Apple polyphenols each day may help keep intestinal inflammation away

Posted on December 19, 2011 by Dr. Jonathan

Summary: phenolic compounds in apples have beneficial effects for autoimmune inflammatory bowel disease.

A paper just published in the Journal of Leukocyte Biology demonstrates the mechanism by which polyphenols in apples help quell the inflammation of the autoimmune diseases ulcerative colitis and Crohn’s disease. The authors state:

“Human IBD, including UC and Crohn’s disease, is characterized by a chronic, relapsing, and remitting condition that exhibits various features of immunological inflammation and affects at least one/1000 people in Western countries. Polyphenol extracts from a variety of plants have been shown to have immunomodulatory and anti-inflammatory effects. In this study, treatment with APP [apple polyphenols] was investigated to ameliorate chemically induced colitis.”

The authors administered APP to study animals genetically predisposed to autoimmune inflammatory bowel disease win whom inflammation as induced by chemical irritation. Their findings documented an protective effect:

“Oral but not peritoneal administration of APP during colitis induction significantly protected C57BL/6 mice against disease, as evidenced by the lack of weight loss, colonic inflammation, and shortening of the colon. APP administration dampened the mRNA expression of IL-1β, TNF-α, IL-6, IL-17, IL-22, CXCL9, CXCL10, CXCL11, and IFN-γ in the colons of mice with colitis.”

A rational treatment strategy for autoimmune disease requires an assessment of the factors involved in the loss of self-tolerance, including integrity of barrier systems, glutathione production and recycling, nitric oxide synthase production, regulatory T cell function, cytokine regulation, antigenic environmental triggering agents, lifestyle factors that modulate genetic expression, etc. For palliation, however, interventions that can reduce inflammation without side effects are desirable. Although an extract concentrates polyphenols more than is obtained by eating apples, compounds like this and resveratrol are worthy of consideration for adjunctive use. The authors conclude:

“…these results show that oral administration of APP protects against experimental colitis and diminishes proinflammatory cytokine expression via T cells.”

Therapeutic resources for inflammatory bowel disease

Posted on January 19, 2011 by Dr. Jonathan

Autoimmune disease in general and inflammatory bowel disease in particular arise from a constellation of causes that should be investigated and addressed on an individual basis. Nonetheless, methods that calm the inflammatory cascade (without harmful side-effects) are important practical tools. As forthcoming posts will describe in greater detail, nitric oxide production is a critical step in the production of damaging inflammation. A paper published in the European Journal of Clinical Investigation highlights this fact:

“Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn’s disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO…”

And of interest for clinical case managment…

“The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis.”

A study published in the British Journal of Pharmacology examines the ability of the natural flavonoid quercitrin (related to quercitin) to inhibit production of iNOS (‘inducible nitric oxide synthase, the ‘bad’ nitric oxide producing enzyme). The authors state:

“Quercitrin, 3-rhamnosylquercetin, is a bioflavonoid with antioxidant properties, which exerts anti-inflammatory activity in experimental colitis. In the present study, different in vivo experiments were performed in order to evaluate the mechanisms of action involved in this effect, with special attention to its effects on proinflammatory mediators, including nitric oxide (NO).”

They examined the effects of quercitrin on inflammation of the intestinal mucosa (‘lining’) induced by DSS (dextran sodium sulfate) both preventatively and, in another cohort, on already established colitis. The results were significant:

“Oral treatment of quercitrin…ameliorated the evolution of the inflammatory process induced when administered in a preventative dosing protocol…on established colitis, it facilitated the recovery of the inflamed mucosa…The beneficial effects exerted by quercitrin were evidenced both histologically and biochemically, and were associated with an improvement in the colonic oxidative status…”

Regarding the role of NO and inflammatory bowel disease…

“…a reduction of colonic NO synthase activity was observed, probably related to a decreased expression in the inducible form of the enzyme [iNOS] via downregulation in the colonic activity of the nuclear factor-κB.”

The authors discuss their findings in summary:

“During the last decade, it has become increasingly clear that NO overproduction by iNOS is deleterious to intestinal function…thus contributing significantly to gastrointestinal immunopathology…the results obtained in the present study reveal that colonic inflammation is associated with a higher colonic NOS activity, mainly attributed to an increase in iNOS expression…the effect showed by quercitrin is most probably related to an inhibition of the expression of this enzyme, which is upregulated as a consequence of the colonic inflammatory process…The antioxidant and/or scavenging properties ascribed to this flavonoid could also contribute to its intestinal anti-inflammatory effect…”

A study published in the European Journal of Immunology sheds more light on the use of quercitin for inflammatory bowel disease. Examining the relationship between quercitrin and quercitin, the authors find…

“…that the in vivo effects of quercitrin…can be mediated by the release of quercetin generated after glycoside’s cleavage by the intestinal microbiota. This is supported by the fact that quercetin, but not quercitrin, is able to down-regulate the inflammatory response of bone marrow-derived macrophages in vitro.”

They also describe evidence for the effect of quercitin on iNOS and the the NF-κB pathway:

“Moreover, we have demonstrated that quercetin inhibits cytokine and inducible nitric oxide synthase expression through inhibition of the NF-κB pathway…(both in vitro and in vivo). As a conclusion, our report suggests that quercitrin releases quercetin in order to perform its anti-inflammatory effect…”

A paper published in the journal Digestive Diseases examines the ability of quercitin to help repair the gut barrier in inflammatory bowel disease. Regarding the intestinal epithelial barrier (‘lining’) the authors state:

“In inflammatory bowel disease (IBD), epithelial barrier function is impaired contributing to diarrhea by a leak flux mechanism and perpetuating inflammation by an increased luminal antigen uptake. This barrier of the intestinal epithelium is composed of the apical enterocyte membrane and the epithelial tight junction (TJ) and can be affected by TJ alterations, induction of epithelial apoptoses and appearance of gross lesions like erosions or ulcers as well as by accelerated transcytotic antigen uptake.”

They note that in addition to therapies that oppose Th1 cytokine activity in Crohn’s disease and Th2 cytokine activity in ulcerative colitis, other agents have been shown to improve barrier function:

“…zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown. Finally, food components can strengthen the epithelial barrier as for example the flavonoid quercetin which has been shown to upregulate claudin-4 within the epithelial TJ.”

Curcumin (extracted from the yellow spice turmeric) should also be considered in the functional management of inflammatory bowel disease. The authors of a study published in the journal Inflammatory Bowel Diseases observe:

“Neutrophils (PMN) are the first cells recruited at the site of inflammation. They play a key role in the innate immune response by recognizing, ingesting, and eliminating pathogens and participate in the orientation of the adaptive immune responses. However, in inflammatory bowel disease (IBD) transepithelial neutrophil migration leads to an impaired epithelial barrier function, perpetuation of inflammation, and tissue destruction via oxidative and proteolytic damage. Curcumin (diferulolylmethane) displays a protective role in mouse models of IBD and in human ulcerative colitis, a phenomenon consistently accompanied by a reduced mucosal neutrophil infiltration.”

They investigated the phenomenon of neutrophil modulation by curcumin in vitro and in vivo. Their accumulated data demonstrated that…

“Curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and secretion of macrophage inflammatory protein (MIP)-2, interleukin (IL)-1β, keratinocyte chemoattractant (KC), and MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a well as the IL-8-mediated chemotaxis of human neutrophils. At nontoxic concentrations, curcumin inhibited random neutrophil migration, suggesting a direct effect on neutrophil chemokinesis.”

In other words, curcumin was shown to significantly attenuate proinflammatory cytokine expression and white blood cell ‘attack movements’. Thus the authors conclude:

“Our results indicate that curcumin interferes with colonic inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil chemotaxis and chemokinesis.”

A double-blind, placebo-controlled trial of curcumin for the treatment of ulcerative colitis was reported in the journal Clinical Gastroenterology and Hepatology. The authors state:

“Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).”

They divided a cohort of 89 patients with quiescent UC into a treatment group of 45 who added 1 gram of curcumin taken two times per day to their usual therapy. The other 44 got a placebo. After 6 months the relapse percentages were 4.65% for those who received curcumin and 20.51% for the placebo group.

“Furthermore, curcumin improved both CAI [clinical activity index] and EI [endoscopic index], thus suppressing the morbidity associated with UC.”

The authors conclude:

“Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.”

It’s also worth noting a paper published in the journal Current Pharmaceutical Design examines the multiple anti-inflammatory effects of curcumin. The authors first state:

“Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life… it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines.”

They note that earlier research has demonstrated that curcumin inhibits inflammation through action on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-κB, a key factor in the production of proinflammatory cytokines), and has a strong anti-oxidant effect.

“Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles…”

And in an early successful human IBD study..

“…patients were given curcumin (360mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD.”

While it’s difficult to predict ahead of time which patients will have the best response to agents such as curcumin and quercitin, since they are so safe and wholesome we can welcome the authors’ conclusion:

“The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-α, IFN-γ, NF-κB and its unrivaled safety profile suggest that it has bright prospects in the treatment of IBD.”

Beneficial E. coli helps heal ulcerative colitis

Posted on August 3, 2010 by Dr. Jonathan

The emerging science of the human microbiome and modulation of the immune system by introducing specific strains of probiotic flora into the gut and other microbial ecosystems is one of the most fascinating and promising developments in medicine. A study published some time back in the journal GUT (An International Journal of Gastroenterology and Hepatology) is among a number of investigations into the benefit of Escherichia coli Nissle 1917 in stimulating the immune system to heal ulcerative colitis:

“We compared the efficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and established therapy with mesalazine in patients with ulcerative colitis.”

The authors assigned 327 patients to receive either the Escherichia coli Nissle 1917 or mesalazine and evaluated the outcomes according to clinical, endoscopic and histologic (tissue microscopic) indices over a twelve month period. Mesalazine is an anti-inflammatory medication administered by suppository that is not without concerns, and a suppressive palliation at best.

“The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses.”

Wouldn’t it be better to stimulate the immune system to express healthier regulation if possible? The data established this notable conclusion:

“The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic treatment further underlines the pathogenetic significance of the enteric flora.”

This is but one example among many more you’ll be hearing about in this fascinating and promising area of research and clinical application.

RDW is an inexpensive but powerful indicator often overlooked on your routine blood test

Posted on March 7, 2010 by Dr. Jonathan

Archives of Internal Medicine 0210 RDW stands for Red (Blood Cell) Distribution Width, an index for the degree of variability in the size and shape of your red blood cells. Recent studies are showing it to be a powerful indicator of overall health and the risk of death from multiple causes. RDW is always included in the standard Complete Blood Count (CBC), one of the most routine lab tests in modern medicine, but there’s evidence that the usual lab reference range is too broad and it’s value is not widely appreciated. It has been established for some time that RDW predicts mortality form cardiovascular disease, but this study recently published in the Archives of Internal Medicine is particularly interesting because it shows that RDW predicts mortality in the general population independent of cardiovascular disease. The authors state:

“Higher RDW values were strongly associated with an increased risk of death…Even when analyses were restricted to nonanemic participants or to those in the reference range of RDW (11%-15%) without iron, folate, or vitamin B12 deficiency, RDW remained strongly associated with mortality. The prognostic effect of RDW was observed in both middle-aged and older adults for multiple causes of death.”

Two weeks later the another paper was published in the same journal on the same topic that begins with this observation:

“Red blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity (eg, anisocytosis) that is largely overlooked, is a newly recognized risk marker in patients with established cardiovascular disease (CVD).”

They set out to investigate

“the association of RDW with all-cause mortality and with CVD, cancer, and chronic lower respiratory tract disease mortality in 15,852 adult participants.”

Their conclusion:

“Higher RDW is associated with increased mortality risk in this large, community-based sample, an association not specific to CVD.”

Another paper just published in The Journals of Gerontology confirms these findings with an analysis of seven community-based studies of older adults. Their conclusion:

“RDW is a routinely reported test that is a powerful predictor of mortality in community-dwelling older adults with and without age-associated diseases.”

Diabetes Care 0210.2 This paper just published in the journal Diabetes Care reports on the link between RDW, metabolic syndrome and cardiovascular disease: “A possible explanation for the observed association between RDW and MetS is that high RDW reflects an underlying inflammatory state that leads to impaired erythrocyte (red blood cell) maturation and anisocytosis (size variation), as suggested previously (1–3). In fact, MetS exacerbates oxidative and inflammatory stress in obese adults, which is a potential mechanism for the increased cardiovascular risk in this condition.”

And as you would expect, the European Journal of Heart Failure recently published a study on heart failure that compares RDW with N-terminal brain natriuretic peptide (NT-proBNP) in which the authors conclude:

“Red cell distribution width is a readily available test in the HF-population with similar independent prognostic power to NT-proBNP across the first to third quartiles. Prognostic models in HF (heart failure) should include RDW.”

And the ‘plot thickens’. In this paper published in the journal Digestive Diseases and Sciences the investigators observe:

“Impaired iron absorption or increased loss of iron was found to correlate with disease activity and markers of inflammation in inflammatory bowel disease (IBD). Red cell distribution width (RDW) could be a reliable index of anisocytosis with the highest sensitivity to iron deficiency.”

Their compelling conclusion:

“Among the laboratory tests investigated, including fibrinogen, CRP, ESR, and platelet counts…analysis indicated RDW to be the most significant indicator of active UC [ulcerative colitis]. For CD [Crohn's disease], CRP was an important marker of active disease.”

Lastly, you’ll appreciate the broadest statement yet about the value of this inexpensive and readily available marker. In a recent paper published in the Archives of Pathology & Laboratory Medicine. The authors begin by chiming in with the neighborhood chorus:

“A strong independent association has been recently observed between elevated red blood cell distribution width (RDW) and increased incidence of cardiovascular events;”

but they aim to

“assess whether RDW is associated with plasma markers of inflammation.”

Their conclusion:

“To our knowledge, our study demonstrates for the first time a strong, graded association of RDW with hsCRP and ESR independent of numerous confounding factors.”

In other words, RDW is inexpensive, easily obtained, and a powerful marker for inflammation in general, the common denominator of most chronic disease.

Here’s the ‘take home’ message (if you’ve gotten this far): If you have almost any blood work done at all it’s likely to include RDW automatically. Make good use of it, keeping in mind that laboratory reference ranges do not reflect the latest research and your doctor may not be aware of this. Functional medicine doctors want RDW to be no more than 13%.

A possible explanation for the observed association between RDW and MetS is that high RDW reflects an underlying inflammatory state that leads to impaired erythrocyte maturation and anisocytosis, as suggested previously (1–3). In fact, MetS exacerbates oxidative and inflammatory stress in obese adults, which is a potential mechanism for the increased cardiovascular risk in this condition

Resveratrol relieves inflammation in the colon

Posted on March 3, 2010 by Dr. Jonathan

Current Drug Metabolism We need evidence-based medicines for chronic inflammation that are free of side-effects and wholesome for the body. Numerous studies have reported on the diverse therapeutic and anti-inflammatory properties of resveratrol. Inflammation in the digestive tract is a ubiquitous component of many chronic disorders; it’s reassuring to see these studies that confirm its biological activity against inflammation in the intestines.

Here we have a study just published in the European Journal of Pharmacology showing the effect of resveratrol in a model of ulcerative colitis, “a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and upregulation of inflammatory mediators.” The authors note that “Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumour and immunomodulatory activities.” They documented the positive effect of resveratrol on a number inflammatory signalling pathways, and observed that the “resveratrol group significantly attenuated the clinical signs such as loss of body weight, diarrhea and rectal bleeding improving results from disease activity index and inflammatory score.” Their conclusion: The “resveratrol diet represents a novel approach to the treatment of chronic intestinal inflammation.”

Here is a paper published in the Journal of Agriculture and Food Chemistry that describes a beneficial effect not only on inflammation and tissue damage with colitis but also on the gut flora from even very small doses of resveratrol. In addition to that, they observed “Resveratrol significantly protected the colonic mucosa architecture, reduced body weight loss, diminished the induced anemia and reduced systemic inflammation markers, colonic mucosa prostaglandin E2, cycloxygenase-2, prostaglandin E synthase and nitric oxide levels.” Their conclusion: “These results reinforce the concept of resveratrol as a dietary beneficial compound in intestinal inflammation at doses possibly attainable with resveratrol-enriched nutraceuticals.”

One more paper, published in the Journal of Investigative Surgery, documents the beneficial effect of resveratrol on healing after colon surgery. The authors defined their task: “Since anastomotic [connecting two severed tubular parts] healing possesses paramount importance to prevent complications in colorectal surgery, the present study is aimed to evaluate the effect of RSV on the healing of experimental left colonic anastomoses.” Their findings and disclosure: “Histopathological analysis revealed that RSV (resveratrol) administration leads to a better anastomotic healing…Although the precise cellular mechanisms by which RSV enhances anastomotic wound healing is not clear, stimulation of neovascularization (new blood vessels), generation of collagen synthesis, inhibition of overinflammation, and restriction of oxidative injury seems to be of paramount importance.”