Inflammatory Bowel Disease (Crohn’s and Ulcerative Colitis)
Nutritional and Alternative Therapy
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-α 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, α-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-β-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-α (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-α 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).
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.