyltransferase (TMPT) genotyping can help predict who will have severe adverse effects from these drugs (Newman 2011).
  • Cyclosporine. This drug inhibits T cell-mediated immune responses, thus reducing the immune reaction that underlies inflammation. It blocks a number of inflammatory cytokines, including TNF-a and various interleukins. Because cyclosporine is associated with significant risk of toxicity, its use is limited to severe ulcerative colitis or Crohn’s disease.
  • Methotrexate. The cancer chemotherapy drug methotrexate is used in Crohn’s patients that are steroid dependent or have not responded to glucocorticoids (Preiss 2010). It can be given orally or by weekly injections under the skin or into the muscles (Xu 2004). Methotrexate is most effective for maintenance of remission when given as an injection (Patel 2009). This drug also interferes with folate metabolism. Folate should be supplemented with it, particularly to help prevent colorectal cancer, which this drug otherwise promotes (Patel 2009; Coogan 2007).
  • Biologics / TNF-inhibitors. During flare-ups, levels of the inflammatory cytokine TNF-a become elevated. This has led to interest in antibodies such as infliximab, adalimumab, certolizumab pegol, and golimumab that block TNF-a. These have all been shown to induce and maintain remission including mucosal healing and restoration of gut barrier function (Malik 2012; Behm 2008; Gisbert 2006). However, these drugs are very expensive, have not been shown to prevent colectomy in severe ulcerative colitis (Aratari 2008), and may cause autoimmune diseases, cancer, infections, and viral reactivation syndromes including shingles (Colombel 2004).
  • The following immunosuppressive agents may be considered as well: tacrolimus, mycophenolate mofetil and thalidomide.

Others

  • Cromolyn sodium. This drug is modified from the natural compound known as khellin and works as a mast cell-stabilizing anti-inflammatory. One clinical trial found that daily administration of 200 mg cromolyn sodium rectally for 15 days induced remission in almost all patients with ulcerative colitis, and this was maintained in 93% of them when they took 240 mg daily for 2—3 years (Malolepszy 1977). In another trial, oral cromolyn sodium at a dose of 1,500 mg daily relieved diarrhea more effectively than an elimination diet (in which problematic foods are avoided) in patients with irritable bowel syndrome (Stefanini 1995). This indicates that cromolyn may ameliorate reactivity to some foods – a factor that possibly drives some inflammation in inflammatory bowel disease. As is so often the case with drugs that are off patent and thus not very profitable, no company or government has seen fit to fund further research on this safe and cheap drug for inflammatory bowel disease.
  • Naltrexone. Originally developed to help treat heroin addiction, lower doses of naltrexone have shown a range of remarkable immunological activities. A placebo-controlled study on the use of low-dose naltrexone (4.5 mg per day at bedtime) suggested that the drug could resolve mucosal inflammation and induce clinical remission in patients with moderate-to-severe Crohn’s disease (Smith 2011). This confirms one earlier uncontrolled study of low-dose naltrexone’s efficacy for Crohn’s disease (Smith 2007). Naltrexone appears to relieve inflammatory bowel disease in part by decreasing expression of proinflammatory cytokines and promoting tissue repair (Matters 2008). At low dosages, the drug may cause drowsiness, but other side effects are uncommon.

Surgery

In severe cases of Crohn’s disease, abscesses can develop in chronically inflamed tissues. These abscesses can grow and tunnel through tissue barriers to produce fistulas, or channels between organs. Almost half of patients who have Crohn’s disease develop perianal disease involving anal fissures, perianal abscesses, and fistulas. These symptoms seldom respond well to conventional therapies (Braunwald 2001; McNamara 2004). Surgery may be required in a high percentage of these patients (Danelli 2003). Complications are frequent.

Surgery may also be recommended to remove severely inflamed portions of the intestinal tract. The goal of surgery is to preserve as much of the intestine as possible. Surgery commonly involves the colon or small intestine. Occasionally, the end of the intestine that has been left in place will need to be brought to the skin's surface to allow waste excretion. When this procedure involves the small intestine, it is called an ileostomy. If the procedure involves the colon, it is called a colostomy. Although Crohn's disease may recur after surgery, the symptoms are likely to be less severe and less debilitating than they were previously (Hwang 2008). Elemental diets (in which simple molecules like glucose and individual amino acids replace whole foods) have been shown to reduce recurrence of Crohn’s disease when employed after surgery (Yamamoto 2007; Esaki 2005).

Newer surgeries, however, have been developed that can preserve fecal continence by using part of the ileum to create a pouch that is connected to the intact rectal sphincter (Hwang 2008). In a thorough review, the use of probiotic supplements was able to significantly reduce the occurrence of pouchitis, or inflammation of the reservoir formed upon surgical creation of an ilio-anal pouch, by 96% compared to placebo after surgery among ulcerative colitis patients (Elahi 2008).

Lifestyle changes and nutritional supplementation synergize to promote healthy digestion and absorption while simultaneously reducing the inflammation and damage associated with inflammatory bowel disease (IBD).

Crohn’s disease

Since aspirin increases the risk of Crohn’s disease (but not ulcerative colitis), people with Crohn’s disease should consider avoiding the medication (Chan 2011).

The GI tract of individuals with Crohn’s disease may also be exceptionally sensitive to the negative effects of smoking. Smoking among those diagnosed with Crohn’s disease may increase the risk of flare ups, impede remission, and increase the overall severity of the condition necessitating more invasive treatments (Johnson 2005). The following steps may help patients with Crohn's disease first reduce their symptoms and then begin long-term repair of the damage caused by their disease:

Avoid troublesome foods. Remove all foods that precipitate symptoms. In one study of Crohn’s disease patients, an elemental diet was followed by food reintroduction with one new food daily. If any food reintroductions led to symptoms such as diarrhea or pain, they were excluded. This approach was more effective than glucocorticoids in preventing relapse of Crohn’s disease in this trial (Riordan 1993). A trial diet of just organic meat, spelt, butter, and organic tea was found to be superior to a low-fat, high-carbohydrate, low-fiber diet for people with Crohn’s disease (Bartel 2008). Long-term remission was achieved in 31% of Crohn’s patients in one study solely using an elimination diet (Giaffer 1991). Other evidence suggests Crohn’s disease patients are more reactive to certain foods (Brown 2010; Van Den Bogaerde 2002). Some research suggests a reduced carbohydrate diet (84 g/day) may be associated with better outcomes in Crohn’s disease (Lorenz-Meyer 1996). Also, elevated levels of trans-fats have been found in the adipose (fat) tissue of people with Crohn's disease (Heckers 1988; Lorenz-Meyer 1996). Baker’s yeast should be avoided in those with elevated yeast antibodies, and has been shown to aggravate Crohn’s disease in some research (Barclay 1992).

Following a diet based upon blood IgG antibody testing for food sensitivities has been shown to reduce stool frequency in Crohn’s patients (Bentz 2010). In one trial, Crohn’s disease symptoms were shown to be aggravated by diverse foods differing among study participants. Elimination of the problematic foods was helpful on an individual basis, but the bothersome foods were not the same for all subjects, underscoring the need to identify specific foods that cause symptoms (Triggs 2010). More information about testing for food allergies and sensitivities is available in the Allergies protocol.

Supplement to correct potential nutritional insufficiencies. The diets of most patients who have IBD are deficient in one or more vitamins or minerals (Tighe 2011). Vitamin D and vitamin K deficiencies are frequently found in those with Crohn’s disease, as well as deficiencies in iron, vitamin B6, carotene, vitamin B12, and albumin (protein). (Nakajima 2011; Vagianos 2007; Siffledeen 2003). Patients with Crohn’s disease are usually under increased oxidative stress and have lower levels of antioxidant vitamins. Supplementation with vitamins C and E reduces oxidative stress (Aghdassi 2003).

Balance intestinal microbiota. A normal healthy intestine contains about 100 trillion microorganisms (Tsai 2009). In a diseased intestine, these bacteria are often not present in adequate amounts and/or have been replaced by pathogenic organisms. Balancing microbiota consists of taking mixtures of friendly bacteria (probiotics), which may include Bifidobacteria and Lactobacilli to promote continued repopulation with these beneficial bacteria (Zigra 2007). The probiotic yeast Saccharomyces boulardii may be considered as well. The role of probiotics in inflammatory bowel diseases is expounded upon below.

In children and adolescents who have Crohn’s disease, a semi-elemental diet has been shown to be as effective as glucocorticoids in maintaining remissions (Scholz 2011). In one study of IBD, 44% of the study population went into remission by consuming an elemental diet (Axelsson 1977; Belli 1988). An elemental diet has also been shown to decrease inflammatory parameters in IBD intestinal tissue. The elemental diet also reduces intestinal permeability in those with Crohn’s disease (Meister 2002; Teahon 1991). When coupled with individualized elimination of food triggers, elemental diets reduce the relapse rate of Crohn’s disease (Jones 1987). In another trial involving 268 Crohn’s disease patients, an elemental diet was associated with a reduced hospitalization rate (Watanabe 2010).

Those who use conventional elemental diets are sometimes noted to develop micronutrient deficiencies, such as of selenium (Kuroki 2003). Therefore supplementation with a high quality multivitamin/mineral, among other nutrients discussed below, may be pertinent.

Ulcerative colitis

Sulphate-reducing bacteria (SRB) have been implicated in the development of ulcerative colitis through the harmful effects of hydrogen sulphide, a waste product of their respiration (Rowan 2009; Pitcher 1996). Hydrogen sulfide is toxic to the colon lining cells, and is associated with ulcerative colitis. Hydrogen sulfide may, in particular, interfere with butyrate metabolism, a critical nutrient for colon cells produced by beneficial bacteria (Roediger 1997). Also, higher exposure to sulfur dioxide air pollution was associated with higher rates of ulcerative colitis in one study (Kaplan 2010).Ulcerative colitis has also been associated with a higher dietary intake of sulfur containing foods. Removing foods rich in sulfur-containing amino acids (such as milk, eggs, and cheese) is associated with benefits in ulcerative colitis (Jowett 2004; Roediger 1998; Wright 1965).

Inflamed intestines may not absorb nutrients properly. Therefore, people with IBD are prone to malnutrition and vitamin deficiencies (Alastair 2011; Mortimore 2010; Campos 2003; Goh 2003).

Probiotics. Variation in the population of microorganisms within the digestive tract is capable of altering immune cell function locally and systemically. One study describes a novel probiotic organism that can directly produce interleukin-10 (IL-10), an anti-inflammatory cytokine that promotes immune tolerance (de Moreno de Leblanc 2011; Lavasani 2010; Chin 2004). Furthermore, ingestion of probiotic bacteria can blunt the effects of pathogenic bacteria via various mechanisms including, competing for epithelial receptor binding, and enhancing the barrier function of the gut (de Moreno de Leblanc 2011; Fedorak 2004; Furrie 2004). Some probiotics also produce butyrate – a short-chain fatty acid important for health of cells within the colon wall (see below) (Sartor 2011).

Clinical trials of probiotic use in IBD populations have indicated beneficial effects. Duration of trials and organisms employed has varied, but there have been several instances of positive results (Rogler 2011). A 2011 trial using a probiotic (Bifidobacterium breve) as well as a prebiotic (galacto-oligosaccharide) demonstrated a marked improvement in clinical status of people with ulcerative colitis (Ishikawa 2011). Clinical trials in Crohn’s disease showed that supplements supplying 50 billion organisms per day or higher improved gut health (Fujimori 2007; Karimi, et al. 2005). In one trial relief was so great for two subjects they were able to discontinue glucocorticoid medication (Fujimori 2007). Other research suggests that probiotics may suppress the likelihood of colorectal cancer development, a major concern for patients with IBD (Azcarate-Peril 2011).

Another organism that has shown promise in IBD is Saccharomyces boulardii - a probiotic yeast. Several trials have proven the efficacy of S. boulardii for ameliorating infectious diarrhea and other gastrointestinal problems (Dinleyici 2012). Moreover, specifically relevant to IBD, S. boulardii appears to modulate the inflammatory response in the intestinal epithelium, reducing TNF-a and IL-6 (Thomas 2011). This same study showed that S. boulardii promotes intestinal tissue repair and immune tolerance in cell samples from patients with IBD. In a randomized, placebo-controlled clinical trial, S. boulardii lessened intestinal permeability in Crohn’s disease patients when it was added to conventional therapy (Garcia Vilela 2008). Supplementation with S. boulardii appears to generally be safe and effective in a variety of pathologic states (McFarland 2010).

Bacteriophages and IBD

Bacteriophages, or phages, are viruses that target bacteria. They are the most abundant organisms on the planet, and the human digestive tract is estimated to contain 1015 bacteriophages (Babickova 2015; McCarville 2016; Clokie 2011). Intestinal bacteriophages appear to play an important role in the ecology of the gut microbial community, including injecting viral genetic material into specific bacteria and, in some cases, causing their rapid death (McCarville 2016; Belizario 2015; Clokie 2011). Despite their abundance, until recently bacteriophages had received relatively little research attention (McCarville 2016; Clokie 2011). Emerging evidence suggest bacteriophages have therapeutic potential for the treatment of inflammatory bowel disease (McCarville 2016; Babickova 2015). 

Bacteriophages appear to modulate immune activity and may impact inflammation in the intestinal lining. Disease-specific patterns of bacteriophage populations have been noted in individuals with inflammatory bowel disease and differ significantly from those seen in healthy individuals (Norman 2015; Wang 2015); in addition, the abundance of certain bacteriophages was found in one study to be related to reduced levels of some types of bacteria (Norman 2015).

Bacteriophage therapy may be safer than antibiotic therapy, in part because it causes minimal disruption to normal gut flora (Loc-Carrillo 2011). In a safety study, oral supplementation with a bacteriophage targeting the intestinal bacteria E. coli led to the detectable presence of these bacteriophages in the stools of healthy volunteers, but their presence was no longer detectable within one week after supplementation ended. Numbers of non-pathogenic E. coli bacteria remained unchanged, and no adverse side effects were noted (Bruttin 2005). Similarly, in a study in healthy adults given a cocktail of nine E.coli-targeting bacteriophages, no E. coli was detected in stool samples collected immediately after phage administration, and no adverse effects were reported or detected in blood, liver, and kidney tests (Sarker 2012).

Omega-3 fatty acids. The two most prominent omega-3’s, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in cold-water fish (Deckelbaum 2012). Omega-3 fatty acids are powerful immunoregulatory agents that reduce circulating inflammatory cytokines and decrease the cytotoxicity of natural killer cells (Iwami 2011; Almallah 1998; Hillier 1991; Ross 1993; Steinhart 1997). Additionally, in one animal study, a-linolenic acid (a plant-derived omega-3 fatty acid) suppressed expression of adhesion molecules, which are important in inflammation, immune responses and in intracellular signaling events (Golias 2011; Ibrahim 2012).

In clinical trials, fish oil supplementation improves the fatty acid profile in Crohn’s disease and ulcerative colitis patients, and is associated with lower levels of inflammatory mediators (Uchiyama 2010; Stenson 1992; Aslan 1992). These changes have some correlation with remission from disease flares (Wiese 2011; Hawthorne 1992). Fish oil may also reduce the dosage of glucocorticoid drugs needed to cause a remission (Hawthorne 1992). Enteric-coated fish oil was found to be helpful in one study of Crohn’s disease patients by reducing the rate of relapse (Belluzzi 1996).

The majority of Americans have unhealthy high ratios of omega-6’s to omega-3’s in their blood – an imbalance strongly associated with inflammatory diseases (Simopoulos 2011). Life Extension recommends that the omega-6 to omega-3 ratio be kept below 4:1 for optimal health (Simopoulos 2002); this may be especially important for IBD patients. You can assess your omega-6 to omega-3 ratio using a convenient blood test called the Omega Check test.

Vitamin D is another powerful immunomodulator. Experimental models have shown that T-cells express a vitamin D receptor, and that lack of vitamin D signaling causes T-cells to produce higher levels of inflammatory cytokines. Moreover, vitamin D is required for development of subsets of Treg cells that are important in suppressing inflammation specifically in the gut (Chambers 2011; Ooi 2012). Patients with IBD often have low vitamin D levels, as revealed by low levels of serum 25-hydroxyvitamin D (Jahnsen 2002). Many other lines of evidence connect low vitamin D levels with IBD as well (Wang 2010; Lim 2005). Administration of 25-hydroxyvitamin D3 or calcitriol (fully activated vitamin D3, a very potent substance available only by prescription) lowered measures of inflammation and improved bone health in 37 patients with Crohn’s disease in remission (Miheller 2009). Taking 1,200 IU of vitamin D3 per day showed a trend toward a lower relapse rate (from 29% to 13% [P = 0.06]) compared to placebo in one double-blind trial involving 94 Crohn’s disease patients in remission (Jorgensen 2010). Moreover, bone loss is a major concern for IBD patients – both the disease and glucocorticoids used to treat it contribute to poor bone health. Supplementation with vitamin D has been shown to maintain bone density in Crohn’s disease (Abitbol 2002).

Life Extension suggests maintenance of 25-hydroxyvitamin D levels within the range of 50 – 80 ng/mL. Testing your vitamin D blood level is inexpensive and convenient. A 25-hydroxyvitamin D blood test should be performed regularly by those supplementing with vitamin D to ensure that they stay in the optimal range.

Antioxidants. Normal digestion produces a host of reactive oxygen and nitrogen species (also known as free radicals), against which the intestinal mucosa maintains an extensive defense system of antioxidants. When presented with excessive oxidant stress, however, the mucosal barrier can sustain damage and become leaky, setting the stage for inflammation (Almenier 2012; Koutroubakis 2004).

In addition, inflammation itself produces large quantities of reactive species, and a destructive cycle can be perpetuated. In patients who have IBD, there are high levels of reactive oxygen species in the intestines, which contributes to the damage caused by the disease (Almeiner 2012). In one study, the antioxidant capacity of individuals with IBD was found to be significantly lower than those without the disease (Kruidenier 2003). Some research has shown that an antioxidant combination of vitamin A, vitamin C, vitamin E, and selenium in combination with fish oil can reduce certain inflammatory markers in Crohn’s disease (Trebble 2004, 2005). Moreover, IBD patients had significantly lower levels of carotenoids and vitamin C, in their blood (Hengstermann 2008).

Curcumin. The efficacy of the turmeric extract curcumin as an anti-inflammatory agent in a variety of settings is well-documented. Prominent among its multiple effects is the inhibition of nuclear factor kappa-B (NF-kB) signaling. NF-kB is a signaling protein that drives production of myriad inflammatory cytokines including interleukin-1b (IL-1b) and interleukin-6 (IL-6). Since NF-kB and related cytokines are central in IBD pathology, curcumin has been investigated as an intervention (Taylor 2011). In one study, curcumin helped reduce symptoms of Crohn’s disease and ulcerative colitis in a small group of patients, many of whom were able to discontinue aminosalicyates and/or glucocorticoids (Holt 2005; Taylor 2011). Curcumin coupled with aminosalicylates reduced recurrence of acute flares and symptom severity compared to placebo plus aminosalicylates in a group of 82 ulcerative colitis patients. In the curcumin group, the relapse rate during 6 months of therapy was 4.6%, while in the control group it was over 20% (Hanai 2006).

Boswellia. Resin from the Boswellia genus of tree contains a powerful anti-inflammatory compound called acetyl-11-keto-ß-boswellic acid (AKBA). One double-blind clinical trial found that boswellia was as effective as mesalamine at improving symptoms of Crohn’s disease with far fewer side effects (Gerhardt 2001). One trial has also found boswellia as effective as sulfasalazine for inducing remission from ulcerative colitis in 30 patients (Gupta 2001). This confirmed an earlier report of efficacy of boswellia for ulcerative colitis patients (Gupta 1997). However, another double-blind trial involving 108 Crohn’s disease patients did not find boswellia superior to placebo for maintaining remission (Holtmeier 2011). An improved extract called AprèsFlex™, or Aflapin®, which combines AKBA with other non-volatile boswellia oils, demonstrated improved anti-inflammatory activity at a lower concentration when compared to other preparations standardized to the same percentage of AKBA (Sengupta 2011).

Wormwood. A standardized extract of wormwood (Artemisia absinthium), a bitter herb native to the Mediterranean region, has been studied in patients with Crohn’s disease. Compared to placebo it was much more effective at maintaining remission in patients who tapered off their medications (Omer 2007). The reason for this may be because wormwood blocks TNF-a (Krebs 2010), a potent proinflammatory cytokine.

Aloe gel. The mucilaginous gel found in the interior of aloe leaves has been used traditionally for ulcerative colitis for many years. One double-blind, randomized trial found that aloe gel at a dose of 3 oz twice a day ended acute flares in ulcerative colitis patients better than placebo without adverse effects (Langmead 2004a). Aloe gel’s immunomodulating, gut healing, and inflammation-quelling properties may all play a role in its efficacy (Langmead 2004b).

Selenium. Selenium is a trace element that is essential for the function of a number of selenium-dependent enzymes. Selenium deficiency is common in people who have IBD (Geerling 2000a; Hinks 1988; Ojuawo 2002). Supplementation helps alleviate this problem, based both on increases in serum selenium and improved glutathione peroxidase function (Geerling 2000b).

Butyrate. Butyrate (also known as butyric acid) is a short-chain fatty acid produced when intestinal fiber is metabolized by certain bacteria. Experimental models have shown that oral butyrate ameliorates inflammation in ulcerative colitis (Vieira 2011). One mechanism by which butyrate may function is to inhibit the activation of the proinflammatory cell–signaling component nuclear factor kappa B (NF-kB) (Segain 2000). In clinical trials, oral butyrate has provided relief in both Crohn’s and ulcerative colitis (Assisi 2008; Di Sabatino 2005). In one trial, nearly 70% of subjects with Crohn’s disease responded to a dose of 4 grams of enteric-coated butyrate tablets daily for 8 weeks. Of those responders, 53% achieved remission and their levels of NF-kB and another inflammatory factor – IL-1b – decreased significantly (Di Sabatino 2005).

L-Carnitine. The amino acid carnitine is necessary for proper cellular metabolism, and insufficient carnitine levels particularly affect cells that require a great deal of energy, such as those of the immune system. Several experiments have shown that carnitine modulates production of inflammatory mediators and that insufficient carnitine levels are associated with greater production of inflammatory cytokines (Abd-Allah 2009; Buyse 2007). Indeed, in a clinical trial involving 36 dialysis patients, 1 gram per day L-carnitine supplementation led to a 29% reduction in CRP levels and a 61% reduction in IL-6 levels (Shakeri 2010). With respect to the gut, L-carnitine significantly blunted the inflammatory response to oxygen deprivation and restoration in intestinal tissue in an animal model (Yuan 2011). In a randomized, placebo-controlled trial involving 121 subjects with ulcerative colitis, propionyl-L-carnitine, at 1 or 2 grams daily, led to greater remission rates than placebo when added to conventional therapy (Mikhailova 2011). In the group receiving 1 gram of carnitine daily, the rate of remission was 55%, while in the placebo group it was only 35%.

Glutamine is a conditionally essential amino acid and the major fuel for the enterocytes (intestinal absorptive cells). Oral glutamine supplementation can stabilize intestinal permeability and mucosal integrity (Den Hond 1999). A study demonstrated that glutamine can help improve capillary blood flow in inflamed segments of the colon in animals with colitis (Kruschewski 1998). Moreover, glutamine levels are low in people with moderate-to-severe Crohn’s disease (Sido 2006). In a randomized clinical trial, a 0.5 g/kg body weight daily dose of glutamine for 2 months decreased intestinal permeability and improved morphology in patients with Crohn’s disease (Benjamin 2011). However, the clinical benefit of glutamine supplementation may be limited to periods of remission, as another trial found that glutamine supplementation during a disease flare did not improve intestinal permeability (Ockenga 2005).

Melatonin. Though melatonin is known as a hormone that helps synchronize sleep-wake cycles, it has also been shown to be produced in the digestive tract in quantities far larger than in the brain (Bubenik 2002). Melatonin reduces TNF-a levels (Johe 2005). Numerous in vitro and animal studies have suggested that melatonin can reduce inflammation in IBD (Terry 2009). Melatonin synthesis increases in IBD patients and higher levels are associated with lower symptoms, suggesting it is part of the body’s attempt to reduce excessive inflammation (Boznanska 2007). In a double-blind trial of 60 patients with ulcerative colitis being treated with mesalazine, half were randomized to take melatonin and half to take placebo for one year (Chojnacki 2011). Inflammation and clinical symptoms rose in the placebo group while the melatonin group remained in remission. This confirms an earlier, uncontrolled study showing that melatonin was helpful for patients with Crohn’s disease and ulcerative colitis (Rakhimova 2010). Caution is warranted though - at least one case study has been published in which melatonin caused a flare of ulcerative colitis that did not respond to glucocorticoids (Maldonado 2008).

Dehydroepiandrosterone (DHEA) plays an important role in preventing chronic inflammation and to maintain healthy immune function. Published studies link low levels of DHEA to chronic inflammation, and DHEA has been shown to suppress levels of proinflammatory cytokines and protect against their toxic effects (Haden 2000; Head 2003). DHEA has been shown to suppress damaging IL-6 levels (Andus 2003).

The deficiency of DHEA in inflammatory diseases also implies a deficiency in peripheral tissue of various sex hormones for which DHEA serves as a precursor. These hormones, both estrogenic and androgenic, are known to have beneficial effects on muscle, bone, and blood vessels. However, mainstream therapy with glucocorticoids lowers androgen levels. Consequently, researchers argue that hormone replacement for patients who have chronic inflammatory diseases should include not only glucocorticoids but also DHEA (Andus 2003; Straub 2000).

Vitamin K. Vitamin K is used by the body to regulate blood clotting. A deficiency in vitamin K can result in bruising or bleeding. Patients with IBD are frequently deficient in vitamin K. One study showed that 31 percent of patients who had ulcerative colitis or Crohn’s disease had a vitamin K deficiency (Krasinski 1985). Low vitamin K activity was linked with higher Crohn’s disease activity in one study (Nakajima 2011). Vitamin K deficiency in IBD patients is associated with lower bone density as well (Nakajima 2011; Duggan 2004).

Fiber. Greater intake of dietary fiber is linked with lower incidence of Crohn’s disease (Hou 2011), while higher sugar consumption is associated with increased risk (Sakamoto 2005). A diet low in refined sugar and high in dietary fiber has been shown to have a favorable effect on the course of Crohn's disease and does not lead to intestinal obstruction compared to a normal diet (Heaton 1979).

Fermentation of dietary fiber by intestinal bacteria is the major source of short-chain fatty acids, such as butyrate, and various studies have shown that vegetable fibers are helpful at preventing flares of ulcerative colitis (Hanai 2004).

Folate and Colon Cancer Risk in Ulcerative Colitis

People with ulcerative colitis are at increased risk of colon cancer (Mitamura 2002). It is assumed that chronic inflammation is what causes cancer in ulcerative colitis. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, and the concomitant presence of other inflammatory manifestations (Itzkowitz 2004). Folate deficiency and an increased level of homocysteine have been linked to greater colon cancer risk in IBD (Phelip 2008).

In a comprehensive review involving data from 13 studies and over 725,000 subjects, each 100 mcg/day increase in folate intake was associated with a 2% decrease in colon cancer risk (Kim 2010). Other evidence highlights multiple ways that folate might protect against colon cancer in ulcerative colitis (Biasco 2005). However, data is conflicting as other studies have come to differing conclusions For example - another review found that long-term folic acid supplementation was associated with increased colon cancer risk (Fife 2011).

Deficiencies in folate and B12 are often observed in IBD (Yakut 2010). Supplementing the diet with vitamin B12 enables the body to metabolize folate better and avoids masking a vitamin B12 deficiency. Vitamin B12 supplementation is important, particularly for older people (when it is less effectively absorbed) and for vegetarians, especially vegans, who receive little B12 in their diet. More information is available in the Colorectal Cancer protocol.

Inflammatory Bowel Disease and Elevated Homocysteine Levels

A number of studies have shown that patients with IBD are more likely to have elevated homocysteine levels. A comprehensive review of published studies found that the risk of having high homocysteine levels was over four times greater in IBD patients compared to controls (Oussalah 2011). In one study, more than 55 percent of patients with IBD had elevated homocysteine levels (Roblin 2006). The greatest risk factor for elevated homocysteine in patients with IBD is reduced folate levels (Zezos 2005). Vitamin B12 deficiencies are also frequently encountered (Mahmood 2005).

The elevated homocysteine level that is typical in patients with IBD contributes to a 3-fold higher risk of blood clots and vascular disease (Fernandez-Miranda 2005; Srirajaskanthan 2005). It also helps explain why patients with IBD are more likely to have early atherosclerosis (Papa 2005).

Certain drugs used to treat IBD, such as methotrexate, are antimetabolites for folic acid, which may help explain why so many patients are deficient in folic acid. Supplementation of folic acid reduces adverse effects caused by methotrexate as well (Patel 2009).

Genetic studies have found that alterations in folate metabolism are associated with IBD (Zintzaras 2010). Therefore, IBD patients may benefit from supplementation with 5-methyltetrahydrofolate, the active form of the nutrient.

More information about managing homocysteine levels is available in the Homocysteine Reduction protocol.

Inflammatory Bowel Disease and Bone Loss

Osteoporosis is a serious complication of IBD that has not received adequate recognition despite its high prevalence and potentially devastating effects (Etzel 2011; Harpavat 2004). Osteoporosis can be caused by IBD itself, or it can be an adverse effect of glucocorticoid treatment. Data derived from a retrospective survey of 245 patients with IBD suggest that the prevalence of bone fractures in people with ulcerative colitis and Crohn’s disease is unexpectedly high, particularly in patients who have a long duration of disease, frequent active phases, and high cumulative doses of glucocorticoid intake (Miheller 2010; Agrawal 2011). Low vitamin D and K levels have also been correlated to higher rates of osteoporosis in IBD patients (Kuwabara 2009). Bone-density measurements to predict fracture risk and define thresholds for prevention and treatment should be performed routinely in patients with IBD (Rogler 2004). Glucocorticoids can also contribute to the risk of osteoporosis because of their effects on calcium and bone metabolism. Glucocorticoids suppress calcium absorption in the small intestine, increase calcium excretion by the kidneys, and alter protein metabolism. Patients with Crohn’s disease who take glucocorticoids have a higher risk of fractures compared to those who do not (Bernstein 2003). Nutrients that can help protect against bone loss include calcium, magnesium, vitamin D, and vitamin K. For more information, see the Osteoporosis protocol.

Inflammatory Bowel Disease and blood clot risk

Inflammatory bowel disease patients are at increased risk of forming blood clots - primarily venous thromboembolism (Kappelman 2011; Solem 2004; Sonoda 2004). These clots can break off and lodge in the blood vessels in the lungs, potentially causing death. Moreover, use of glucocorticoids by IBD patients potentiates clotting propensity (Kappelman 2011). Conventional medicine often relies on warfarin or heparin to mitigate thrombotic risk in IBD patients, but these drugs are prone to cause negative side effects and require clinical monitoring (Koutroubakis 2005). Vitamin E, vitamin D, and resveratrol, may all help offset the risk of clotting in IBD patients, though specific clinical trials are lacking (Phang 2011). IBD patients should review the Blood Clot Prevention protocol for further discussion of strategies to mitigate risk for blood clots.

References

Abd-Allah AR et al. Pro-inflammatory and oxidative stress pathways which compromise sperm motility and survival may be altered by L-carnitine. Oxid Med Cell Longev. 2009 Apr-Jun;2(2):73-81.

Abitbol V et al. Osteoporosis in inflammatory bowel disease: effect of calcium and vitamin D with or without fluoride. Aliment Pharmacol Ther. 2002 May;16(5):919-27.

Abraham C and Cho JH. Inflammatory bowel disease. N Engl J Med. 2009 Nov 19;361(21):2066-78.

Aghdassi E, Wendland BE, et al. Antioxidant vitamin supplementation in Crohn's disease decreases oxidative stress: a randomized controlled trial. Am J Gastroenterol. 2003 Feb;98(2):348-53.

Agrawal M et al. Bone, inflammation, and inflammatory bowel disease. Curr Osteoporos Rep. 2011 Dec;9(4):251-7.

Alastair F et al. Nutrition in inflammatory bowel disease. JPEN J Parenter Enteral Nutr. 2011 Sep;35(5):571-80. Epub 2011 Aug 8.

Almallah YZ et al. Distal procto-colitis, natural cytotoxicity, and essential fatty acids. Am J Gastroenterol. 1998 May;93(5):804-9.

Almeiner HA, Al Menshawy HH, Maher MM, Al Gamal S. Oxidative stress and inflammatory bowel disease. Front Biosci 2012;E4:1335-44.

Andus T, Klebl F, et al. Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study. Aliment Pharmacol Ther. 2003 Feb;17(3):409-14.

Aratari A, Papi C, et al. Colectomy rate in acute severe ulcerative colitis in the infliximab era. Dig Liv Dis 2008;40:821-6.

Aslan A et al. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992 Apr;87(4):432-7.

Assisi RF; GISDI Study Group. Combined butyric acid/mesalazine treatment in ulcerative colitis with mild-moderate activity. Results of a multicentre pilot study. Minerva Gastroenterol Dietol 2008;54(3):231-8.

Axelsson C and Jarnum S. Assessment of the therapeutic value of an elemental diet in chronic inflammatory bowel disease. Scand J Gastroenterol. 1977;12(1):89-95.

Azcarate-Peril Ma et al. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G401-24. Epub 2011 Jun 23.

Babickova J, Gardlik R. Pathological and therapeutic interactions between bacteriophages, microbes and the host in inflammatory bowel disease. World journal of gastroenterology: WJG. Oct 28 2015;21(40):11321-11330.

Barclay GR, McKenzie H, et al. The effect of dietary yeast on the activity of stable chronic Crohn's disease. Scand J Gastroenterol 1992;27:196-200.

Bartel G, Weiss I, et al. Ingested matter affects intestinal lesions in Crohn’s disease. Inflamm Bowel Dis 2008;14:374-82.

Bebb JR, Scott BB. How effective are the usual treatments for Crohn's disease? Aliment Pharmacol Ther. 2004 Jul 15;20(2):151-9.

Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease. Cochrane Database System Rev 2008;(1):CD006893.

Belizario JE, Napolitano M. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Front Microbiol.2015;6:1050.

Belli DC et al. Chronic intermittent elemental diet improves growth failure in children with Crohn's disease. Gastroenterology. 1988 Mar;94(3):603-10.

Belluzzi A, Brignola C, et al. Effect of enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med 1996;334(24):1557-60.

Benjamin J et al. Glutamine and Whey Protein Improve Intestinal Permeability and Morphology in Patients with Crohn's Disease: A Randomized Controlled Trial. Dig Dis Sci. 2011 Oct 26. [Epub ahead of print]

Bentz S, Hausmann M, et al. Clinical relevance of igg antibodies against food antigens in Crohn’s disease: a double-blind cross-over diet intervention study. Digestion 2010;81:252-64.

Bernstein CN, Blanchard JF, Metge C, Yogendran M. The association between corticosteroid use and development of fractures among IBD patients in a population-based database. Am J Gastroenterol 2003;98(8):1797-801.

Bernstein CN, Nugent Z, Blanchard JF. 5-Aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. Am J Gastroenterol 2011;106:731-6.

Biasco G et al. Folate and prevention of colorectal cancer in ulcerative colitis. Eur J Cancer Prev. 2005 Aug;14(4):395-8.

Boznanska P, Wichan P, et al. 24-hour urinary 6-hydroxymelatonin sulfate excretion in patients with ulcerative colitis. Pol Merkur Lekarski 2007;22(131):369-72 [in Polish].

Braunwald E. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001.

Brown AC, Roy M. Does evidence exist to include dietary therapy in the treatment of Crohn's disease? Expert Rev Gastroenterol Hepatol 2010;4(2):191-215.

Bruttin A, Brussow H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrobial agents and chemotherapy.Jul 2005;49(7):2874-2878.

Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002;47(10):2336-48.

Buyse J et al. Dietary L-carnitine supplementation enhances the lipopolysaccharide-induced acute phase protein response in broiler chickens. Vet Immunol Immunopathol. 2007 Jul 15;118(1-2):154-9. Epub 2007 May 3.

Campos FG, Waitzberg DL, et al. Pharmacological nutrition in inflammatory bowel diseases. Nutr Hosp. 2003 Mar;18(2):57-64.

Chambers ES et al. The impact of vitamin D on regulatory T cells. Curr Allergy Asthma Rep. 2011 Feb;11(1):29-36.

Chan SSM, Luben R, et al. Aspirin in the aetiology of Crohn’s disease and ulcerative colitis: a European prospective cohort study. Aliment Pharmacol Ther 2011;34:649-55.

Chibani-Chennoufi S, Sidoti J, Bruttin A, Kutter E, Sarker S, Brussow H. In vitro and in vivo bacteriolytic activities of Escherichia coli phages: implications for phage therapy. Antimicrob Agents Chemother.Jul 2004;48(7):2558-2569.

Chin J. Intestinal microflora: negotiating health outcomes with the warring community within us. Asia Pac J Clin Nutr. 2004;13(suppl):S24-S25.

Chojnacki C, Wisniewska-Jarosinska M, et al. Evaluation of melatonin effectiveness in the adjuvant treatment of ulcerative colitis. J Physiol Pharmacol 2011;62(3):327-34.

Clokie MRJ, Millard AD, Letarov AV, Heaphy S. Phages in nature. Bacteriophage.Jan-Feb 2011;1(1):31-45.

Colombel JF, Loftus EV Jr, et al. The safety profile of infliximab in patients with Crohn’s disease: the Mayo Clinic experience in 500 patients. Gastroenterology 2004;126;19-31.

Coogan PF, Rosenberg L. The use of folic acid antagonists and the risk of colorectal cancer. Pharmacoepidemiol Drug Saf 2007;16(10):1111-9.

Connerton PL, Timms AR, Connerton IF. Campylobacter bacteriophages and bacteriophage therapy. J Appl Microbiol.Aug 2011;111(2):255-265.

Cosnes J. Can we modulate the clinical course of inflammatory bowel diseases by our current treatment strategies? Dig Dis 2009;27:516-21.

Dalmasso M, Hill C, Ross RP. Exploiting gut bacteriophages for human health. Trends in microbiology.Jul 2014;22(7):399-405.

Dalmasso M, Strain R, Neve H, Franz CM, Cousin FJ, Ross RP, Hill C. Three New Escherichia coli Phages from the Human Gut Show Promising Potential for Phage Therapy. PloS one.2016;11(6):e0156773.

Danelli P, Bartolucci C, et al. Surgical options in the treatment of perianal Crohn's disease [in Italian]. Ann Ital Chir. 2003 Nov;74(6):635-40.

de Moreno de Leblanc A et al. Importance of IL-10 modulation by probiotic microorganisms in gastrointestinal inflammatory diseases. SRN Gastroenterol. 2011;2011:892971. Epub 2011 Feb 8.

Deckelbaum RJ et al. The omega-3 Fatty Acid nutritional landscape: health benefits and sources. J Nutr. 2012 Mar;142(3):587S-91S. Epub 2012 Feb 8.

Den Hond E, Hiele M, et al. Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn's disease. JPEN J Parenter Enteral Nutr 1999;23(1):7-11.

Di Sabatino A, Morera R, et al. Oral butyrate for mildly to moderately active Crohn's disease. Aliment Pharmacol Ther 2005;22(9):789-94.

Dinleyici Ec et al. Effectiveness and safety of Saccharomyces boulardii for acute infectious diarrhea. Expert Opin Biol Ther. 2012 Feb 16. [Epub ahead of print]

Duggan P, O'Brien M, Kiely M, et al. Vitamin K status in patients with Crohn's disease and relationship to bone turnover. Am J Gastroenterol 2004;99(11):2178-85.

Elahi B, Nikfar S, et al. On the benefit of probiotics in the management of pouchitis in patients that underwent ileal pouch anal anastomosis: a meta-analysis of controlled clinical trials. Dig Dis Sci 2008;53(5):1278-84.

Esaki M, Matsumoto T, et al. Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with reference to ?ndings determined by intra-operative enteroscopy. Scand J Gastroenterol 2005;40:1431-7.

Etzel JP et al. Assessment and management of low bone density in inflammatory bowel disease and performance of professional society guidelines. Inflamm Bowel Dis. 2011 Jan 13. [Epub ahead of print]

Fedorak RN, Madsen KL. Probiotics and the management of inflammatory bowel disease. Inflamm Bowel Dis. 2004 May;10(3):286-99.

Feller ER, Ribaudo S, et al. Gynecologic aspects of Crohn's disease. Am Fam Physician. 2001 Nov 15;64(10):1725-8.

Fernandez-Miranda C, Martinez Prieto M, et al. Hyperhomocysteinemia and methylenetetrahydrofolate reductase 677C-->T and 1298A-->C mutations in patients with inflammatory bowel disease. Rev Esp Enferm Dig. 2005 Jul;97(7):497-504.

Fife J et al. Folic acid supplementation and colorectal cancer risk: a meta-analysis. Colorectal Dis. 2011 Feb;13(2):132-7. doi: 10.1111/j.1463-1318.2009.02089.x.

Fujimori S, Tatsuguchi A, Gudis K, et al. High dose probiotic and prebiotic cotherapy for remission induction of active Crohn's disease. J Gastroenterol Hepatol. 2007;22(8):1199-204.

Furrie E, Macfarlane S, et al. Systemic antibodies towards mucosal bacteria in ulcerative colitis and Crohn's disease differentially activate the innate immune response. Gut. 2004 Jan;53(1):91-8.

Garcia Vilela E et al. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn's disease in remission. Scand J Gastroenterol. 2008;43(7):842-8.

Geerling BJ, Badart-Smook A, Stockbrügger RW, Brummer RJ. Comprehensive nutritional status in recently diagnosed patients with inflammatory bowel disease compared with population controls. Eur J Clin Nutr 2000a;54(6):514-21.

Geerling BJ, Badart-Smook A, van Deursen C, et al. Nutritional supplementation with N-3 fatty acids and antioxidants in patients with Crohn's disease in remission: effects on antioxidant status and fatty acid profile. Inflamm Bowel Dis 2000b;6(2):77-84.

Gerhardt H, Seifert F, et al. Therapy of active Crohn disease with Boswellia serrata extract H 15. Z Gastroenterol 2001;39:11-7 [in German].

Giaffer MH, Cann P, Holdsworth CD. Long-term effects of elemental and exclusion diets for Crohn's disease. Aliment Pharmacol Ther 1991;5(2):115-25.

Gisbert JP, Gonzalez-Lama Y, Mate J. Systematic review: infliximab therapy in ulcerative colitis. Aliment Pharmacol Ther 2006;25:19-37.

Goh J, O'Morain CA. Review article: nutrition and adult inflammatory bowel disease. Aliment Pharmacol Ther. 2003 Feb;17(3):307-20.

Golias C et al. Physiology and pathophysiology of selectins, integrins, and IgSF cell adhesion molecules focusing on inflammation. A paradigm model on infectious endocarditis. ll Commun Adhes. 2011 Jun;18(3):19-32. Epub 2011 Sep 5.

Gupta I, Parihar A, et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res 1997;2:37-43.

Gupta I, Parihar A, et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med 2001;67:391–5.

Haden ST, Glowacki J et al. Effects of age on serum dehydroepiandrosterone sulfate, IGF-I, and IL-6 levels in women. Calcif Tissue Int. 2000 Jun;66(6):414-8.

Hanai H, Iida T, et al. Curcumin maintenance therapy for ulcerative colitis: Randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4(12):1502-6.

Hanai H, Kanauchi O, et al. Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. Int J Mol Med 2004;13(5):643-7.

Harpavat M, Keljo DJ et al. Metabolic bone disease in inflammatory bowel disease. J Clin Gastroenterol. 2004 Mar;38(3):218-24.

Hawthorne AB, Daneshmend TK, et al. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial. Gut 1992;33(7):922-8.

Head KA et al. Inflammatory bowel disease Part 1: ulcerative colitis--pathophysiology and conventional and alternative treatment options. Altern Med Rev. 2003 Aug;8(3):247-83.

Heaton KW, Thornton JR, Emmett PM. Treatment of Crohn's disease with an unrefined-carbohydrate, fiber-rich diet. Br Med J 1979;ii:764-6.

Heckers H, Melcher FW, et al. Chemically prepared fats and Crohn disease: a pilot study of the occurrence of trans-fatty acids in the subcutaneous tissue of Crohn patients in comparison with healthy controls as a parameter of long-term fat intake. Z Gastroenterol. 1988;26(5):259-64.

Hengstermann S et al. Altered status of antioxidant vitamins and fatty acids in patients with inactive inflammatory bowel disease. Clin Nutr. 2008 Aug;27(4):571-8. Epub 2008 Mar 7.

Henriksen M, Jahnsen J, Lygren I, et al. C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study. Gut 2008;57(11):1518-23.

Hillier K et al. Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease. Gut 1991;32(10):1151-5.

Hinks IJ, Inwards KD, Lloyd B, Clayton B. Reduced concentration of selenium in mild Crohn's disease. J Clin Pathol 1988;41:198-201.

Holt PR et al. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005 Nov;50(11):2191-3.

Holtmeier W, Zeuzem S, et al. Randomized, placebo-controlled, double-blind trial of Boswellia serrata in maintaining remission of Crohn's disease: good safety profile but lack of efficacy. Inflamm Bowel Dis 2011;17(2):573-82.

Homik J, Suarez-Almazor ME, et al. Calcium and vitamin D for corticosteroid-induced osteoporosis. Cochrane Database Syst Rev 2000;(2):CD000952.

Hou JK et al. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011 Apr;106(4):563-73.

Hwang JM et al. Surgery for inflammatory bowel disease. World J Gastroenterol. 2008 May 7;14(17):2678-90.

Ibrahim A et al. Dietary a-linolenic acid-rich formula reduces adhesion molecules in rats with experimental colitis. Nutrition. 2012 Jan 18. [Epub ahead of print]

Ishikawa H et al. Beneficial effects of probiotic bifidobacterium and galacto-oligosaccharide in patients with ulcerative colitis: a randomized controlled study. Digestion. 2011;84(2):128-33. Epub 2011 Apr 28.

Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G7-G17.

Iwami D et al. Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells. Int Immunopharmacol. 2011 Mar;11(3):384-9. Epub 2010 Dec 18.

Jahnsen J, Falch JA, et al. Vitamin D status, parathyroid hormone and bone mineral density in patients with inflammatory bowel disease. Scand J Gastroenterol 2002;37(2):192-9.

Jaiswal A, Koley H, Ghosh A, Palit A, Sarkar B. Efficacy of cocktail phage therapy in treating Vibrio cholerae infection in rabbit model. Microbes Infect.Feb 2013;15(2):152-156.

Jansen G et al. Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications ofr combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum. 2004 Jul;50(7):2130-9

Johe PD, Osterud B. The in vivo effect of melatonin on cellular activation processes in human blood during strenuous physical exercise. J Pineal Res 2005;39:324–330.

Johnson GJ, Cosnes J, Mansfield JC. Review article: smoking cessation as primary therapy to modify the course of Crohn's disease. Aliment Pharmacol Ther 2005;21:921–31.

Jones VA. Comparison of total parenteral nutrition and elemental diet in induction of remission of Crohn's disease. Long-term maintenance of remission by personalized food exclusion diets. Dig Dis Sci 1987;32(12 Suppl):100S--7S.

Jorgensen SP, Agnholt J, et al. Clinical trial:Vitamin D3 treatment in Crohn's disease---A randomized double-blind placebo-controlled study. Aliment Pharmacol Ther 2010;32:377-83.

Jowett SL, Seal CJ, et al. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut 2004;53(10):1479-84.

Kaplan GG, Hubbard J, et al. The inflammatory bowel diseases and ambient air pollution: a novel association. Am J Gastroenterol 2010;105(11):2412-9.

Kappelman MD, Horvath-Puho E, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011;60:937–43.

Karimi O, Peña AS, van Bodegraven AA. Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn's disease: A pilot study. Drugs Today (Barc) 2005;41(7):453-9.

Kim DH et al. Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control. 2010 Nov;21(11):1919-30. Epub 2010 Sep 5.

Koutroubakis IE, Malliaraki N, et al. Decreased total and corrected antioxidant capacity in patients with inflammatory bowel disease. Dig Dis Sci. 2004 Sep;49(9):1433-7.

Koutroubakis IE. Therapy insight: Vascular complications in patients with inflammatory bowel disease. Nat Clin Pract Gastroenterol Hepatol 2005;2(6):266-72.

Krasinski SD, Russell RM et al. The prevalence of vitamin K deficiency in chronic gastrointestinal disorders. Am J Clin Nutr 1985;41(3):639-43.

Kruidenier L, Kuiper I, et al. Intestinal oxidative damage in inflammatory bowel disease: semi-quantification, localization, and association with mucosal antioxidants. J Pathol. 2003 Sep;201(1):28-36.

Kruschewski M, Perez-Canto S et al. [Protective effect of glutamine on microcirculation of the intestine in experimental colitis]. Langenbecks Arch Chir Suppl Kongressbd. 1998;115(Suppl I):229-31.

Kuroki F, Matsumoto T, et al. Selenium is depleted in Crohn's disease on enteral nutrition. Dig Dis. 2003;21(3):266-70.

Kuwabara A, Tanaka K, et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int 2009;20(6):935-42.

Langmead L et al. Anti-inflammatory effects of aloe vera gel in human colorectal mucosa in vitro. Aliment Pharmacol Ther. 2004b Mar 1;19(5):521-7.

Langmead L et al. Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis. Aliment Pharmacol Ther. 2004a Apr 1;19(7):739-47.

Lavasani S et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One. 2010 Feb 2;5(2):e9009.

Lim WC, Hanauer SB, Li YC. Mechanisms of disease: vitamin D and inflammatory bowel disease. Nat Clin Pract Gastroenterol Hepatol 2005;2(7):308-15

Loc-Carrillo C, Abedon ST. Pros and cons of phage therapy. Bacteriophage.Mar-Apr 2011;1(2):111-114.

Lorenz-Meyer H, Bauer P, et al. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease: a randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group). Scand J Gastroenterol. 1996;31:778-85.

Mahmood A, Needham J, et al. Prevalence of hyperhomocysteinaemia, activated protein C resistance and prothrombin gene mutation in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2005;17:739-44.

Maldonado MD, Calvo JR. Melatonin usage in ulcerative colitis: a case report. J Pineal Res 2008;45(3):339-40.

Malik T, Mannon P. Inflammatory bowel diseases: emerging therapies and promising molecular targets. Front Biosci 2012;S4:1172-89.

Malolepszy J, Kuczymska-Sekieta K, Chachaj W. Sodium cromoglycate therapy in ulcerative colitis. Acta Allergol 1977;13:82–86.

Matters GL et al. The opioid antagonist naltrexone improves murine inflammatory bowel disease. J Immunotoxicol. 2008 Apr;5(2):179-87.

McCarville JL, Caminero A, Verdu EF. Novel perspectives on therapeutic modulation of the gut microbiota. Therapeutic advances in gastroenterology.Jul 2016;9(4):580-593.

McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol. 2010 May 14;16(18):2202-22.

McNamara DA, Brophy S, Hyland JM. Perianal Crohn’s disease and infliximab therapy. Surgeon. 2004 Oct;2(5):258-63.

Meader E, Mayer MJ, Steverding D, Carding SR, Narbad A. Evaluation of bacteriophage therapy to control Clostridium difficile and toxin production in an in vitro human colon model system. Anaerobe.Aug 2013;22:25-30.

Meister D, Bode J, et al. Anti-inflammatory effects of enteral diet components on Crohn's disease-affected tissues in vitro. Dig Liver Dis. 2002 Jun;34(6):430-8.

Miheller P et al. Clinical relevance of changes in bone metabolism in inflammatory bowel disease. World J Gastroenterol. 2010 Nov 28;16(44):5536-42.

Miheller P, Muzes G, et al. Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn's disease patients. Inflamm Bowel Dis 2009;15:1656-1662.

Mikhailova TL et al. Randomised clinical trial: the efficacy and safety of propionyl-L-carnitine therapy in patients with ulcerative colitis receiving stable oral treatment. Aliment Pharmacol Ther. 2011 Nov;34(9):1088-97.

Mitamura T, Sakamoto S et al. The more an ulcerative colitis is repeated, the more the risk of colorectal carcinogenesis is increased in mice. Anticancer Res. 2002 Nov-Dec;22(6C):3955-61.

Mortimore M and Florin TH. A role for B12 in inflammatory bowel disease patients with suppurative dermatoses? An experience with high dose vitamin B12 therapy. J Crohns Colitis. 2010 Oct;4(4):466-70. Epub 2010 Mar 21.

Muijsers RB, Goa KL. Balsalazide: a review of its therapeutic use in mild-to-moderate ulcerative colitis. Drugs. 2002;62(11):1689-705.

Nakajima S, Iijima H, et al. Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease. Nutrition 2011;27(10):1023-8.

Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepinski P, Douce GR, Clokie MR. Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo. Antimicrob Agents Chemother.Feb 2016;60(2):968-981.

Neuman MG. Signaling for inflammation and repair in inflammatory bowel disease. Rom J Gastroenterol. 2004 Dec;13(4):309-16.

Newman WG et al. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study. Pharmacogenomics. 2011 Jun;12(6):815-26. Epub 2011 May 3.

Norman JM, Handley SA, Baldridge MT, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell.Jan 29 2015;160(3):447-460.

Ockenga J et al. Glutamine-enriched total parenteral nutrition in patients with inflammatory bowel disease. Eur J Clin Nutr. 2005 Nov;59(11):1302-9.

Ojuawo A and Keith L. The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease. Cent Afr J Med. 2002 Sep-Oct;48(9-10):116-9.

Omer B, Krebs S, Omer H, Noor TO. Steroid-sparing effect of wormwood (Artemisia absinthium) in Crohn's disease: A double-blind placebo-controlled study. Phytomedicine 2007;14(2-3):87-95.

Ooi JH et al. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med. 2012 Feb;33(1):77-82. Epub 2011 Nov 6.

Oussalah A et al. ta-analysis: hyperhomocysteinaemia in inflammatory bowel diseases. Aliment Pharmacol Ther. 2011 Nov;34(10):1173-84. doi: 10.1111/j.1365-2036.2011.04864.x. Epub 2011 Oct 3.

Papa A, Santoliquido A, et al. Increased carotid intima-media thickness in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2005 Nov 1;22(9):839-46.

Patel V, Macdonald JK, et al. Methotrexate for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2009 Oct 7;(4):CD006884.

Phang M, Lazarus S, Wood LG, Garg M Diet and thrombosis risk: nutrients for prevention of thrombotic disease. Semin Thromb Hemost 2011;37(3):199-208.

Phelip JM et al. Association of hyperhomocysteinemia and folate deficiency with colon tumors in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2008 Feb;14(2):242-8.

Pitcher MCL, Cummings JH. Hydrogen sulphide: a bacterial toxin in ulcerative colitis? Gut 1996;39:1-4.

Preiss JC et al. Use of methotrexate in patients with inflammatory bowel disease. Clin Exp Rheumatol. 2010 Sep-Oct;28 (5 Suppl 61):S151-5

Rakhimova OIu . Use of melatonin in combined treatment for inflammatory bowel diseases. Ter Arkh 2010;82(12):64-8 [in Russian].

Riordan AM, Hunter JO, et al. Treatment of active Crohn's disease by exclusion diet: East Anglian Multicentre Controlled Trial. Lancet 1993;342:1131-4.

Roblin X, Germain E, et al. Factors associated with hyperhomocysteinemia in inflammatory bowel disease: prospective study in 81 patients [in French]. Rev Med Interne. 2006 Feb;27(2):106-10.

Roediger WE. Decreased sulphur aminoacid intake in ulcerative colitis. Lancet 1998;351(9115):1555.

Roediger WEW, Moore J, Babidge W. Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig Dis Sci 1997;42:1571-9.

Rogler G, Scholmerich J. Extraintestinal manifestations of inflammatory bowel disease [in German]. Med Klin (Munich). 2004 Mar 15;99(3):123-30.

Rogler G. Prebiotics and probiotics in ulcerative colitis: where do we stand? Digestion. 2011;84(2):126-7. Epub 2011 Apr 15.

Ross E. The role of marine fish oils in the treatment of ulcerative colitis. Nutr Rev. 1993;51(2):47-9.

Rowan FE, Docherty NG, Coffey JC, O'Connell PR. Sulphate-reducing bacteria and hydrogen sulphide in the aetiology of ulcerative colitis. Br J Surg 2009;96(2):151-8.

Ruffolo C et al. Subclinical intestinal inflammation in patients with Crohn's disease following bowel resection: a smoldering fire. J Gastrointest Surg. 2010 Jan;14(1):24-31. Epub 2009 Nov 10.

Rutgeerts P, Löfberg R, et al. A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med 1994;331:842–5.

Sakamoto N et al. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis. 2005 Feb;11(2):154-63.

Sarker SA, McCallin S, Barretto C, et al. Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh. Virology.Dec 20 2012;434(2):222-232.

Sartor RB. Efficacy of probiotics for the management of inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2011 Sep;7(9):606-8.

Sato S, Sasaki I, et al. Management of urinary complications in Crohn's disease. Surg Today. 1999;29(8):713-7.

Scholz D. The role of nutrition in the etiology of inflammatory bowel disease. Curr Probl Pediatr Adolesc Health Care. 2011 Oct;41(9):248-53.

Segain JP, Raingeard de la Bletiere D, et al. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease. Gut. 2000 Sep;47(3):397-403.

Sengupta K et al. Cellular and molecular mechanisms of anti-inflammatory effect of Aflapin: a novel Boswellia serrata extract. Mol Cell Biochem. 2011 Aug;354(1-2):189-97. Epub 2011 Apr 11.

Shakeri A et al. Effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein, lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia. Hemodial Int. 2010 Oct;14(4):498-504.

Sido B, Seel C, Hochlehnert A, et al. Low intestinal glutamine level and low glutaminase activity in Crohn's disease: a rational for glutamine supplementation? Dig Dis Sci 2006;51(12):2170-9.

Siffledeen JS, Siminoski K, et al. The frequency of vitamin D deficiency in adults with Crohn's disease. Can J Gastroenterol. 2003 Aug;17(8):473-8.

Simopoulos AP. Importance of the omega-6/omega-3 balance in health and disease: evolutionary aspects of diet. World Rev Nutr Diet. 2011;102:10-21. Epub 2011 Aug 5.

Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002 Oct;56(8):365-79.

Smith JP, Bingaman SI, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Dig Dis Sci 201156:2088-97.

Smith JP, Stock H, Bingaman S, et al. Low-dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol 2007;102:820-8.

Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ. Venous thromboembolism in inflammatory bowel disease. Am J Gastroenterol 2004;99(1):97-101.

Sonoda K, Ikeda S, et al. Evaluation of venous thromboembolism and coagulation-fibrinolysis markers in Japanese patients with inflammatory bowel disease. J Gastroenterol 2004;39(10):948-54.

Srirajaskanthan R, Winter M, et al. Venous thrombosis in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2005 Jul;17(7):697-700.

Stefanini GF et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol. 1995 Jun;30(6):535-41.

Steinhart AH et al. Nutrition in inflammatory bowel disease. Curr Opinion Gastroenterol. 1997;13(2):140-5.

Stenson WF et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992 Apr 15;116(8):609-14.

Straub RH, Scholmerich J, et al. Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory diseases: substitutes of adrenal and sex hormones. Z Rheumatol. 2000;59(suppl 2):II/108-18.

Tavarela VF. Review article: skin complications associated with inflammatory bowel disease. Aliment Pharmacol Ther. 2004 Oct;20(suppl 4):50-3.

Taylor RA et al. Curcumin for inflammatory bowel disease: a review of human studies. Altern Med Rev. 2011 Jun;16(2):152-6.

Teahon K, Smethurst P, et al. The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease. Gastroenterology. 1991 Jul;101(1):84-9.

Terry PD, Villinger F, Bubenik GA, Sitaraman SV. Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflamm Bowel Dis 2009;15:134-40.

Thomas S et al. Anti-inflammatory effects of Saccharomyces boulardii mediated by myeloid dendritic cells from patients with Crohn's disease and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol. 2011 Dec;301(6):G1083-92. Epub 2011 Sep 8.

Tighe MP, Cummings JR, Afzal NA. Nutrition and inflammatory bowel disease: primary or adjuvant therapy. Curr Opin Clin Nutr Metab Care. 2011 Sep;14(5):491-6.

Trebble TM, Arden NK, et al. Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr. 2004 Nov;80(5):1137-44.

Trebble TM, Stroud MA, et al. High-dose fish oil and antioxidants in Crohn's disease and the response of bone turnover: a randomised controlled trial. Br J Nutr. 2005 Aug;94(2):253-61.

Triggs CM, Munday K, et al. Dietary factors in chronic inflammation: food tolerances and intolerances of a New Zealand Caucasian Crohn's disease population. Mutat Res 2010;690(1-2):123-38.

Tsai F and Coyle WJ. The microbiome and obesity: is obesity linked to our gut flora? Curr Gastroenterol Rep. 2009 Aug;11(4):307-13.

Tursi A et al. h prevalence of celiac disease among patients affected by Crohn's disease. Inflamm Bowel Dis. 2005 Jul;11(7):662-6.

Uchiyama K et al. N-3 polyunsaturated fatty acid diet therapy for patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010 Oct;16(10):1696-707.

Vagianos K et al. tion assessment of patients with inflammatory bowel disease. JPEN J Parenter Enteral Nutr. 2007 Jul-Aug;31(4):311-9.

Van Den Bogaerde J, Cahill J, et al. Gut mucosal response to food antigens in Crohn's disease. Aliment Pharmacol Ther 2002;16(11):1903-15.

Vermeire S, Peeters M, et al. Anti-Saccharomyces cerevisiae antibodies (ASCA), phenotypes of IBD, and intestinal permeability: a study in IBD families. Inflamm Bowel Dis 2001;7(1):8-15.

Vieira EL et al. Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J Nutr Biochem. 2011 Jun 8. [Epub ahead of print]

Wang TT, Dabbas B, Laperrier D, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta-2 innate immune pathway defective in Crohn disease. J Biol Chem 2010;285(4):2227-31.

Wang W, Jovel J, Halloran B, et al. Metagenomic Analysis of Microbiome in Colon Tissue from Subjects with Inflammatory Bowel Diseases Reveals Interplay of Viruses and Bacteria. Inflamm Bowel Dis.Jun 2015;21(6):1419-1427.

Watanabe O et al. Enteral nutrition decreases hospitalization rate in patients with Crohn's disease. J Gastroenterol Hepatol. 2010 May;25 Suppl 1:S134-7.

Wiese DM et al. The effects of an oral supplement enriched with fish oil, prebiotics, and antioxidants on nutrition status in Crohn's disease patients. Nutr Clin Pract. 2011 Aug;26(4):463-73.

Wright R, Truelove SC. A controlled therapeutic trial of various diets in ulcerative colitis. Br Med J 1965;2:138-41.

Xu CT, Meng SY et al. Drug therapy for ulcerative colitis. World J Gastroenterol. 2004 Aug 15;10(16):2311-7.

Yakut M et al. Serum vitamin B12 and folate status in patients with inflammatory bowel diseases. Eur J Intern Med. 2010 Aug;21(4):320-3. Epub 2010 Jun 8.

Yamamoto T, Nakahigashi M, et al. Impact of long-term enteral nutrition on clinical and endoscopic recurrence after resection for Crohn's disease: A prospective, non-randomized, parallel, controlled study. Aliment Pharmacol Ther 2007;25:67-72.

Yuan Y et al. Protective effects of L-carnitine on intestinal ischemia/reperfusion injury in a rat model. J Clin Med Res. 2011 Apr 4;3(2):78-84

Zezos P, Papaioannou G, et al. Hyperhomocysteinemia in ulcerative colitis is related to folate levels. World J Gastroenterol. 2005 Oct 14;11(38):6038-42.

Zigra PI, Maipa VE, Alamanos YP. Probiotics and remission of ulcerative colitis: a systematic review. Netherlands J Med 2007;65(11):411--18.

Zintzaras E. Genetic variants of homocysteine/folate metabolism pathway and risk of inflammatory bowel disease: a synopsis and meta-analysis of genetic association studies. Biomarkers. 2010 Feb;15(1):69-79.

  • Probiotics: Per label instructions
  • Fish oil (with olive polyphenols): At least 1400 mg/day of EPA and 1000 mg/day of DHA
  • Vitamin D: 5000 – 8000 IU daily, depending on blood test results
  • Glutamine: 1.95 g daily
  • Comprehensive multivitamin: Per label instructions
  • Saccharomyces boulardii: 250 mg twice daily
  • Zinc: 30 mg daily
  • Vitamin C: 500 – 2000 mg daily
  • Natural Vitamin E: 100 – 400 IU alpha-tocopherol and 200 mg gamma-tocopherol daily
  • Vitamin A: 500 IU acetate and 4500 IU beta-carotene daily
  • Vitamin K: 2100 mcg daily; providing K1, MK-4 and MK-7
  • B-Complex vitamins (many of these should be included in high potency multi-vitamin supplements):
    • Thiamine (B1): 75 – 125 mg daily
    • Riboflavin (B2): 50 mg daily
    • Niacin (B3): 50 – 190 mg daily
    • Folate (preferably as L-methylfolate): 400 – 1000 mcg daily
    • Vitamin B6 (preferably as pyridoxal-5-phosphate): 75 – 105 mg daily
    • Vitamin B12: 300 – 600 mcg daily
    • Biotin: 300 – 3000 mcg daily
    • Pantothenic acid: 100 – 600 mg daily
  • Selenium: 100 – 200 mcg daily
  • Iron: 15 – 60 elemental mg daily (depending on ferritin blood test results)
  • Curcumin (as highly absorbed BCM95®): 400 – 800 mg daily
  • Boswellia serrata (as highly absorbed ApresFlex™): 100 mg daily
  • Propionyl-L-Carnitine: 1000 – 2000 mg daily
  • Trans-resveratrol: 100 – 500 mg daily
  • Wormwood; standardized extract: per label instructions
  • Aloe gel: per label instructions
  • Soluble fiber: 5 – 15 g per day
  • Melatonin: 0.3 – 5 mg before bed (sometimes up to 10 mg)
  • DHEA: 15 – 25 mg daily for women, and 25 – 75 mg daily for men (depending on blood test results)

In addition, the following blood tests can provide helpful information:

 
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