The gut microbiota is the diverse community of microorganisms that reside within the gastrointestinal tract. The importance of the composition (what types of microorganisms), function (what they are doing), and the metabolites (what are they producing) has been highlighted in health and disease. In the case of chronic kidney disease (CKD), it is of great interest as the gut microbiota has been linked to the disease itself and the progression of kidney dysfunction.

The gut microbiota in chronic kidney disease

In CKD there are changes at the level of composition and function (e.g., enzymatic capacity) and metabolites produced by gut microbes. These changes have been assessed by examining mostly stool samples through experimental models (e.g., mouse or rat models of kidney disease by removing a large portion of the kidneys (5/6th) or by providing a toxic agent in the diet (i.e., adenine)) or in individuals with CKD not yet on dialysis and those undergoing dialysis treatment.

The changes in composition of the gut microbiota include having less bacterial species richness (amount of diversity within a sample) and an increased abundance of bacteria that are considered pathogenic or “bad”, while there is a reduction in the abundance of bacteria that are traditionally considered symbiotic or “good”. With these changes, the gut microbiota of CKD patients is considered dysbiotic or out of balance.

At the functional level, it has been reported that the fecal samples from individuals undergoing dialysis have an increased amount of enzymes that produce toxins that are increased as kidney function declines, mostly those that produce protein degradation metabolites (i.e., urea, uric acid, tyrosine, and tryptophan). Also, there is a decrease in the enzymes needed for the production of short-chain fatty acids, which are mostly produced from the fermentation of dietary fiber and thus are traditionally considered “good”.

At the metabolite level, mirroring the effect on the enzymes needed for the production of toxins derived from amino acid and protein degradation, metabolites such as indoles and phenols derived exclusively from the gut microbes are increased in the plasma of CKD patients.

Therapies that target the composition, function, and metabolites produced are of great interest in the CKD community

Due to the changes mentioned above, therapies that target the composition of the gut microbiota, the function of the gut microbiota, and what the gut microbes are producing are of great interest to try to reduce the burden of CKD. These therapies may include the use of pro-, pre-, and synbiotics.

The use of probiotics in CKD is not supported by the current evidence

Probiotics are live microorganisms that when consumed in specific amounts may give the individual a benefit. There are several probiotic bacteria, including species and strains within the Bifidobacterium and Lactobacillus families. Probiotic bacteria have been studied extensively in healthy individuals and those with several diseases. Some of the benefits in patients with CKD may include binding to pathogenic bacteria, decreased levels of inflammation, reduction of toxins produced by the microbes, and improvement of the health of the gastrointestinal tract.

Although the possible beneficial effects of supplementation with probiotics sounds promising, the current evidence does not support their use. In a recent meta-analysis by McFarlane and collaborators, they found no benefit of the use of probiotics on the levels of serum urea, indoles, and phenols. In fact, when you go to the individual studies, some of them found increases in these toxins and markers of inflammation, while they report no changes in the composition of the gut microbiota.

The use of prebiotics may have a beneficial effect in CKD

Prebiotics are substrates (including dietary fibers that are fermented by the microbes) that are used by the gut microbes producing short-chain fatty acids to provide a benefit to the host. While probiotics have not been associated with beneficial effects, the use of prebiotics may provide a better solution in patients with CKD.

The use of prebiotic substances in CKD has been limited to the use of prebiotic fibers, such as resistant starch, oligofructose-enriched inulin, and arabinoxylans, among others. In the meta-analysis by McFarlane and collaborators, they found that the use of prebiotics reduced levels of serum urea. However, there was no effect on other metabolites produced by gut microbes or the composition of the gut microbiota.

Not pro- or prebiotics, but what about synbiotics?

Synbiotics are the combination of pro- and prebiotics. While the use of pro- or prebiotics on their own have not yielded the expected results, the use of synbiotics seems promising.

Rossi and collaborators examined the effect of a synbiotic in patients with CKD not yet on dialysis. The synbiotic contained 15g of a combination of prebiotic fibers and a probiotic with nine strains from the Lactobacillus, Bifidobacteria, and Streptococcus genera. They found decreases in serum indoxyl sulfate (derived from the fermentation of the amino acid tryptophan) and changes in the composition of the gut microbiota.

Viramontes-Hörner and collaborators found that the use of a probiotic gel with 2.3g of prebiotic fiber, a probiotic with Lactobacillus and Bifidobacterium, omega-3 fatty acids and vitamins decreased the severity of gastrointestinal symptoms, a highly prevalent problem in patients with CKD.

So, should we recommend the use of pro-, pre-, and synbiotics in patients with CKD?

Although the fundamental idea makes sense, the use of these interventions targeting the gut microbiota has not produced the expected results. However, CKD is a complex disease and individuals with reduced kidney function are often recommended a restrictive diet low in dietary fiber and a variety of medications with unknown effects on the gut microbiome. This may be the reason why some of these interventions may not be enough to cause a change in the gut microbiome. Hopefully, future interventions will apply a more holistic approach to assess and target the gut microbiome in patients with CKD.

Breastfeeding as an issue of significance in the world of public health and nutrition has gained considerable traction in recent months. With globally publicized opposition by the US to the World Health Assembly Resolution on Infant and Young Child Feeding (triggered by severe restrictions on milk products for older infants and young children) and reports of coercion to further corporate interests, the issue is of great pertinence in today’s times. It being World Breastfeeding Week, this blog will delve into the science of breastfeeding, a nutrition-focused behavior that has amassed a tremendous body of evidence in its favor when concerning infant and young child health [1].

The Lancet series published in 2016 describes both the micro and macro level benefits of breastfeeding for infants in countries of all economic strata. One paper [2] from the series estimates that approximately 823,000 annual deaths among children <5 years of age and 20,000 annual deaths of women from breast cancer can be avoided through the promotion of improved breastfeeding practices. Additionally, breastfeeding has long lasting impacts on morbidity and improves the cognitive capacity and educational potential of children, with economic benefits including higher wages in adulthood [2]. Greater benefits are achieved with longer durations of breastfeeding, and this behavior has impact on morbidity with evidence showing protective benefits against diarrhea, respiratory infections, and asthma [3].

Additionally, a growing body of evidence shows overwhelming support for breastfeeding as protective behavior against long-term health outcomes related to non-communicable diseases including obesity [3]. An analysis of 113 studies shows that longer durations of breastfeeding are associated with a 26% reduction (95% CI: 22-30) in the odds of obesity across income groups. Another pooled analysis of 11 studies showed a 35% reduction (95% CI: 14-51) in the incidence of type 2 diabetes [3]. Prior work has shown that breastfeeding confers protection against obesity later in life, with lower prevalence rates after adjusting for confounders such as socioeconomic status, birthweight and sex [4].

Recent papers published in the American Journal of Clinical Nutrition highlight the nuanced impact of breastfeeding on child growth trajectories. A study by Kramer et al. (2018) showed, using various different statistical analyses, a causal effect of randomization to a breastfeeding promotion intervention on growth during the first 2-3 months of life [5]. Additionally, these authors noted that children in a breastfeeding intervention group and those who were breastfed for ≥12 months experienced faster growth when compared to those in the control group or those breastfed for <12 months, particularly during the first 2-3 months. The differences in growth velocity between groups was lower in subsequent months and almost equalized by 12 months of age.

A study by Eny et al. conducted in Canada found that maternal BMI was positively correlated to infant BMI [6]. These authors note that maternal BMI has been shown to modify BMI growth rates among children beginning at birth up to 12 years of age [7]. These authors note that the trajectories for growth differed by breastfeeding duration, maternal BMI and birth weight from 1-3 months of age.

Results from these studies and others highlight the need for more prospective research to assess how, when and whether breastfeeding practices influence infant weight gain, and what factors within breastmilk impact lean and fat mass growth [8]. Overall, the case for early initiation, exclusivity of breastfeeding for the first 6 months and continued breastfeeding up to 2 years remain strong and programs, policies and incentives to encourage and promote adequate breastfeeding behaviors remain the need of the hour. So this World Breastfeeding Week, may mothers’ across the world be motivated, encouraged and supported to continue gifting their young one of the most valuable gifts nature has accorded us!

References:
[1] Jacobs, A. (2018). Opposition to breast-feeding resolution by the US stuns world health officials. Retrieved from: https://www.nytimes.com/2018/07/08/health/world-health-breastfeeding-ecuador-trump.html
[2] Rollins, N.C., Bhandari, N., Hajeebhoy, N., Horton, S., Lutter, C.K., Martines, J.C., Piwoz, E.G., Richter, L.M., Victora, C.G. (2016). Why invest, and what it will take to improve breastfeeding practices? Lancet, 387, 491-504.
[3] Victora, C.G., Bahl, R., Barros, A.J., Franca, G.V.A., Horton, S., Krasevec, J., Murch, S., Sankar, M.J., Walker, N., Rollins, N.C. (2016). Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet, 287, 475-490.
[4] Armstrong, J., Reilly, J.J., & Child Health Information Team. (2002). Breastfeeding and lowering the risk of childhood obesity. Lancet, 359 (9322), 2003-2004.
[5] Kramer, M.S., Davies, N., Oken, E., Martin, R.M., Dahhou, M., Zhang, X., & Yang, S. (2018). Infant feeding and growth: putting the horse before the cart. American Journal of Clinical Nutrition, 107, 635-639.
[6] Eny, K.M., Anderson, L.N., Chen, Y., Lebovic, G., Pullenayegum, E., Parkin, P.C., Maguire, J.L., Birken, C.S. (2018). Breastfeeding duration, maternal body mass index, and birth weight are associated with differences in body mass index growth trajectories in early childhood. American Journal of Clinical Nutrition, 107, 584-592.
[7] Bornhorst, C., Siani, A., Russo, P., Kourides, Y., Sion, I., Molnar, D., Moreno, L.A., Rodrigues, G., Ben-Shlomo, Y., Howe, L., et al. (2016). Early life factors and inter-country heterogeneity in BMI growth trajectories of European children: the IDEFICS study. PLoS One, 2016:11:e0149268.
[8] Hay, W.W. Jr. (2018). Breastfeeding newborns and infants: some new food for thought about an old practice. American Journal of Clinical Nutrition, 107, 499-500.

The popularity of the essential polyunsaturated omega-3 fatty acids (O3FA) is on the rise. In 2017, O3FA achieved a spot on the top 20 foods and ingredients list that Americans are adding to their diets (The Hartman Group). In addition, the global fish oil market is expected to reach a whopping 4.08 billion dollars in the next four years!  The proposed health benefits are likely the driving force behind the increasing demand.

Despite their booming popularity, a large percentage of adults are not meeting the O3FA recommended intake. There are three primary O3FAs with distinct characteristics: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Although commonly grouped under the umbrella term O3FAs, are all O3FAs created equal?

Unique Characteristics of O3FAs

Omega-3 fatty acids cannot be sufficiently produced in the body earning them the title of “essential fatty acids.” The plant-derived omega-3, ALA, is the parent precursor to EPA and DHA. Unfortunately, the conversion rate in our bodies is very low.  It is important to realize that in the process of metabolizing ALA to EPA and DHA, a series of anti-inflammatory markers are produced (leukotrienes, prostaglandins and thromboxane). As these anti-inflammatory metabolites are beneficial, direct EPA and DHA consumption is needed to meet bodily requirements.

Independent and Complementary Health Benefits

The majority of current research focuses on the health benefits of marine fatty acids.  DHA and EPA consumption portray an array of shared and complementary benefits related to the treatment of cardiovascular disease, depression diabetes, sleep disorders and more. DHA is more significantly associated with decreases in resting heart rate, blood pressure and with improvements in cellular membrane health due to its additional double bond and longer carbon chain. Increased cellular levels of EPA have been shown to benefit coronary heart disease, hypertension and to decrease inflammation. EPA and DHA are both associated with reduced gene expression related to fatty acid metabolism, reduced inflammation and oxidative stress.

Specific supplementation of ALA is not consistently associated with cardiovascular health. Although plant-derived ALA can be easily substituted in for excess omega-6 fatty acids (O6FAs). Research has shown that by reducing the O3FA:O6FA ratio, you can decrease bodily inflammation, increase anti-inflammatory markers and more efficiently utilize EPA and DHA.

An ALA, EPA and DHA-Rich Diet

The 2015-2020 Dietary Guidelines for Americans recommends that healthy adults consume at least 8 ounces of a variety of non-fried fatty seafood per week. For EPA and DHA requirements, the American Heart Association recommends fatty marine sources containing 500 mg or more of EPA and DHA per 3oz cooked serving (e.g., salmon and tuna).   ALA is the most commonly consumed O3FA in the Western diet as it is found in plant-based foods (e.g., dark green leafy vegetables, walnuts, canola oil, flax seed). Unlike EPA and DHA, an Adequate Intake (AI) level is established at 1.6 g/day and 1.1 g/day for men and women respectively.

The Final Verdict 

The wide range of benefits stemming from marine O3FAs indicates the importance of regular consumption of fatty seafood and EPA and DHA-containing products.  The incorporation of plant-derived ALA may serve more importantly as a substitute for omega-6 fatty acids to reduce bodily inflammation, decrease the high O3FA:O6FA ratio typically observed in the Western diet, and to help elevate EPA and DHA levels in the body. EPA and DHA may be featured as the health promoting “dynamic duo,” but ALA is still invited to the party!

 

References

1.         Yanni Papanikolaou JB, Carroll Reider and Victor L Fulgoni. U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003–2008. Nutrition Journal 2014.

2.         Harris WS, Mozaffarian D, Lefevre M, Toner CD, Colombo J, Cunnane SC, Holden JM, Klurfeld DM, Morris MC, Whelan J. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J Nutr 2009;139(4):804S-19S. doi: 10.3945/jn.108.101329.

3.         Frits A. J. Muskiet MRF, Anne Schaafsma, E. Rudy Boersma and Michael A. Crawford. Is Docosahexaenoic Acid (DHA) Essential? Lessons from DHA Status Regulation, Our Ancient Diet, Epidemiology and Randomized Controlled Trials. Journal of nutrition 2004;134.

4.         Mozaffarian D, Wu JH. (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012;142(3):614S-25S. doi: 10.3945/jn.111.149633.

5.         Bork CS, Veno SK, Lundbye-Christensen S, Jakobsen MU, Tjonneland A, Schmidt EB, Overvad K. Dietary Intake of Alpha-Linolenic Acid Is Not Appreciably Associated with the Risk of Ischemic Stroke among Middle-Aged Danish Men and Women. J Nutr 2018. doi: 10.1093/jn/nxy056.

6.         Evangeline Mantzioris MJJ, Robert A Gibson and Leslie G Cleland Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites. Am J Clin Nutr 1995;61:320-4.

7.         Agriculture. USDoHaHSaUSDo. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015.

Suppose you’ve been told to eat an anti-inflammatory diet, or maybe you’re a practitioner whose clients want to know whether this is right for them. Before hopping on this buzzy bandwagon, ask yourself ‘For what purpose?’

Without missing a beat, you say ‘Well, to reduce my inflammation!’

While technically a noble intention, let’s first acknowledge that this term is used loosely in everyday conversation, but it’s more misunderstood than one might initially believe. Let’s talk about this elephant in the room, dive in, and answer a few key questions: What’s inflammation in the first place? What factors (dietary and otherwise) contribute to, or mitigate it? And finally, how might we modify our diets and our behavior to reduce it?

 

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What is inflammation?

In broad terms, inflammation is the body’s immune system’s response to a stimulus.1This can be in response to common injuries such as burning your finger, or falling off of a bicycle, after which you feel the affected area become red, warm, and puffy- this is a localized response to injury, characterized by ‘increased blood flow, capillary dilation, leucocyte infiltration, and production of chemical mediators.’2In short, an inflammatory response means the innate (non-specific) immune system is ‘fighting against something that may turn out to be harmful.’

It turns out that while inflammation is often cast in a negative light, it’s actually essential in small amounts for immune-surveillance and host defense.2 In true ‘Goldilocks’ form, too little and too much inflammation both pose problems; in fact, most chronic diseases are thought to be rooted in low-grade inflammation that persists over time. This inflammation may go unnoticed by the host (you!) until overt pathologies arise, which include, but are not limited to, diabetes, cardiovascular disease, nonalcoholic fatty liver disease, obesity, autoimmune disorders, inflammatory bowel disease, and even clinical depression. This concept is called ‘The inflammation theory of disease,’ in which inflammation is the common underlying factor among the leading causes of death.3

How do we measure inflammation?

Although measuring low-grade chronic inflammation (read: A chronic, low-grade immune response) carries a number of limitations, studies frequently measure cellular biomarkers such as activated monocytes, cytokines, chemokines, various adhesion molecules, adiponectin, non-specific markers such as C-reactive protein, fibrinogen, and serum amyloid alpha. Key inflammatory pathways include sympathetic activity, oxidative stress, nuclear factor kappaB (NF-kB) activation, and proinflammatory cytokine production.4 Now you might wonder, ‘What does this mean for me? What modifiable factors can activate my key inflammatory pathways?’ If we are to address this question appropriately, let us turn our attention to both dietary and behavioral moderators.

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What makes up an anti-inflammatory diet?

Prolonged low-grade inflammation is associated with excessive oxidative stress and altered glucose and lipid metabolism in our fat (adipose) cells, muscle, and liver.4 Therefore, research suggests that certain dietary components can modulate these key inflammatory pathways and clinical pathologies. Dr. Barry Sears explains in a review paper that “anti-inflammatory nutrition is the understanding of how individual nutrients affect the same molecular targets affected by pharmacological drugs.” 5

Compelling research from large-scale, longitudinal observational studies including the Women’s Health Initiative Observational Study6 and Multi-Ethnic Study of Atherosclerosis (MESA) study7suggest that a diet with appropriate calories that is low in refined carbohydrates, high in soluble fiber, high in mono-unsaturated fatty acids, a higher omega-3 to omega-6 ratio, and high in polyphenols, all have anti-inflammatory effects on the body. A Mediterranean diet pattern that incorporates olive oil, fish, modest lean meat consumption, and abundant fruits and vegetables, legumes, and whole grains, shows more anti-inflammatory effects when compared to a typical American dietary pattern. Other observational and interventional studies have also suggested that dietary patterns incorporating green and black tea, walnuts, ground flaxseed, and garlic are also associated with reduced inflammation.

drmarkhyman.com

 

Can my stress levels influence inflammation, too?

To conclude our discussion with anti-inflammatory dietary strategies would be a half-told story. In fact, “Communication between the systemic immune system and the central nervous system (CNS) is a critical but often overlooked component of the inflammatory response to tissue injury, disease or infection.”3

Behavioral studies have shown that prolonged psychological stress can activate the same pro-inflammatory pathways we’ve been discussing all along. While chronic psychological stress can promote over-expression of pro-inflammatory mediators, it can also promote overeating unhealthful foods in the absence of hunger. 8 Repetitively stress-eating calorie-dense, nutrient-poor foods not only further exacerbates psychological distress and creates a vicious cycle of stress-eating, but over time promotes adiposity, which we’ve described is itself a pro-inflammatory state.

painisnotprison.com

Integrative strategies and considerations

This ‘cross-talk’ between the brain and body suggests that strictly dietary or strictly behavioral interventions are not enough to reduce inflammation on their own. Instead, we must consider integrative diet and lifestyle preventions/interventions simultaneously. Going forward, we’ll need better biomarkers and more research looking at individual responses to diet (personalized nutrition!), and better understanding of how food components and behavioral factors modulate genetic targets involved in the inflammatory response.

 

References:

  1. What is an inflammation? National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072482/. Published January 7, 2015. Accessed March 16, 2018.
  2. Hunter P. Stress, Food, and Inflammation: Psychoneuroimmunology and Nutrition at the Cutting Edge. EMBO Reports. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492709/. Published November 2012. Accessed March 16, 2018.
  3. Hunter, Philip. The Inflammatory Theory of Disease. EMBO Reports, Nature Publishing Group, Nov. 2012, ncbi.nlm.nih.gov/pmc/articles/PMC3492709/.
  4. Galland, Leo. “Diet and Inflammation.” Sage, 7 Dec. 2010, journals.sagepub.com/doi/abs/10.1177/0884533610385703?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed.
  5. Sears, Barry, and Camillo Ricordi. “Anti-Inflammatory Nutrition as a Pharmacological Approach to Treat Obesity.” Journal of Obesity, Hindawi Publishing Corporation, 2011, ncbi.nlm.nih.gov/pmc/articles/PMC2952901/.
  6. Thomson, C A, et al. “Association between Dietary Energy Density and Obesity-Associated Cancer: Results from the Women’s Health Initiative.” Journal of the Academy of Nutrition and Dietetics., U.S. National Library of Medicine, ncbi.nlm.nih.gov/pubmed/28826845.
  7. “Associations of Dietary Long-Chain n-3 Polyunsaturated Fatty Acids and Fish With Biomarkers of Inflammation and Endothelial Activation (from the Multi-Ethnic Study of Atherosclerosis [MESA]).” The American Journal of Cardiology, Excerpta Medica, 4 Mar. 2009, www.sciencedirect.com/science/article/pii/S0002914909001088?via=ihub.
  8. Tryon, M., Carter, C., DeCant, R. and Laugero, K. (2013). Chronic stress exposure may affect the brain's response to high calorie food cues and predispose to obesogenic eating habits. Physiology &amp; Behavior, 120, pp.233-242.

Many dangerous fad diets exist that purport to treat diseases such as cancer by manipulating the pH of blood with different foods. While there is no good evidence that acidic foods alter the body’s pH and promote disease, the hypothesis that “dietary acid load” relates to disease should not be completely dismissed. The kidney serves to regulate blood pH, but if kidney function declines and other tissues catabolize to maintain pH, then it is very plausible that manipulating the diet to reduce the acid load could spare tissues and improve outcomes in chronic kidney disease (CKD). After all, for example, the metabolism of amino acids yields hydrogen ions, whereas fruits and vegetables contain organic salts that generally reduce acid load when metabolized. Recently, a growing number of human studies that manipulate diet acid load using fruits and vegetables and sodium bicarbonate support this hypothesis. Let’s take a look at some of them.

The first randomized controlled trial on bicarbonate supplementation and CKD progression was published in 2009 by de Brito-Ashurst and colleagues. Bicarbonate is produced by the kidneys and serves to neutralize acid. Supplementation of bicarbonate for 1 year in CKD patients slowed the progression of kidney disease as suggested by creatinine clearance and reduced the need for dialysis. The next year, in 2010, a 5-year trial was published by Donald Wesson’s group that found a slowed kidney decline as measured by estimated glomerular filtration rate (eGFR) with bicarbonate supplementation. Several subsequent studies by his group have used bicarbonate or fruits and vegetables to achieve beneficial outcomes. Goraya et al. gave oral bicarbonate or enough fruits and vegetables that were estimated to reduce dietary acid load by 50% to CKD patients for 30 days and also observed a slowed reduction in eGFR in patients at moderate, but not mild, stages of the disease. In patients with more advanced stages of CKD, one year of bicarbonate or fruits and vegetables did not slow the decrease in eGFR, though several urinary markers of kidney injury were reduced. Their most recent trial tested if kidney function might be preserved through a reduction in angiotensin II in moderate stage CKD patients. Three years of bicarbonate or increased fruits and vegetables lessened the decline in eGFR and resulted in a corresponding decrease in the marker angiotensin II. Other studies using bicarbonate from six months to two years have provided strong evidence that reducing acid load consistently slows the decline of eGFR, and improves markers of bone health and muscle function.

Each of the studies described provided fruits and vegetables to patients free of charge to increase adherence. It will be important to test if adherence can be maintained through education alone. Additionally, it may be that “prescribing” fruits and vegetables is effective at improving outcomes and reducing health care costs more so than bicarbonate since they also reduce blood pressure. While “alkaline diets” in general should be viewed skeptically, there is accumulating evidence that fruits and vegetables as dietary alkali do indeed help in kidney disease.

By Allison Dostal, PhD

Gastrointestinal problems are one of the most common unpleasant issues that we all experience at some time or another. But what if your upset stomach wasn’t just a passing discomfort? What if severe abdominal pain, cramping, fatigue, and diarrhea became more of your norm and less of a passing annoyance? For more than 1.4 million Americans, these symptoms typify their experience with inflammatory bowel disease (IBD), a disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. The specific cause (or causes) of IBD remain unknown, but one leading hypothesis is that the bacteria that inhabit our GI system – termed the gut microbiome – play a central role. In this post, we’ll take a closer look at this condition and highlight research aimed at elucidating the impact of the microbiome in IBD development, progression, and treatment.

Characteristics, Diagnosis, and Treatment of IBD

Inflammatory bowel disease is unique in that its symptoms vary from person to person, and an individual’s own experience with their condition can differ markedly from another affected person. Most people are diagnosed with one of the two most common types of IBD, which are ulcerative colitis (UC) and Crohn’s disease (CD). The primary distinguishing factor between the subtypes is that in UC, symptoms are limited to the colon. In contrast, any part of the GI tract – from the mouth to the anus – can be affected in CD. In addition, UC only involves the innermost layer of the colon, while CD can extend deeper into the cell layers of the GI tract. Lastly, in CD, the inflammation can “skip”, leaving normal areas between patches of affected GI tract.

Making a clear IBD diagnosis isn’t always as easy as meeting – or not meeting – these criteria. There is no gold standard available for a clear-cut diagnosis, and 5-15% of cases do not meet strict criteria for either UC or CD. These patients fall into the “IBD type unclassified” (IBDU) group. And in up to 14% of patients, the diagnosis changes over time. Despite the difficulty in specific diagnosis, all subtypes of IBD have one strong feature in common: an abnormal response by the body’s immune system. The immune system is composed of various cells and proteins that usually protect our bodies from infection. However, in people suffering from IBD, the immune system reacts inappropriately, and mistakes benign or beneficial cells and bacteria for harmful foreign substances. When this happens, the immune system produces an inflammatory response within the GI tract and produces the symptoms of IBD. This adverse reaction is termed a “flare”, and can result in symptoms such as abdominal pain and cramping, diarrhea, fever, and blood in the stool. People with IBD often have deficiencies in vitamins, minerals and macronutrients stemming from loss of appetite, reduced food intake, and malabsorption from the GI tract. The lack of nutrients can lead to worsening of symptoms or development of new complications.

Treatment for IBD is centered around two goals: achievement of remission and prevention of flares. Anti-inflammatory drugs such as aminosalicylates and antibiotics are often the first line of treatment, and can be followed by corticosteroids, immunomodulators, and/or biologic agents. In severe cases, removal of the affected part of the GI tract is needed if a patient is not responsive to other treatments.

The Role of the Microbiome in IBD

In recent years, it has become clear that the microbes in our gut have a key role in IBD, but the bacteria involved and their associated functions remain largely unknown. An imbalance of the normal gut bactera due to loss or overabundance of certain species is important in the persistence of the inflammatory responses seen in IBD. The role of the gut microbiota in IBD pathogenesis has been demonstrated by studies showing that antibiotic use can reduce or prevent inflammation – antibiotics work by reducing the number and types of bacteria found in the gut, therefore killing microbes that are causing IBD symptoms. Also, results from studies with UC patients who underwent a transfer of stool collected from healthy donors – called a fecal microbiota transplant – had notable disease remission. However, results have not been consistent between studies, due to differences in populations studied, official diagnosis, treatment methods and doses, and methods of assessing study endpoints. Therefore, no consensus on the microbiome’s relationship to IBD has been reached.

Research Endeavors

As you can imagine, the combination of unpleasant, potentially severe symptoms and an uncertain diagnosis or treatment can result in significant stress on IBD sufferers, their caregivers, and health care providers. The scientific efforts dedicated to identifying causes and cures for IBD have rapidly expanded in recent years due to advances in technology that allow researchers to work toward refining a clear diagnosis, map specific gut bacteria associated with disease development and symptoms, and identify defined targets for therapy. One of these initiatives is the Crohn’s and Colitis Foundation of America (CCFA) Microbiome Initiative, which is dedicated to understanding the role of the gut microbes in IBD, IBD families, and disease flares. Thus far, there are 7 active projects and 30 published manuscripts stemming from the Initiative, which have determined that different subsets of IBD are characterized by signature bacterial compositions and that people carrying different IBD genes have different microbiome compositions, among other accomplishments.

Other organizations are also supporting IBD research endeavors, including the Kenneth Rainin Foundation, whose Innovator Awards program provides $100,000 grants for one-year research projects conducted at non-profit research institutions, and the NIH’s Human Microbiome Project, which has funded several projects aimed at genetic and metabolomic elucidation of risk for Crohn’s disease. Several randomized trials are ongoing at this time, and their results will inform future directions for diagnosis, treatment, and eventual resolution of IBD.

References

Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol.2004;38(6):475–483.

Bull MJ, Plummer NT. Part 1: The Human Gut Microbiome in Health and Disease. Integr Med. 2014 Dec; 13(6):17-22.

Crohn’s and Colitis Foundation of America:http://www.ccfa.org/

Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease.J Clin Microbiol. 2005;43(7):3380–3389.

Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: state of the art and future perspectives. World J Gastroenterol. 2015 Jan 7;21(1):21-46.

By: Emma Partridge, MS Candidate

Green tea contains a high concentration of polyphenols, most of which are flavanols. Flavanols are commonly known as catechins, the most active catechin being epigallocatechin-3-gallate (EGCG).1 Within the world of nutrition, green tea is consistently touted as a beverage with a plethora of health benefits. These benefits are far-reaching and specific roles of green tea have been identified to improve symptoms or reverse disease damage amongst people with autoimmune disease, heart disease, cancer, liver disorders, smoking complications, chronic inflammation, and more. The roles of green tea often overlap and while green tea consumption is important for those with various diseases, the consumption of green tea by healthy individuals may be integral in the prevention of many of the following diseases.

Chronic Inflammatory Disease
EGCG may be most important flavanol when it comes to inflammation control.2 EGCG has been shown to suppress the production of cytokines, pro-inflammatory mediators. Suppressing cytokines decreases long-term inflammation and has been shown to improve inflammation-related symptoms in arthritis models.3,4

Autoimmune Disease
In addition to helping to control the chronic inflammation associated with most autoimmune diseases, EGCG has been shown to suppress auto-reactive T cell proliferation. Auto-reactive T cells act against the body, resulting in various forms of autoimmune diseases. EGCG may also help to regulate T-helper cell balance, which may decrease the pathogenesis of arthritic diseases, especially rheumatoid arthritis.3

Type 2 Diabetes Risk
Type 2 Diabetes is sweeping America, and food production practices, availability, and affordability are making it harder for people to access healthy options. The ease of accessing and affording unhealthy foods is increasing the risk of diabetes among populations. Green tea, as well as coffee, has been associated with lowering the risk of type 2 diabetes, though the mechanism is unknown and the data inconsistent. However, in a study of 40,000+ people followed for 10 years, researchers found that daily consumption of at least three cups of coffee or tea may lower type 2 diabetes risk.5

Heart Disease & Stroke Risk
In an article published by the American Heart Association, researchers found that people who drank two to three cups of green tea per day had a 14% lower risk of stoke.6 The research on green tea and stroke risk comes on the wake of multiple studies finding links between green tea and heart health. Multiple studies found green tea consumption to lower risk of death from heart attacks by 26% and lower risk of coronary artery disease by 28%.7

Cancer & Tumor Growth
Cancer is a leading cause of death in the United States, behind heart disease. Green tea has already been shown to be beneficial in preventing the leading cause of death; now studies have now shown that the EGCG may affect transformed cells by inhibiting the growth of certain cell lines, inducing apoptosis, and altering gene expression to prevent transformed cells from becoming cancerous.8

Smoking
The polyphenols in green tea have shown to work against carcinogens, while the antioxidant effects may reverse endothelial dysfunction in healthy smokers.8 The reversal of endothelial dysfunction in smokers is important because it plays a role in the pathogenesis of atherosclerosis and cardiovascular disease.9

Liver Disease
Green tea’s aforementioned anti-carcinogenic affect may play a role in preventing liver disease. Active polyphenols detoxify reactive oxygen species, preventing oxygen free radicals from destroying hepatocytes and causing oxidative DNA damage. Multiple studies have shown that, most likely via this method, green tea intake can attenuate liver disease or liver cancer.10

Weight Loss & Weight Maintenance
Green tea’s affect on weight loss may be attributed to two components: EGCG and caffeine. Caffeine alone does play some role in increasing energy expenditure, but when combined with EGCG, the mixture stimulates energy expenditure and fat oxidation to a greater degree. This may trigger weight loss, and additional evidence reveals that continual green tea consumption can further help to maintain weight.11

In determining whether or not green tea is for you, the answer is likely yes. While there are risks by way of overconsumption, a few glasses a day has been shown to be beneficial for the all-around healthy person in preventing disease and for the person suffering from various diseases or ailments.

1.Ehrlich SD. Green Tea. 2011; http://umm.edu/health/medical/altmed/herb/green-tea.
2.Hamer M. The beneficial effects of tea on immune function and inflammation: a review of evidence from in vitro, animal, and human research. Nutrition Research. 2007;27(7):373-379.
3.Wu DY, Wang JP, Pae M, Meydani SN. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Molecular Aspects of Medicine. 2012;33(1):107-118.
4.Kim HR, Rajaiah R, Wu QL, et al. Green Tea Protects Rats against Autoimmune Arthritis by Modulating Disease-Related Immune Events. Journal of Nutrition. 2008;138(11):2111-2116.
5.van Dieren S, Uiterwaal C, van der Schouw YT, et al. Coffee and tea consumption and risk of type 2 diabetes. Diabetologia. 2009;52(12):2561-2569.
6.Green tea, coffee may help lower stroke risk. 2013; http://newsroom.heart.org/news/green-tea-coffee-may-help-lower-stroke-risk.
7.Green tea may lower heart disease risk. Harvard Heart Letter 2012; http://www.health.harvard.edu/heart-health/green-tea-may-lower-heart-disease-risk.
8.Chen ZP, Schell JB, Ho CT, Chen KY. Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts. Cancer Letters. 1998;129(2):173-179.
9.Nagaya N, Yamamoto H, Uematsu M, et al. Green tea reverses endothelial dysfunction in healthy smokers. Heart. 2004;90(12):1485-1486.
10.Jin X, Zheng R-h, Li Y-m. Green tea consumption and liver disease: a systematic review. Liver International. 2008;28(7):990-996.
11.Hursel R, Viechtbauer W, Westerterp-Plantenga MS. The effects of green tea on weight loss and weight maintenance: a meta-analysis. International Journal of Obesity. 2009;33(9):956-961.

By Ann Liu, PhD

Historically, immunology and metabolism have been distinct disciplines. However in recent decades we have learned that metabolic diseases such as obesity and type 2 diabetes result in major changes in inflammation and the immune response. Conversely, it has also become clear that certain behaviors and properties of lymphocytes are regulated by internal metabolic processes. Thus the new field of immunometabolism has emerged to examine the crosstalk between immune and metabolic processes. Speakers at the symposium “Diet and Immunometabolism,” co-sponsored by the Nutritional Immunology and Obesity RIS, highlighted the role of nutrients and metabolites in inflammatory processes on March 31.

While we may traditionally think of iron’s role in anemia and fetal development, it is also required for proper immune function and adipogenesis. Elevated serum ferritin levels are associated with type 2 diabetes, gestational diabetes, and metabolic syndrome. Excess iron also induces lipolysis and insulin resistance. Dr. Alyssa Hasty from Vanderbilt University School of Medicine presented data from mouse models indicating that iron homeostasis is disrupted during obesity. Iron is traditionally stored in the liver, however during obesity it appears that iron levels decrease in the liver and increase in adipocytes.

These changes may be related to changes in macrophage populations, which are important mediators of adipose tissue inflammation. Hasty identified two distinct macrophage populations based on their iron content. Some macrophages have high iron content which allows them to be isolated using a magnet while others have low iron content. Lean animals have both types of macrophages. However obese animals have increased levels of macrophages with low iron content.

This indicates that iron levels are changing in both adipocyte and macrophage populations during obesity and suggests that the ability of macrophages to sequester iron may be impaired. Further study is needed to identify the mechanisms of crosstalk between macrophages and adipocytes and examine potential functional consequences.

By Sheela Sinharoy

Tuesday’s minisymposium ‘Nutrition and Inflammation’ covered a wide range of topics and research designs from clinical, lab, and public health perspectives.

Starting with clinical research, Wendy Ward of Brock University (Canada) presented on associations of dietary intake with periodontal healing. She explained that 42% of adults in the US are affected by periodontal disease, which is characterized by inflammation of tissues around the teeth that can eventually lead to loss of alveolar bone. One treatment is the mechanical removal of bacteria below the gum line through sanative therapy. Dr. Ward’s group found that higher dietary intakes of fruits and vegetables, β-carotene, vitamin E, and α-linolenic acid were associated with greater healing following sanative therapy.

Taking a more public health-oriented perspective, Mercedes Sotos Prieto of Harvard University spoke about the development of a healthy lifestyle score (HLS) and its association with inflammatory markers among Puerto Rican adults in Boston. The HLS included five components: diet, physical activity, smoking, social network and support, and sleep. Dr. Sotos Prieto found that a 20-unit increase in the HLS was associated with a decrease in the inflammatory biomarkers IL-6 and TNF-α when adjusted for a number of covariates. These in turn were associated with obesity and hypertension but not with diabetes or heart disease.

Presentations from Yaw Addo and Leila Larson of Emory University also had clear public health implications. They looked at biomarkers of iron and vitamin A status, respectively, and their relationship with biomarkers of inflammation. First, Dr. Addo explained that transferrin receptor was strongly associated with α-1 acid glycoprotein (AGP) in women of reproductive age across six countries, though the magnitude of the association varied by country. Next, Ms. Larson showed that retinol binding protein (RBP) was significantly associated with both C-reactive protein (CRP) and AGP among preschool children in Liberia. Both of these analyses suggested that it may be important to account for inflammation, particularly with RBP, where adjusting for inflammation through linear regression decreased the prevalence of vitamin A deficiency by almost 20 percentage points.

Moving to lab studies, Marie-Caroline Michalski of the University of Lyon (France) presented research on the effects of dietary lipids on plasma endotoxins and lipopolysaccharides (LPS), which contribute to low-grade inflammation. She showed that in a sample of normal weight and obese men, ingestion of a higher-fat test meal led to postprandial endotoxemia only in obese subjects. Qiaozhu Su of the University of Nebraska then presented data showing that the cAMP responsive element binding protein H (CREBH), which is activated by the inflammatory cytokine TNF-α, induces expression of apolipoprotein B. This in turn increases secretion of very low density lipoproteins (VLDL) and may play a role in hepatic steatosis, hyperlipidemia, and insulin resistance. Finally, Sadiq Umar of Washington State University showed that thymoquinone, a compound derived from Nigella sativa, or black cumin, inhibits TNFα-induced production of the inflammatory cytokines IL-6 and IL-8 as well as the pro-inflammatory mediator ASK1.

Given the associations between inflammation and many chronic diseases, we will likely hear a great deal more about these topics in years to come.

By Sheela Sinharoy

How does one estimate the prevalence of anemia in a population? Historically, this has been a fairly straightforward matter of testing hemoglobin levels and comparing them to set cutoff figures. However, as we learn more about the physiological effects of infection and inflammation, the validity of our estimates is called into question.

Monday’s symposium on the Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA) project highlighted some of these issues and potential approaches to address them. Parminder Suchdev of the Centers for Disease Control and Emory University began with an overview. He explained that the immune response triggers inflammation, which leads to temporarily decreased serum zinc and retinol and increased ferritin, transferrin receptor, and hepcidin. Although we know that these nutrients and biomarkers are affected by the inflammatory response, there is no widely accepted approach to effectively account for inflammation when analyzing and interpreting micronutrient data.

In order to address this gap, the BRINDA project team has been analyzing data from 15 countries representing all six WHO regions. Sorrel Namaste of Helen Keller International presented the key findings. Using C-reactive protein (CRP) and α-1 acid glycoprotein (AGP) as biomarkers of inflammation, they found that the prevalence of inflammation varied by country but was, on average, approximately 20% based on CRP and 40% based on AGP. Different methods of adjusting for CRP and AGP in the data analysis produced varying results, with a linear regression method being the most successful. These findings indicated that it is necessary to measure both CRP and AGP and to adjust for them in the analysis phase.

Next, Grant Aaron of Global Alliance for Improved Nutrition presented preliminary findings related to preschool aged children. In the sample, the burden of anemia was approximately 45%. Among children with anemia, 30% of the anemia was attributable to iron deficiency (unadjusted for inflammation). The age of the child, presence of inflammation, and anthropometric measures were associated with anemia in a majority of countries. Using an external correction factor, the proportion of anemia attributable to iron deficiency was adjusted to 35% for this age group.

Finally, Ken Brown of the Bill & Melinda Gates Foundation shared his interpretation of the findings. He emphasized the need for these biomarkers to establish the presence and magnitude of the problem, identify high risk sub-groups, and measure their response to interventions. This will require addressing practical challenges relating to specimen collection, analysis, and interpretation. He also pointed out that the need to collect biomarkers of any potential adverse effects of interventions. Ultimately, he encouraged the BRINDA team to make specific recommendations that other researchers can follow.

Overall, a major conclusion of the project thus far is that accounting for inflammation is necessary in order to improve the validity of anemia estimates. In acting on this conclusion, it will be important for researchers to ensure consistency in the parameters that are measured and to strengthen coordination between programs, evaluators and the academic community to build the evidence base.