Many people would be surprised that the immune system, the gastro-intestinal tract and stress interact, but that is what the most recent of a number of studies shows. In this study on mice, (Brain, Behavior, and Immunity Volume 25, Issue 3, March 2011, Pages 397-407. http://www.ncbi.nlm.nih.gov/pubmed/21040780)  researchers demonstrated that  psychological stress causes almost immediate changes to the gut bacterial population, and that some of these affected sub-populations strongly influence the effect that stress has on immunity. In the study, the researchers exposed mice to social disruption, which is known to cause increases in circulating cytokines ('hormones of the immune system), which themselves induce enhanced reactivity in the immune system.  The researchers found that social disruption altered bacterial counts of some gut bacteria sub-populations, particularly when the bacteria were assessed immediately after stress exposure. Stress exposure  increased the relative abundance of bacteria in the genus Clostridium, which often causes prolonged and severe diarrhea (generally after antibiotc use). The stressor also increased circulating levels of IL-6  which was significantly correlated with stressor-induced changes to certain other sub-populations. In a second experiment, these researchers found that a combination of antbiotics prevented the stress induced increase IL-6. This means that certain gut bacteria are necessary for stressor-induced increases in circulating cytokines.So, not only does stress affect the gut bacterial population, but these organisms are also required for  activation of the immune system.

This information becomes even more relevant for psychiatric disorders such as OCD, and depression, as activation of IL-6 has clearly been associated with depression. In fact blockers of IL-6 (eg etanercept) have been shown to reduce depression scores. Furthermore, we can now see, that stress, via its effect on gut bacteria, and hence the immune system (IL-6) can change brain function. We know this because IL-6 activates a certain enzyme (IDO), which actually 'steals' or syphons-off  tryptophan from its normal metabolic pathway ( ie conversion into serotonin and then melatonin) and instead converts it into chemicals that increase activity of glutamate (in depression) at an excitatory-and some times toxic- receptor (NMDA) in the brain. The result of all of this is increased depression, anxiety, and reduced memory. In mice this effect can take moths to reverse. The upshot of all of this, is that stress, the gut, the brain and the immune system are really intimately linked, and inseparable. While this might be news to most psychiatrists, it is not news when one understands the Whole Psychiatry model.

Nutrition, Methylation, and Depression
Nutritional support for the methylation cycle is another area in which nutrition plays a critical role.  The methylation cycle is essential for mental and physical health.  It is critical to the metabolism of catecholamines in the synapse via an enzyme (COMT) as well as the synthesis of ‘depression-relevant’ compounds such as melatonin, myelin basic protein, carnitine, CoQ10, etc.  Methylation is required to inactivate histamine.

Basic nutrients necessary for normal function of this cycle include B12, glycine, serine, activated B6, selenium, cysteine, methionine and folic acid.

Several studies have shown the utility of folic acid as an adjunct to medication use for depression.  In one study (10) the average HAM-D (a standard measure of depression) score decreased from 27 to 7 in those receiving P (fluoxetine) plus F (folic acid), and from 27 to 12 in those on P plus Pl (placebo (p<0.001). Recovery (full) was attained in 73% of the women receiving P +F, but only 47% of those on P + Pl (p<0.06).

A variety of genetic polymorphisms (single nucleotide polymorphisms or SNP’s) exist, which can alter function the methylation cycle.  One important SNP is the MTHFR SNP, which when present in both copies of a persons genes, indicates the need for a special form of folic acid: L-methyl folate (which crosses the blood brain barrier). This gene acts by reducing the function of the methylation cycle-specifically reducing the conversion of 5,10 methyl-tetrahydrofolate to 5-methyltetrahydrofolate.  This reduces the synthesis of methionine (needed for the COMT enzyme, which requires s-adenosylmethionine to function), results in increased homocysteine (a marker of methylation status), and altered (decreased or increased) DNA methylation, leaving certain genes turned on or off, when they should not be. In fact, in a review of 1280 psychiatric cases and 10,429 controls, the odds of having depression was 36% greater if a person had two copies of the MTHFR SNP (8).  This means low levels of available folic acid, in this case for genetic reasons, but in other cases due to medications or diet, increases one’s risk for depression by 36%.

In some fascinating research in the area of epigenetics (epigenetics describes the part of the genome that is modified by experience as well as methylation, acetylation, ubiquitination, phosphorylation) suggests that genes that are turned on or off by one’s environment, one’s diet, by stress, or by one’s experience are transmitted to subsequent generations.  One author suggests that the biological underpinnings of bipolar affective disorder are not primarily genetic, but are epigenetic (10).  Another author  (11) presents data that suggests that the fact that identical twins are not fully concordant for depression may have to do with reduced methylation of the COMT gene may be associated with bipolar disorder and schizophrenia, as only 26-29% of these patients, when compared with controls showed normal methylation of the COMT gene in the pre-frontal cortex.  The environmental exposures at key developmental phases may result in long standing neuro-biological changes leading to pathology.  Direct evidence is limited at this point.

One of the critical ingredients for the methylation cycle is B12.  B12 plays a vital role in the metabolism of fatty acids essential for the maintenance of myelin in the brain. Absorption of B12 requires the secretion from the cells lining the stomach of a glycoprotein, known as intrinsic factor.  The B12-intrinsic factor complex is then absorbed in the ileum (part of the small intestine) in the presence of calcium.

Many physicians think that to assess B12 one must measure B12 levels.  However, it is well-established that B12 levels are not a sensitive marker for adequacy of B12 function (17).  Some people suggest that measuring methylmalonic acid (MMA) is more sensitive.  But at least one study (18) shows that B12 function has a minimal effect on levels of MMA. Assessment of B12 status in practice involves measurement of a number of parameters, including the physical exam (depression, impaired balance, panic, neuropathy) the size of red blood cells (MCV), Hematocrit, homocysteine, and functional immunoassays.

References:
1) Rush, AJ. STAR-D: What have we learned? Am J Psychiatry. 2007;164-201
2) Pigott, et al. Efficacy and Effectiveness of Antidepressants: Current Status:Psychother Psychosom. 2010;79(5):267-79.
3) Bourre, JM: J. Nutrition, Health & Aging: Vol 10(5) 2006: 377-385. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain: Part 1: micronutrients.
4)Miller HL :et al.: Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. Vol.53( 2):117-128.
5) Spillmann MK. Et.al.; Tryptophan depletion in SSRI recovered depressed outpatients. Psychopharmacology (Berl)2001, May;155 (2):123-127
6) Maes M.,et al.:Hypozincemia in depression. J Affective Disorders; 31(2):13Maes M.: “Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness” Biol Psychiatry: 42(5):349-358 (1997). 5-140 (1994)
7)Maes M.Et.al.: Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J. Affect Disord 1999:56(2-3):189-194
8)Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms (C677T variant) and Psychiatric Disorders: A HuGE Review: Am J Epidemiol 2007;165:1–13
9)Coppen A, et al.: Enhancement of antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord: 2000:60(Nov.):121-130
10)Rutten: Epigenetic Mediation of  Environmental influences in Major Psychotic Disorders Schizophrenia Bulletin; 2009: Vol 35 (6):1045-1056
11)McGowan: the epigenetics of social adversity in early life: Implications for mental health outcomes. Neurobiology of Disease (2010): In Press
12)Hedelin, M. Dietary Intake of Fish, Omega 3’s, Omega 6 PUFA’s and Vitamin D and the pPrevalence of Psychotic Symptoms in a Cohort of 33,000 Women from the General Population. BMC  Psychiatry 2010 (10): 38; 1-13
13)Wilkins CH., et al.: Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatric Psychiatry, 2006 Dec;14(12):1032-40
14)Van Praag: Depression, glucose tolerance, peripheral glucose uptake and their alterations under the influence of anti-depressive drugs of the hydrazine type. Psychopharmacologia (Berlin) 1965;8:67-78.)
15)Cassidy, F. et.al.: Elevated Frequency of Diabetes Mellitus in Hospitalized Manic-Depressive Patients. Am J Psychiatry 1999;156 1417-1420.
16)Weiss JH., et.al.: Zn(+2): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 2001: 21(12):112-3
17)Lindenbaum J. et.al.: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytois. N Engl J Med 1988;318:1720-1728.
18)Vogiatzoglou, A. Determinants of Methylmalonic Acid in a Large Population: Implications for Assessment of Vitamin B12 Status. Clinical Chemistry (55)12: 2198-2206 (2009)

Most people (except those with liver and kidney disease) do not get enough protein (fish, meat, eggs) for breakfast and lunch. Try increasing your protein at breakfast and lunch for five days and see if you don’t notice a difference in your energy, reduced cravings at night, improved mood, and less of an afternoon slump within five days. I was so impressed by this effect that it was part of the motivation for my second book.