The immune-brain-gut-endocrine axis

This is the third installment of my short review of immune function. For part one (basics) see here and part two (vitamin D) see here. A discussion of CPPS and immunity and some other related topics will follow within the next days.

While the existence of communication between the immune system and other bodily organs may seem an obvious proposition it was not so not long ago. It is only during the last 30 years that it has been appreciated that the immune system and especially the brain (or rather certain parts of the brain) and the immune system “talk” with each other. The exchange of information modulates behavioral and physiological responses to immune insults and immune responses to conscious and semi-conscious behavioral responses to environmental stressors.

Two pathways link the brain and the immune system: signaling through nerves (e.g. neocortical-sympathetic axis and brainstem-vagus pathway) of the autonomic nervous system (ANS), and “neuroendocrine humoral outflow via the pituitary” (that is: substances transported by/in blood, lymph, saliva etc) or rather under HPA axis control. The major ANS component involved in this is the sympathetic nervous system (SNS). This connection has also been evidenced by the alteration of immune function through behavioral conditioning (e.g. that stress both can drive a pro- and anti-inflammatory response) and specific brain lesions.

The ANS is further divided in three sub-systems: the sympathetic (or noradrenergic) nervous system, the parasympathetic (or cholinergic) nervous system and the (semi-autonomous) enteric nervous system that lies entirely within the wall of the gastrointestinal tract (a sort of second brain in the belly) and that connects to both the SNS and PSNS (via e.g. the vagus nerve).(1)

During immune challenge (or cellular damage for any reason) or stress (work, social etc) the immune system is similarly activated. Levels of norepinephrine (noradrenalin), CRH, vasopressin and other substances change inducing immune activation. The the individual differences in activation are dependant both on early-life events and genes.(2)

Pro-inflammatory cytokines activate the HPA axis which induces increased plasma concentrations of CRH, vasopressin, ACTH and cathecolamines (e.g. epinephrine and noreepinephrine). Activation of the immune system does also induce fever (not always) and sickness behaviour. That immune cytokines cause sickness behaviour has been amply demonstrated due to cytokine therapy of cancer patients, as the symptoms almost immediately disappear upon discontinuation of treatment. It may be interesting to note that “full blown” sickness behaviour is caused by IL-2 and/or IFN-alpha(3). Of special interest is that the fatigue and irritability, commonly seen in CPPS is “caused” by IFN-alpha (which btw, in conjunction with IFN-beta, is central to anti-viral immune response).

An overactive HPA-axis with concomitant hypercortisolemia, is commonly seen in (cytokine-induced) depression. Some anti-depressants have been shown to induce cytokine suppression (and thus immune suppression and regulation), which is interesting in view of the use of anti-depressants against over-active bladder and other micturition disorders. The exact mechanisms are not fully known.

Other cytokine-“antagonists” used in micturition disorders are etanercept and infliximab (both are TNF-alpha-antagonist). (4)

Human visceral obesity is associated with HPA alterations. Cause and effect are still unclear though, but low testosterone and high glucocorticoids result in increased fat. As visceral fat increases it will suppress testosterone and enhance cortisol. (5)

Other substances affecting the immune system are e.g. prolactin, TSH, GH, GNRH and IGF-1. Hyperprolactinemia has e.g. been observed in 20% of SLE sufferers. Low IGF-1 is associated with cognitive decline and sickness behaviour, and low GH with anxiety and depression. IGF-1 is interesting as excercise increases its ratio visavi pro-inflammatory cytokines. Maybe a reason (in addition to the ussal endorphins) why CPPS sufferers (and others) feel better after excercise?(6)

CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, immune brain gut endocrine axis, enteric immune system, vagus nerve, immunity, cytokines.
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(1) Elenkov IJ, Wilder RL, Chrousos GP, Vizi S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595-638, 2000.
(2) Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. [2008 CCNP Heinz Lehman Award Paper]. J Psychiatry Neursci 34(1):4-20, 2009.
(3) IFN-beta causes fatigue, depression and “mental fog”. TNF-alpha fatigue and anorexia. IL-2 fatigue, anhedonia (listlessness), dysphoria (depression, anxiety, irritability, restlessness) and “mental fog”. IFN-alpha fatigue, depression, psychomotor slowing, anxiety, social withdrawal, irritability, anorexia and “mental fog”.
(4) Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 29(2):201-217, 2005.
(5) Nieuwenhuizen AG, Rutters F. The HPA axis in the regulation of energy balance.
(6) Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun 21:384-292, 2007.

Nocturia and neurological health

Two interesting studies by Asplund and Asplund et al. showed that self-reported poor somatic and mental health, pain, sick leave and visual impairement all increased with increasing nocturnal voids, while quality of life decreased.(1,2) This is very interesting in view of the importance of sleep for immune function (see below) and the possibility of neurological causes. Hypercalciuria has been implicated with nocturia in children and with concomitant hypokalemia also with diabetes insipidus, while in adults hypertension has been associated with nocturia. Sugaya et al. (7) have also shown that patients with nocturia have higher levels of serum catecholamines (adrenaline, noradrenaline and dopamine) which indicates that nocturia is stressful per se, or caused by a disorder of or affecting the adrenal gland. Other causes are: heart disease, sleep apnea, bladder and prostate problems, diabetes mellitus, HPA dysfunction (nocturnal polyuria and diabetes insipidus).

Nocturia is the leading cause of sleep disruption in adults. It is not a sickness of old age but afflicts young adults, 35+, too. "Nocturia patients are sleeping on average only 2-3 hours before waking for the first void." Traditionally nocturia has been indicated if two or more voids per night, but nocturia once a night is almost as disruptive as twice a night. Especially if the void occurs during slow wave sleep (during the first 4 hours of sleep).(3) "This results in disruption of the restorative sleep period with physiological consequences such as mood disturbance, cognitive and memory impairment and reduced performance at work. In addition, it is accountable for increased morbidity and mortality, increased risk of falling, cardiovascular disease, depression and lowered immune response." Sleep disruption also causes lowered testosterone and LH levels. Especially if disruption occurs during REM sleep.(8) It is more bothersome for younger people especially as they have work and families to care for and cannot take a nap or two during the day.(4) (Notice that lack of sleep causes daytime tiredness, mood disturbances, memory impairment, increased falling, accidents, more often sick, decreased life expectancy, depression, diabetes, obesity etc.) Nocturia affects QoL as much or even more as prostate cancer (except terminal cancer) and cardio-vascular disease regardless whether it is one or more nightly voiding.(5)

The preferred treatment for nocturia is desmopressin as it ensure the longest uninterrupted sleep period. Time to first void is on average 4-5 hours. Desmopressin increaes mean initial sleep period with about 100 minutes while indiplon and temazepam only with about 45-50 and 65-70 minutes.(6)

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, nokturi, överaktiv blåsa
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(1) Asplund R, Marnetoft S-U, Selander J, Åkerström B. Nocturia in relation to somatic health, mental health and pain in adult men and women. BJU Int 95:816-819, 2005.
(2) Asplund R. Visual impairment, sleep and nocturia in the elderly. Arch Gerontol Geriatr. 41(1):61-67, 2005.
(3) N Stanley, Sleep, is it a waste of time and is nocturia causing relevant problems?, EUA 2009 Congress
(4) JP Norgaard, Nocturia: a disease or a natural consequence of ageing, EUA 2009 Congress
(5) T Holm-Larsen Why treat nocturia... EUA 2009 Congress
(6) van Kerrebroeck et al Eur Urol 52:221-229, 2007
(7) Sugaya K, Nishijima S, Miyazato M, Ogawa Y. Central nervous control of micturition and urine storage. J Smooth Muscle Res 41(3):117-132, 2005.
(8) In papers by Luboshitzky and Axelsson. Additional detail in post about testosterone.

Micturition frequency in CPPS

Disrupted urinary frequency is an important problem in CPPS. Causes are unknown, but vasopressin dysregulation or desensitization of the kidney vasopressin receptors is likely, as may also be detrusor dyssynergia (meaning the muscles controlling the bladder do not function as they should either due to neurological causes or localized muscular dysfunction). In addition to this muscles in the pelvis floor and urethra may be dysfunctional ("uncoordinated").
See posts on the physiology of micturition and on nocturia for additional detail.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfrekvens, miktion

Counter indications part 2 -- why alcohol, caffeine and citrus?

I cannot but speculate, but all of these have in common that they affect vasopressin levels and the CNS.

Alcohol (ethanol)
“Humans have practiced the art of fermentation for millennia, observing the many actions of ethanol on physiology and behavior in the process. Despite our familiarity with ethanol, we have remarkably little insight into the mechanisms by which it reduces inhibitions and anxiety, nor do we know much about how it produces signs of more severe intoxication.” (1)

What is known is that ethanol affects plasma AVP concentrations thus affecting water balance. Ethanol does also affect the HPA axis in other ways modulating the release of e.g. adrenocorticotropic hormone (ACTH) and corticosterone (CORT)(2) and human growth hormone (hGH). The latter is interesting as acute application of GH results in a reduced urinary electrolyte and water excretion(3), while alcohol suppresses hGH secretion and LH, FSH, testosterone, estradiol etc.

Coffee, tea and chocolate (caffeine)
Caffeine has been shown to induce relaxation and increased alertness and cognition in lower doses, as well as anxiety and nervousness as dosage increases. Even panic attacks in individuals with high anxiety (Bourin et al. 1998). Caffeine also increases corticosterone, cortisol and ACTH levels.

Citrus fruits
It is intriguing that citrus fruit would affect CPPS. Current hypothesis suggest that citrus fruit act as irritants in the bladder. New research suggest that apigenin (a bioflavonoid found in citrus fruits, but also e.g. celery and parsley) may affect the CNS (HPA-axis). Murine tests has e.g. shown it to affect dopamine and serotonin, and to decrease serum corticosterone levels.(4) Other research indicate that it "inhibits the proliferation of prostatic stromal cells"(5), i.e. may inhibit the development of benign prostatic hyperplasia. Is there enough apigenin in eaten citrus etc to have any effects? Further research is needed.

Added nov 18 2009:
As vitamin C deficiency causes diminished thrombosis and fibrinolysis (blood clotting) a speculative cause for citrus exacerbations may be improved blood clotting ability. Especially as most successful CPPS treatments seem to decrease the propensity for blood clotting.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb
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(1) Harris RA, Trudell JR, Mihic SJ. Ethanol's molecular targets. Sci Signal. 1(28):re7, 2008. (I liked the introduction to their report.)
(2) Haddad JJ. Alcoholism and neuro-immune-endocrine interactions: physiochemical aspects. Biochem Biophys Res Commun. 323(2):361-71, 2004.
(3) Dimke H, Flyvbjerg A, Frische S. Acute and chronic effects of growth hormone on renal regulation of electrolyte and water homeostasis. Growth Horm IGF Res. 17(5):353-68, 2007
(4) Yi LT, Li JM, Li YC, Pan Y, Xu Q, Kong LD. Antidepressant-like behavioral and neurochemical effects of the citrus-associated chemical apigenin. Life Sci 82(13-14):741-751, 2008.
(5) Bektic J, Guggenberger R, Spengler B, Christoffel V, Pelzer A, berger AP, Ramoner R, Bartsch G, Klocker H. The flavonoid apigenin inhibits the proliferation of stromal cells via the MAPK pathway and cell-cycle arrest in G1/S. Maturitas 55(S1):S37-46, 2006.

Counter indications

Anecdotal information indicates that coffee, citrus fruit, tomatoes, vinegar, alcohol and spicy foods may worsen symptoms, but a study of 1759 participants shows no correlation with these (1). (It may be interesting to note that porphyria, AIP, may be triggered by some of these irritants.) The same irritants are also mentioned by IC patients(2). But it may be so that foods increasing uric acid (protein rich foods) or potassium levels (like apple and orange juice) are causing exacerbations, if the patients problems are caused by uric acid or potassium irritation from reflux of urine or bladder epithelium abnormalities.

Alcohol and caffeine (in coffee, tea and chocolate) and nicotine cause increased urgency and frequency because both inhibit vasopressin (AVP) production. AVP may also affect mood – anger, anxiety, depression etc (3).

Finally substances causing muscle relaxation may cause disruption.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, vasopressin
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(1) Hochreiter WW, Madersbacher S, Temml C, Zbrun S, Wolfensberger P, Studer UE Prevalence of prostatitis symptoms and LUTS in 1759 men using validated questionnaires. 2005 EAU meeting, Istanbul.
(2) Shorter B, Lesser M, Moldwin RM, Kushner L. Effect of comestibles on symptoms of interstitial cystitis. J Urol. 178(1):145-152, 2007.
(3) Caldwell HK, Lee HJ, Macbeth AH, Young WS 3rd. Vasopressin: behavioral roles of an "original" neuropeptide. Prog Neurobiol. 84(1):1-24, 2008.