Intestinal Serotonin and Bone Loss

Also see:
Carbohydrates and Bone Health
Ray Peat, PhD on the Benefits of the Raw Carrot
Bowel Toxins Accelerate Aging
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
Linoleic Acid and Serotonin’s Role in Migraine
Hypothyroidism and Serotonin
Estrogen Increases Serotonin
Gelatin, Glycine, and Metabolism
Whey, Tryptophan, & Serotonin
Tryptophan, Sleep, and Depression
Anti-Serotonin, Pro-Libido
Serotonin and Melatonin Lower Progesterone

“In previous newsletters I have talked about the ability of intestinal irritation and the associated increase of serotonin to cause headaches, asthma, coughing, heart and blood vessel disease, muscular dystrophy, flu-like symptoms, arthritis, inflammation of muscles and nerves, depression, and inflammatory brain diseases. With the new recognition that serotonin is a basic cause of osteoporosis, intestinal health becomes a major issue in aging research.” -Ray Peat, PhD

“A few years ago, the “serotonin reuptake inhibitor” antidepressants, already known to increase prolactin by increasing the effects of serotonin, were found to be causing osteoporosis after prolonged use. Estrogen increases serotonin, which besides promoting the secretion of prolactin, also stimulates the production of parathyroid hormone and cortisol, both of which remove calcium from bone, and contribute to the calcification of blood vessels. The association between weakened bones and hardened arteries is now widely recognized, but researchers are being careful to avoid investigating any mechanisms that could affect sales of important drug products, especially estrogen and antidepressants.

Following the recognition that the SSRI drugs were causing osteoporosis, it was discovered that the serotonin produced in the intestine causes bone loss, and that inhibiting intestinal serotonin synthesis would stop bone loss and produce a bone building anabolic effect (Inose, et al., 2011). One group that had been concentrating on the interactions of genes commented that, recognizing the effects of intestinal serotonin, they had suddenly become aware of “whole organism physiology” (Karsenty and Gershon, 2011).

In previous newsletters I have talked about the ability of intestinal irritation and the associated increase of serotonin to cause headaches, asthma, coughing, heart and blood vessel disease, muscular dystrophy, flu-like symptoms, arthritis, inflammation of muscles and nerves, depression, and inflammatory brain diseases. With the new recognition that serotonin is a basic cause of osteoporosis, intestinal health becomes a major issue in aging research.” -Ray Peat, PhD

“One factor involved in the increased production of TSH in hypothyroidism is that the low metabolic rate allows estrogen to accumulate, leading to increased serotonin production. Serotonin stimulates both TSH and prolactin. Serotonin and prolactin both happen to cause bone loss. They increase nitric oxide, which inhibits mitochondrial respiration. Serotonin increases a cytokine, osteoprotegerin, that inhibits osteoclasts, reducing bone turnover. However, serotonin’s other antimetabolic effects outweigh that effect, and it is a major factor in causing osteoporosis. The antimetabolic factors that slow the rate ofliving also slow the rate of renewal, and on balance lead to tissue atrqphy, fibrosis, inflammation, and degeneration.” -Ray Peat, PhD

J Bone Miner Res. 2011 Sep;26(9):2002-11. doi: 10.1002/jbmr.439.
Efficacy of serotonin inhibition in mouse models of bone loss.
Inose H, Zhou B, Yadav VK, Guo XE, Karsenty G, Ducy P.
In a proof-of-concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy-induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy-induced bone loss in aged mice. It also cures the low bone mass of Lrp5-deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone-loss disorders.

Gastroenterology. 2011 Aug;141(2):439-42. Epub 2011 Jun 17.
The importance of the gastrointestinal tract in the control of bone mass accrual.
Karsenty G, Gershon MD.
One of the least anticipated and less heralded outcomes of mouse genetics has been to rediscover whole organism physiology. Among the many unexpected findings that it has brought to our attention has been the realization that gut-derived serotonin is a hormone-inhibiting bone formation. The importance of this discovery presented in this review is 2-fold. First, it provides a molecular explanation for 2 human genetic diseases-osteoporosis, pseudoglioma, and high bone mass syndrome; second, it suggests a novel and anabolic way to treat osteoporosis. These findings illustrate the importance of the gastrointestinal tract in the regulation of organ physiology at yet another extraluminal site.

Nat Med. 2010 Mar;16(3):308-12. Epub 2010 Feb 7.
Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.
Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P.
Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Cell. 2008 Nov 28;135(5):825-37.
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G.
Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.

Annu Rev Med. 2011;62:323-31.
Regulation of bone mass by serotonin: molecular biology and therapeutic implications.
Karsenty G, Yadav VK.
The molecular elucidation of two human skeletal dysplasias revealed that they are caused by an increase or a decrease in the synthesis of serotonin by enterochromaffin cells of the gut. This observation revealed a novel and powerful endocrine means to regulate bone mass. Exploiting these findings in the pharmacological arena led to the demonstration that inhibiting synthesis of gut-derived serotonin could be an effective means to treat low-bone-mass diseases such as osteoporosis.

Clin Calcium. 2010 Dec;20(12):1850-956.
[Control of bone remodeling by nervous system. The role of serotonin in the regulation of bone metabolism].
[Article in Japanese]
Inose H.
There is increasing evidence for a contribution of serotonin to the regulation of bone metabolism. In the periphery, gut derived serotonin (GDS) regulates osteoblast proliferation and bone formation. In the brain, brain derived serotonin regulates bone mass through sympathetic nervous system. In addition, inhibition of GDS biosynthesis can treat osteoporosis in ovariectomized rodents by increasing bone formation. The emerging evidence has suggested that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis in humans.