Hyperhomocysteinemia decreases intestinal motility leading to constipation

Abstract

Elevated levels of plasma homocysteine (Hcy) called hyperhomocysteinemia (HHcy) have been implicated in inflammation and remodeling in intestinal vasculature, and HHcy is also known to aggravate the pathogenesis of inflammatory bowel disease (IBD). Interestingly, colon is the pivotal site that regulates Hcy levels in the plasma. We hypothesize that HHcy decreases intestinal motility through matrix metalloproteinase-9 (MMP-9)-induced intestinal remodeling leading to constipation. To verify this hypothesis, we used C57BL/6J or wild-type (WT), cystathionine β-synthase (CBS(+/-)), MMP-9(-/-), and MMP-9(-/-) + Hcy mice. Intestinal motility was assessed by barium meal studies and daily feces output. Plasma Hcy levels were measured by HPLC. Expression of ICAM-1, inducible nitric oxide synthase, MMP-9, and tissue inhibitors of MMPs was studied by Western blot and immunohistochemistry. Reactive oxygen species (ROS) including super oxide were measured by the Invitrogen molecular probe method. Tissue nitric oxide levels were assessed by a commercially available kit. Plasma Hcy levels in the treated MMP-9 group mice were comparable to CBS(+/-) mice. Barium meal studies suggest that intestinal motility is significantly decreased in CBS(+/-) mice compared with other groups. Fecal output-to-body weight ratio was significantly reduced in CBS(+/-) mice compared with other groups. There was significant upregulation of MMP-9, iNOS, and ICAM-1 expression in the colon from CBS(+/-) mice compared with WT mice. Levels of ROS, superoxide, and inducible nitric oxide were elevated in the CBS(+/-) mice compared with other groups. Results suggest that HHcy decreases intestinal motility due to MMP-9-induced intestinal remodeling leading to constipation.

The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

“…Today, it is widely accepted that an elevated level of Hcy (more than 15 μM) is an independent risk factor for cardio and cerebrovascular diseases. Recent studies have demonstrated a strong correlation between elevated Hcy levels and neurological disorders, chronic kidney disease, osteoporosis, gastrointestinal disorders, cancer and congenital defects development [44,61,62,63,64]. …”

Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-mediated hypertension.

“…However, in chronic stage of oxidative stress the defense mechanisms will be exhausted and it would lead to antioxidant reduction that was confirmed by previous reports [181]. In the meantime, studies have shown an increase of SOD-1 and SOD-2 in oxidative stress [182] or HHcy [174,183].…”

Different pathways involved in the stimulatory effects of homocysteine on rat duodenal smooth muscle

“…The gastrointestinal tract accounts for 25% of whole body transmethylation and transsulfuration pathways and is a prominent site of net Hcy release [15]. As reported previously, Hcy has been shown to change intestinal motility, in both a procinetic and inhibitory pattern, acting by modulation of nitrergic innervation or by potassium channels [26,39].…”

“…Choe et al [41] demonstrated that methionine, the Hcy precursor, enhanced the contractile activity of human colon smooth muscle in vitro. In contrast, HHC mice model showed delayed intestinal transit due to elevated levels of infl ammatory cytokines and increased expression and activity of MMP-9 in colonic mucosa [15]. Although there is proven higher contractility during D,L-Hcy treatment, the mechanism by which D,L-Hcy affects duodenal contractility has not been clearly elucidated.…”

“…Literature data are controversial about the effects of HHC on gastrointestinal contractility. Intestinal contractility is decreased in HHC due to matrix metalloproteinase-9 (MMP-9)-induced intestinal remodeling in mice colon [15]. Increased plasma Hcy concentration has been implicated in constipation (lowered fecal output), indicating that HHC itself may be causing gastrointestinal distress.…”