Chronic constipation: focus on microbiome-targeted therapies with prebiotics, probiotics, and synbiotics

Abstract

Chronic constipation is a global medical, social, and economic problem due to its negative impact on patients’ quality of life and increased risk of colorectal cancer, cardiovascular and cerebrovascular disorders. The gut microbiota plays an important role in the pathophysiology of constipation through its interplay with the immune system, enteral and central nervous system, representing a promising therapeutic target. Gut dysbiosis in patients with constipation is characterized by reduced relative numbers of bacteria producing lactate (Lactobacillaceae, Bifidobacteriaceae) and butyrate (Lachnospiraceae, Oscillospiraceae), as well as with increased numbers of those producing hydrogen sulfide (Desulfovibrionaceae) and methanogenic archaea (Methanobacteriaceae). The leading pathogenetic mechanism related to intestinal dysbiosis in chronic constipation, can be microbial metabolic abnormalities (metabolic dysbiosis) characterized by altered production of short-chain fatty acid, methane, hydrogen sulfide, tryptophan metabolites and by abnormal bile acid biotransformation. It has been proven that dysbiotic abnormalities of the intestinal microbiome play a role in the pathophysiology of constipation, which allows for the use of prebiotics, probiotics, and synbiotics for effective microbiome-modulating therapy in patients with chronic constipation. The proven role of dysbiotic abnormalities of the intestinal microbiome in the pathophysiology of chronic constipation determines the effectiveness of microbiome-modulating therapy (prebiotics, probiotics, synbiotics) in patients with this syndrome. Inulin is the most studied preboitic; it is a soluble food fiber that markedly contributes to the regulation of intestinal microbiota, stimulates the growth of beneficial bacteria, and production of anti-inflammatory metabolites. Inulin normalized the intestinal function in patients with chronic constipation increasing the stool frequency, softening the stool, and reducing the intestinal transit time. In addition, inulin modulates the immune response and impacts the absorption of minerals, appetite, and satiety. Treatment with probiotics is also associated with reduced intestinal transit time, compared to controls. According to a systematic review and meta-analysis of 30 randomized controlled trials, only Bifidobacterium lactis strains (but not other probiotics) significantly increase stool frequencies in chronic constipation in adults. Clinical studies have shown that the targeted probiotic Bifidobacterium lactis HN019 can significantly increase the stool frequencies in patients with low (≤ 3 per week) stool frequency up to 4.7–5.0 per week, reduce the intestinal transit time and the rate of functional gastroenterological symptoms in adults with constipation. Beyond its clinical effects, Bifidobacterium lactis HN019 leads to beneficial changes in intestinal microbiota, significantly increasing the bifidobacteria and decreasing the enterobacteria numbers. The results of trials confirm the importance of synbiotic correction of dysbiotic microbiota in all patients with constipation to increase stool frequencies and improve fecal consistency, as well as to prevent the chronic disorders associated with constipation. Synbiotics, such as a combination of Bifidobacterium lactis HN019 and inulin, with the properties of both complementary and synergic synbiotic, may have the greatest microbiome-modulating and functional potential to significantly improve clinical outcomes in patients with chronic constipation compared to probiotics or prebiotics used alone.