Nutrition & Neurodegenerative Diseases

As you guys have figured out this far into the semester, nutrition plays a huge role in regulating inflammation. It's certainly no different when it comes to neurodegenerative diseases.

http://www.jneurosci.org/content/29/41/12795.full.pdf+html
This article from the Journal of Neuroscience outlined the benefits of different food categories on neurodegeneration. Phytochemicals, such as antioxidants, are substances in plants that go beyond providing calories and vitamins/minerals; they have protective effects against disease, even in the plants from which they come. The study first looks at the effects of berry polyphenols on aged mice and found that those treated with blueberry and strawberry extracts experienced improved working memory along with other benefits from each extract individually, such as improved balance, cognition and coordination. Blueberry extracts may be protective against stress signaling to inhibit production of nitric oxide and inflammatory markers. Polyunsaturated fatty acids from walnuts and fish are important for maintaining membranes on the neurons, synapses and signal pathways responsible for stability in the hippocampus, cerebellum and cortex. Curcuminoids (curcumin), the yellow substance in tumeric, may also be protective by inhibiting proinflammatory cytokines and stimulating clearance of amyloid plaques. There has also been significant research that calorie restriction has a protective effect against inflammation since the act of eating, itself, has an inflammatory effect on the body.

One looming problem in the field of nutrition is determining the correct dosage of phytochemicals that is bioavailable (able to be absorbed by the body) and protective. As our food has multiple compounds within it that interact with one another, it is difficult, if not impossible, to isolate any single compound as being preventive against disease. There have been many cases (such as with Vitamin E), where the food sources have been seen as protective but the supplement form can lead to increased cancer risk. In addition, cancer takes years to develop so by the time supplements are recommended, they may have proliferative effects rather than protective (Crider, 2011).

It is my personal opinion as a student of nutrition that we should get our vitamins/minerals/phytochemicals from whole foods and not from supplements. We are at the advantage that we have years to protect our bodies against cancer & other preventative diseases- why not start now? What are your opinions??

Caloric Restriction and Immunology

I know it's not particularly relevant to any disease being discussed in class right now, but I was doing some research on caloric restriction (CR) and found an interesting link between CR and immunology:

Caloric restriction (CR) is defined as a decrease in what an organism would consume ad libitum, but still above the level of malnutrition. It is arguably the most robust means of extending lifespan and has been shown to boost longevity in a wide array of organisms, ranging from yeast to rhesus monkeys. A few studies have analyzed the effects of CR on the immune system, which is known to decline with aging [1].

Given that Type 2 Diabetes is associated with inflammation that worsens with time, one such study analyzed the development of inflammation in liver, muscle, hypothalamus, and adipose tissue during aging and CR. Expression of inflammatory cytokines (TNFalpha, IL1-beta, IL-12B, and IL-6), macrophage and TLR4 markers (CD11c, CD11b, and arginase1), and proteins involved in the recruitment of macrophages (MCP-1, CCR2) were all analyzed as a function of age and CR. Interestingly, most of these markers were shown to decrease in response to CR [2]. The aging cardiovascular system is also greatly benefited by CR, with reported reductions in both inflammation and oxidative stress [3]. Some evidence also exists that CR may help to prevent/alleviate some chronic inflammatory disorders such as periodontal disease [4].

Whether or not CR mediates its effects on lifespan through significant regulation of the immune system has yet to be determined, but it's certainly an intriguing area of research.

1. Fontana L, Partridge L, Longo VD. Extending Healthy Life Span - From Yeast to Humans. Science 2010; 328(5976):321-326.

2. Horrillo D, Sierra J, Arribas C, Garcia-San Frutos M, Carrascosa JM, Lauzurica N, Fernandez-Agullo T, Ros M. Age-associated development of inflammation in Wistar rats: Effects of caloric restriction. Arch Physiol Biochem 2011; 117(3): 140-150.

3. Weiss EP, Fontana L. Caloric restriction: powerful protection for the aging heart and vasculature. Am J Physiol Heart Circ Physiol 2011; 301(4):H1205-19.

4. Gonzalez O, Tobia C, Ebersole J, Novak M. Caloric restriction and chronic inflammatory diseases. Oral Dis 2011; doi: 10.1111/j. 1601-0825.2011.01830

Inflammatory Bowel Disease: An Overview

Inflammatory bowel disease (IBD) consists of two primary inflammatory disorders – Crohn’s disease (CD) and ulcerative colitis (UC). Given that family history is a major risk factor for the development of IBD, genetics are thought to play an imperative role in establishment of disease phenotypes. On a basic level, IBD is caused by an inappropriate and long-term immune response to commensal microbes. The reality is much more multifaceted, however, with the pathobiology including interaction of genetic factors “with microbial and environmental cues within tissue-specific contexts, the biological checkpoints involved, the selective decisions made during the course of disease and how plasticity of the biological response results in the capacity for different phenotypes” [1].

Due to the complexity of IBD, both CD and UC are currently labeled as idiopathic. Evidence exists that, in addition to genetic susceptibility, environmental factors such as sanitation, hygiene, smoking, and geography can yield mucosal inflammation. Infectious microbes and ethnic origin have also been reported to uniquely affect immune dysregulation and inflammation [2]. UC is distinguished by inflammation that is localized to the colon. Beginning the in the rectum, it spreads proximally. CD is distinct in that inflammation can occur in any part of the gastrointestinal tract, with the most common affected areas being the terminal ileum or the perianal region. Unlike ulcerative colitis, the spread is non-continuous and is frequently associated with “strictures, abscesses, and fistulas” [1].

Through the use of transcriptional profiling of circulating T cells derived from UC or CD patients, Lee et al. was able to identify CD8+ T cell transcriptional signatures that divvied patients into 2 distinct subgroups. UC and CD patients in these subgroups suffered from higher incidences of frequently relapsing disease and had elevated expression of genes involved in antigen-dependent T cell responses. Interestingly, no equivalent correlation was observed for CD4+ T cell gene expression [3].

Numerous other genes have been reported to play paramount roles in mediating these diseases. Given that abnormal intestinal permeability has been observed in IBD patients (as well as their immediate relatives), candidate genes involved in barrier integrity were investigated. Candidate genes that may regulate this process include CDHI, GNA12, and PTPN2. Truncated forms of E-cadherin (encoded by CDH1) have been associated with CD, with intestinal biopsies of CD patients showing inappropriate protein localizeationand cytosolic accumulation. Myriad transcription factors, such as HNF4A (regulates crypt cell proliferation), have been also been associated with IBD [1].

Autophagy, the catabolic process by which a cell degrades its own compartments, contributes both to the recycling and degradation of cytosolic contents and organelles. It also contributes to the removal of intracellular microbes and thus resistance against infection. ATG16LI, a gene essential for all forms of autophagy, appears to play a role in CD. Humans with the coding mutation T300A have an increased risk of Crohn’s disease and mouse models possessing defects in autophagy show abnormalities consistent with CD. Together these data all suggest an important role for autophagy in IBD [1].

In sum, perturbations of the host-commensal relationship caused by environmental and genetic factors lead to the pathogenesis of IBD. Consisting of CD and UC, IBD is marked by inappropriate immune responses to otherwise benign microbes and has been reported to involve alterations in intestinal permeability, autophagy, T cell gene regulation, and many other factors.

Citations:

1) Khor et al. Genetics and pathogenesis of inflammatory bowel disease. Nature 474: 307-217. 2011.

2) Baumgart et al. Inflammatory bowel disease: cause and immunobiology. Lancet 369: 1627-1640. 2007.

3) Lee et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest. 121 (10): 4170-4179. 2011