The results of the present study could be summarized as follows: 1) concomitant use of probiotics was effective to settle subject’s defecation even when they have symptoms of chronic constipation and/or diarrhea, 2) probiotics, especially BIO-THREE treatment, improved the status of severe constipation, 3) BIO-THREE treatment led to soften stool form properly correlated with chlorpromazine equivalent.
There are several potential mechanisms of action by which probiotics may benefit functional constipation [19]. First, probiotics modify the gastrointestinal microbiota, intestinal permeability and the systemic immune response, which is known to be altered in constipation [20, 21]. Second, probiotic metabolites may alter gut function, including suppression of stress induced visceral hypersensitivity [22] and regulation of irritable bowel syndrome [23]. Third, some probiotics increase the production of lactate and short-chain fatty acids (SCFAs), reducing luminal pH, which will enhance colonic peristalsis and shorten WGTT [24, 25]. The latest, the levels of proliferation of probiotics in the intestine correlates with the magnitude of host physiological responses, such as IgA production and mucin secretion modifying T-cell responses [26], and the manipulation of intestinal dysbiosis affect gut motility through regulation of serotonin biosynthesis [27].
Butyrate, one product of SCFAs, plays a strong regulatory role in microbial Toll-like receptors-dependent sensing, which is implicated in gut motility by secreting PYY and GLP-1 [28]. Ge X et al. reported that the butyrate levels were significantly lower in mice from slow-transit constipation (STC) donors than in mice from healthy donors. After supplementation with butyrate, the results of mice from STC donors were reversed in pellet frequency, water percentage, and colonic contractility. Therefore, fecal microbiota from STC donors might regulate gut motility by affecting the production of SCFAs [29].
In culture supernatants, BIO-THREE appeared to stimulate the Th1 immune response, downregulate pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and upregulate anti-inflammatory cytokine (IL-10), that is reasonable to speculate that BIO-THREE redirected the immune system toward an anti-inflammatory phenotype, rather than an aggressive immune response [30]. In clinical studies evaluating the effectiveness of Bio-Three for inducing remission in patients with ulcerative colitis (UC), the decrease in the UC disease activity index after treatment correlated with the decrease in the fecal butyrate concentration [31], and an increased butylate/asetae ratio resulting from decreased absorption of butyrate, an indicator of anti-inflammatory activity is associated with a higher risk of relapse in patients with UC [32].
There are few published studies of probiotic supplementation for patients with a primary psychiatric disorder. Dickerson FB et al. found that in schizophrenia patients receiving ongoing antipsychotic treatment, the probiotic supplemented (combined Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) group compared to placebo group was significantly less likely to develop severe bowel difficulty in a randomized, double-blind, placebo-controlled trial [33]. They also reported later that probiotic-induced alterations in the same group of subjects are related to regulation of immune and intestinal epithelial cells through the interleukin-17 (IL-17) family of cytokines, and hypothesize that supplementation of probiotics to schizophrenia patients may improve control of gastrointestinal leakage [34]. Thus, overlapping multiple these mechanism, probiotics may had a beneficial effect on stool consistency in psychiatric subjects.
As for the mechanism of psychotropic drug-induced chronic constipation, its anticholinergic effect on propulsive motility of the colorectum has been highlighted for many years. However, the central dopamine neurotransmission is important for bowel movement because the spinal dopamine system is involved in controlling the defecation reflex through the descending pain inhibitory pathways. In animal study, dopamine in the lumbosacral defecation center causes strong propulsive motility of the colorectum. The effect of dopamine is a result of activation of sacral parasympathetic preganglionic neurons via dopamine D2 receptors of the descending pain inhibitory pathway [35]. Considering that the dopamine D2 blockade may reduce the stool frequency of schizophrenia patients dose-dependently, the beneficial effects of probiotics on stool consistency may be modulated by the chlorpromazine equivalent levels.
Psychobiotics are beneficial bacteria (probiotics) or support for such bacteria (prebiotics) that influence bacteria–brain relationships. Psychobiotics exert anxiolytic and antidepressant effects characterized by changes in emotional, cognitive, systemic, and neural indices. Bacteria-brain communication channels through which psychobiotics exert effects include the enteric nervous system and the immune system [36]. Therefore, a microbiome-mediated psychological or psychiatric effect sharing a signaling mechanism with psychobiotics should be investigated in an additional study.
There are several limitations to the present study. First, it was a single-center retrospective study design from one psychiatric hospital, and the duration of probiotic treatment was limited to just two months. Second, most of patients received several medications for the treatment of constipation, and lack of control subjects. Third, we used Bristol stool form scale as the only one simple method of assessing change in intestinal function, though change in WGTT from base line correlated with change in defecation frequency and with change in stool output but best with change in stool form as shown in previous study [18]. Finally, the fecal microbiota was not identified and luminal factors modulated by the microbiota such as SCFAs were not measured. So we could not evaluate these changes before and after probiotics supplementation.