AHS13 Amber Dukes — Diet, Inflammation, and Depression

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Depression is an insidious issue in the US and elsewhere. Lifestyle habits that are very different from our ancestral environment may be to blame, and one particularly problematic area is food choice. Depressive symptoms share much in common with the adaptive features of sickness behavior, which is functional when operating in an environment of ancestrally normal immune stressor. Modern diets likely activate the immune system (primarily the inflammatory response) and induce the cascade of adaptive responses that collective make up sickness behavior. Due to their similarities, these may then diagnosed as depression. In this talk, I discuss the links among diet, depression, and inflammation, as well as highlighting some specific dietary components that contribute to this response.

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  • Here’s a roadmap of what I’ll cover in the next few minutes. This will necessarily be only an introduction due to the time allowed. I’ve got a paper in preparation with my collaborators that we hope to submit by the end of this year. (Refer to bullet points to explain the order of the argument).
  • Depression is a serious and growing problem in the US and other western nations,May be a problem of modernization
  • Since we’re talking about food, let’s talk about the gut. The gut has the complex task of differentiating among self-tissues, food, and pathogens that might get in on the food. Sometimes the gut makes mistakes, but we’ll go into that later.There are 3 recognized major categories of inhabitants in the gut. The first is commensals, commonly refered to as gut flora. We can get these in the form of probiotics. These number up to 100 trillion at any time. They aid in intestinal motility, immunity, nutrient absorption and metabolism. These also compete against pathogens for space in the gut. They can affect inflammation through synthesis and secretion of anti-inflammatory cytokine IL-10.Pseudocommensals are tolerated. More on these later.Pathogens lead to immune activation.Brain-gut-enteric….refer to slide. There is bi-directional feedback. Communication from the gut include pro-inflammatory cytokines and short chain fatty acids.There is a link between the gut and depression: persons with major depressive disorder have increased leakage of LPS into their system, causing immune activation.
  • We all know that a primary tenet of the paleo movement is that we have a mismatch between the modern diet and an ancestral diet. I’ll talk briefly about 3 components that are believed to be a mismatch. The first is lectins. These are carbohydrate binding plant defense proteins. We find these in grains and legumes. These cause such problems as IL-2 activation, leaky gut, overgrowth of E Coli in the gut, which is a bad combination. They also inhibit nutrient absoprtion in the gut. And, there can be cross reaction with self tissues. This is a defense that the plants have evolved in order to reduce the population of organisms that consume them. In the past, humans have found ways around this through traditional food preparation methods like soaking, sprouting and fermenting. This leads me to the next category: Processed foods. With today’s busy lifestyles, there is less time given for traditional preparation. Cheese is made in a factory without the benefit of fermentation. Wheat is sent straight to a factory for processing—at AHS last year, Joel Salatin mentioned the natural breakdown of some of the gluten that occurs just from storing grain for longer periods than it is stored now. Beans are served whole rather than as a slurry, which releases the lectins for breakdown by heat. High carb + high fat, so the typical fast food meal, leads to post-prandialdysmetabolism with endothelial dysfunction, oxidative stress, and inflammation. Trans fats are inflammatory. Dense acellular carbohydrates, which means, for instance, grinding foods into flour or squeezing fruits into juice. This breaks down the cell wall of plant cells that changes the way we metabolize foods. Drinking juice means getting sugar without the fiber—both commensals and pathogens can thrive on sugar, but only commensals will thrive on the fiber. We also have the problem with the lack of anti-inflammatories. An intervention of high fruit consumption can decrease inflammation in men typically eating a western diet. Some of that may be just from displacement of other foods, of course, but some of it is the anti-inflammatory actions of plant flavonoids. Eating vegetables at a meal can blunt the harmful effects of the high carb/high fat meal. And, as Gad mentioned, spices are Anti-microbial spices, but many modern americans use little beyond salt and pepper. We also have the problem of high omega-6 consumption with low omega-3 consumption, which is needed to resolve the inflammation caused by the seemingly ubiquitous omega 6’s. We see higher 6:3 ratios in depressed than non-depressed persons. We also consume fewer fermented foods, which, in addition to breaking down or reducing proteins and sugars, also introduce commensal bacteria in the gut to help immunoregulation, as Chris Kresser mentioned in his talk.
  • Responding to food is costly, so why would we expect an inflammatory response? This is apart from the prevalent theory in paleo that it is a mismatch. We do not respond to pseudocommensals usually, so why might we respond to some foods?Alcock et al 2012 paper outlined an adaptive response to foods. What they found was that pro-inflammatory fats are those that tend to increase the growth of pathogens in the gut. Thus, the body would be expected to increase the inflammatory response of the immune system to prepare for this overgrowth of pathogens. Anti-inflammatory fats do not cause this same response, and in fact, can fight against pathogens by breaking down their cell walls or preventing adhesion to the intestinal lining. The same is expected with sugars, such as glucose and fructose. SCFAs are indicative of the population in the gut. Also influence anti-inflammatory responsesFatsSome FFAs are protective, others notGram-negative bacteria/LPS (Alcock et al., 2012)Inflammatory fats support gram-negative bacteria (Desbois & Smith, 2010)SugarsGlucose and sucrose aid bacteria (Goepfert & Hicks, 1969)GI and inflammation (Du et al 2008)Fructose and fermentation (Gibson et al., 2007)
  • Here’s how it works. We eat something containing fat. The body takes the type of fat as a cue to what will happen next. If it is something pathogens can be easily fueled on, the body increases inflammation to fight that response. If it prevents pathogens from growing in numbers, the body can then decrease inflammation. So, which fats are we talking about? The inflammatory fats include transfats and long-chain saturated fatty acids. The anti-inflammatory fats include short and medium chain fatty acids and unsaturated fats which includes the PUFAs and MUFAs. These categories are not clean. Some saturated fats are protective. And some PUFAs, like omega 6, are inflammatory.Long-chain fatty acids (LCFAs) have greater than 16 carbon atoms; those with shorter chains (4 to 12 carbons) tend to have a stronger anti-pathogenic effect (Alcock et al., 2012). SCFAs can prevent pathogens from binding to the gut and decrease gut pH (Lin, Tsai, Lin, Tsen, Tsai, 2008). Although most saturated fats (SFAs) are inflammatory, some are anti-inflammatory; the most potently bactericidal SFAs are those with 10-12 carbons and their activity tends to decrease if shorter or longer (see Desbois & Smith, 2010).
  • Ok, so I’ve established now that the gut is extremely important in the link between diet and inflammation, and from inflammation we get depression. The issue is further complicated by the condition of the modern gut. We have a problem stemming from the lack of “Old Friends” in our modern gut. Our ancestors, and those still living rural lifestyles, have much more exposure to pseudocommensals and parasitic worms. These are important for “training” the immune system. We evolved in an environment where these things were everywhere. For the pseudocommensals, there is no point in fighting them—they either pass through or are not eliminated by the inflammatory response and are thus tolerated. We also have markedly different populations of commensals, some of which regulate the immune system through the release of IL-10. In addition, pathogens can sometimes hijack the immune system and convince it to leave them alone, sometimes through secretion of anti-inflammatory mediators. But, regardless of how they work, all of these gave the immune system something to keep it busy. Without these, the immune system is looking for something to work on. Instead, it can turn on itself in the form of auto-immune disorders, it can become allergic to usually relatively harmless food proteins or commensals and environmental irritants. I think it may also react even more adversly to irritants such as lectins due to the problems of gut barrier issues that come from not having normal flora. This leads to increased inflammation and depression. Proponents of the Old Friends Hypothesis have suggested a strong link between this lack of old friends and the increase in major depressive disorder. Supportive evidence comes from the Phillipines (more exposure to farm animals and less overall sanitation), where, although they have depression due to social circumstances, they do not see the link between inflammation and depression in the way that we do in the US. Sensitivity and allergensNormal flora needed for oral tolerance to foods (Sudo et al., 1997)Gut barrier issues (Sicherer & Sampson, 2006)Reactions below detectable serum levels (ibid)
  • And here is the ultimate explanation.There are marked similarities between sickness behavior and depression. So, with all of what is going on in the gut, it’s possible that at least some people are sick rather than depressed. Why the similarities?Sickness: conservation of energy for healing (Hart, 1988)Depression: withdrawal of energy for reconsideration, no further investment (e.g. Keller & Nesse, 2005)Sickness behavior was co-opted by depression to serve a similar energy conservation goal. I am not saying that all persons who are depressed are having dietary issues. Many people have depression that stems from their social situation. These people also experience increased depression. However, I think that some people are experiencing depression as the result of the combination of their overly sensitive guts and the modern dietary enironement. This includes the adaptive response to foods that is increasingly problematic because of the use of added sugars and trans fats.
  • AHS13 Amber Dukes — Diet, Inflammation, and Depression

    1. 1. Amber Dukes, MSc MPH Student, Psychology PhD candidate University of New Mexico adukes@unm.edu
    2. 2.  Intro  Depression  Inflammation  The gut  Foods  Mismatches in modern diet  Adaptive responses  The modern gut  Ultimate explanation  Conclusion
    3. 3.  2nd leading cause of disability by 2020 (Murray & Lopez, 1996)  Cost: US $83 billion per year (Greenberg et al., 2003)  Increased risk of suicide, substance abuse  50% of children/adolescents  20 % of adults  10 % on antidepressants (Leahy, 2010)
    4. 4.  Signals injury or infection  Recognition of pathogens (Lipopolysaccharide – LPS)  Release of cytokines (e.g. Dantzer, 2008)  Occurs with modern diseases (e.g. Raison et al., 2006)  Associated with depression (e.g. Raison et al.,,2006)  Increased immune disorders in depressed persons  Depression in cytokine therapy (Dunn et al., 2005)
    5. 5.  Residents  Gut flora/commensals (up to 100 trillion; Sekirov et al., 2011)  Pseudocommensals  Pathogens  Brain-gut-enteric microbiota axis (e.g. Raison et al., 2010)  Central nervous system, neuroendocrine & neuroimmune systems, sympathetic & parasympathetic autonomic nervous system, enteric nervous system, & intestinal microbiota  Gut & depression  Increased leakage of LPS (Maes et al., 2008)
    6. 6. Lectins • Grains, legumes • Leaky gut • Immune activation Processed Foods • High carb + high fat • Dense acellular carbs (Spreadbury, 2012) • Lack of traditional preparation Lack of Anti- Inflammatories • Plant flavonoids • Spices • Lack of fermented foods
    7. 7. Fats • Fuel for Gram- negative bacteria • Anti-microbial free fatty acids Sugars • Glucose protects bacteria • Pre-biotic oligosaccharides Alcock et al., 2012 Nutrient signalling: Evolutionary origins of the immune-modulating effect s of dietary fats. The Quarterly Review of Biology, 87, 187-223
    8. 8. Fat Effect on bacteria Pro-microbial Increase inflammation Anti- microbial Decrease inflammation Inflammatory • Trans Fats • Long-Chain Saturated Fats Anti-Inflammatory • Short/Medium Chain saturated • Unsaturated Fats • PUFA (& MUFA) • Omega-3Alcock et al., 2012 Nutrient signalling: Evolutionary origins of the immune-modulating effect s of dietary fats. The Quarterly Review of Biology, 87, 187-223
    9. 9. Inflammation  Depression Food proteins Auto-immune Environmental Irritants Fewer “Old Friends” Reduced immune training Overactive immune response Raison et al., (2010). Inflammation, sanitation, and consternation. Arch Gen Psychiatry, 67
    10. 10. • Inflammation o IL-1, -2, -6, TNF-α, CRP, and sickness behavior o Also in depression • Evidence o Elevated in chronic illness (Capuron et al ., 2002) o Depression in cytokine treatment (Raison et al., 2006; Dunn et al., 2005) o Higher IL-1β (170%) in depressed persons (Thomas et al., 2005) o Depression and LPS (Dantzer, 2006; Moreau et al., 2008)
    11. 11. Sickness Behavior • Fatigue • Lethargy • Loss of interest • Social withdrawal • Hyperalgesia • Anxiety • Difficulty concentrating • Hypersomnia • Loss of appetite • Malaise Depression • Fatigue • Lethargy • Loss of interest • Social withdrawal • Hyperalgesia • Anxiety • Difficulty concentrating • Change in sleep patterns • Overeating or loss of appetite • Hopelessness Reprioritization & conservation of energy Sickness  healing Depression  reevaluate and seek new solutions, get help through social support
    12. 12.  Some may be sick, not depressed  Heal the gut to heal the mind  Traditional diets better for mental health  OTC anti-inflammatory drugs not the answer  Intervention studies needed  Diet and changes in depression/inflammation  Diet and changes in gut flora
    13. 13.  Alcock et al., (2012) Nutrient signaling: Evolutionary origins of the immune- modulating effect s of dietary fats. The Quarterly Review of Biology, 87, 187-223  Raison et al., (2010). Inflammation, sanitation, and consternation. Arch Gen Psychiatry, 67
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