Chu JR, Kang S-Y, Kim S-E, Lee S-J, Lee Y-C, Sung M-K. Prebiotic UG1601 mitigates constipation-related events in association with gut microbiota: a randomized placebo-controlled intervention study. World J Gastroenterol. 2019;25(40):6129-6144.
To assess the efficacy of a specific prebiotic (UG1601) on symptoms of mild constipation and microbiota composition.
Randomized, double-blind, placebo-controlled trial.
The investigators divided 40 participants into either an intervention arm or placebo arm (n=20). The participants comprised 10 men (median age 25 years; median body mass index (BMI)=23.43) and 30 women (median age 24 years; median BMI=21.33).
Inclusion criteria included 1 or more of the following for more than 3 months and less than 6 months:
- Sensation of incomplete evacuation >25% of the time
- Stool frequency <3 times per week
- Straining at defecation >25% of the time
Exclusion criteria included the presence of any disease of the bowel, history of major surgery, use of any probiotic, prebiotic, or synbiotic within the past month, and any antibiotic use during the 3 months before the start of the study. The study also excluded volunteers who were smokers, pregnant, or lactating.
Participants received either a prebiotic (UG1601), composed of 61.5% inulin, 34.6% lactitol, and 3.9% aloe vera gel, or an identical-appearing placebo containing maltodextrin. Participants consumed 13 grams of either the prebiotic or placebo dissolved in water every day for 4 weeks (the investigators did not specify the time of day).
Primary Outcome Measures
Time points for data collection were baseline, 4 weeks, and 2 weeks after the intervention (6 weeks from baseline). Participants kept a dietary record 3 days of each week. Blood and fecal samples were taken at baseline and at the end of the intervention period (4 weeks).
Bowel regularity has always been integral to wellness, and this study provides further evidence that it is, indeed, central to health.
Frequency of bowel movements (BM) was tracked using a 6-point scale called the stool frequency score (0–5): less than 1 BM =0 points on the scale; 1 to <2 BM per week =1; 2 to <3 BM =2; 3 to <4 BM =3; 4 to <5 BM =4; and 5 or more BM for the week =5.
Gastrointestinal (GI) symptom assessment
Participants reported the following parameters as worsened, unchanged, or improved:
- Stool consistency
- Feeling of incomplete evacuation
- Time required for evacuation
Investigators measured markers of endotoxemia including lipopolysaccharide (LPS) and its receptor, cluster of differentiation 14 (CD14).
They also determined the concentrations of the 3 major short-chain fatty acids (SCFA) acetate, propionate, and butyrate using standard gas chromatography–mass spectrometry. Investigators determined relative abundance of SCFA-producing bacteria using 11 representative bacteria:
- Acetate-producing bacteria Bifidobacterium longum, Bifidobacterium adolescentis (B. adolescentis), and Bifidobacterium catenulatum (B. catenulatum);
- Propionate-producing bacteria Prevotella ruminicola (P. ruminicola), Propionibacterium acidipropionici (P. acidipropionici), and Propionibacterium freudenreichii (P. freudenreichii);
- Butyrate-producing bacteria Faecalibacterium prausnitzii (F. prausnitzii), Clostridium leptum (C. leptum), and Roseburia hominis (R. hominis);
- Prebiotic-sensitive bacteria Bifidobacterium lactis (B. lactis) and Lactobacillus acidophilus (L. acidophilus)
The stool frequency score improved in both the prebiotic (P=0.001) and the placebo (P=0.002) groups after 4 weeks of intervention when compared to baseline. While the prebiotic group had less GI symptomology, this did not reach statistical significance between groups.
Serum LPS concentration as well as CD14 concentration decreased in both groups over the 4-week study but reached statistical significance only in the prebiotic group (LPS, P<0.001; CD14, P=0.012). The reduction in LPS was also significantly greater in the prebiotic group when compared to the placebo-group reduction (P<0.001).
SCFA concentration did not differ between the 2 groups after 4 weeks. The only bacterial species that increased significantly was butyrate-producing R. hominis (which increased 15.3%) after 4 weeks in those who received the prebiotic. This increase was significantly larger than that seen in the placebo group (P=0.045).
Of the 20 participants in the prebiotic group, 12 were considered “responders,” defined as those who experienced a decrease in their time for evacuation and whose serum CD14 concentration decreased by >10%. Subgroup analysis of the responders versus nonresponders found many differences in subordinate taxa between the groups, such as a decrease in the phylum Firmicutes (P=0.031), the class Clostridia (P=0.058), and the order Clostridiales (P=0.058) and increases in several other bacteria, including Prevotella stercorea, Bacteroides plebeius, and Bacteroides stercoris.
In this study, there were measurable changes in the microbiota and frequency of bowel movements after just 4 weeks of soluble fiber supplementation. A change in bowel function with 13 grams of supplemental fiber may not be surprising to practitioners. The net effect of more frequent evacuations and microbial population shifts decreased endotoxemia (ie, LPS and its receptor, CD14, in circulation). This result is the most intriguing aspect of the study. A reduction of endotoxemia is likely to have ramifications for the entire body. Bowel regularity has always been integral to wellness, and this study provides further evidence that it is, indeed, central to health.
Lipopolysaccharides (LPS), which are a component of gram-negative bacteria cell membranes, are often synonymous with endotoxins. Once the bacteria are damaged (ie, lysed), LPS is recognized as a pathogen-associated molecule responsible for initiating host defenses against these bacteria.1 The immune response is stimulated when LPS binds toll-like receptors (TLRs), a protein class that triggers inflammation. In bacterial infections, acute inflammation is necessary to clear the pathogen and resolve the infection. This LPS-induced inflammatory process is necessary to protect us from infections with gram-negative bacteria, as well as some gram-positive infections.2
So, what happens when LPS is found chronically in circulation? The presence of endotoxins (ie, LPS) in the blood is the definition of endotoxemia. Not surprisingly, when the evacuation frequency is lower, LPS is higher, due to the absorption of gut bacterial components, including LPS, as bacteria go through their life cycles within the bowel. In the study currently under review, every participant who received the prebiotic had a decrease in their circulating LPS. Whether it was a shift in the type of bacteria in the gut or adsorption of LPS to soluble fiber that led to the reduction of circulating LPS is academic. From a clinical perspective, this soluble-fiber combination achieved a desirable effect, the reduction of endotoxemia.
LPS is a remarkably reliable stimulator of the inflammatory process, as suggested by its extensive use in animal research models of systemic inflammation. The cascade is as follows: LPS binds TLR-4, which is the intermediary in the activation of NF-κB (nuclear factor kappa light-chain enhancer of activated B cells) and AP-1 (activator protein 1), both master cellular “switches” that lead to the expression of hundreds of genes involved in inflammation.3 Ultimately, cytokines such as TNF-α (tumor necrosis factor alpha), IL-1β (interleukin 1 beta), and IL-6 (interleukin 6) are all upregulated as part of the inflammatory process. If LPS is continually present, then the inflammation becomes chronic, and chronic inflammation underlies many disease processes.
One limitation of the current study under review was that the duration was only 4 weeks. If the changes seen in the prebiotic group continue over time, and the presumed reduction in systemic inflammation occurs, then one would expect that many chronic inflammatory conditions may abate. This could include common complaints such as pain from osteoarthritis as well as more insidious (and painless) processes such as atherosclerosis. Indeed, a similarly designed study that includes quality-of-life measures, pain scales, and additional laboratory measures of inflammation over a more extended period of time could be informative.
There is 1 caveat to the product used in this study. It contained just over 34% lactitol, a sugar alcohol sometimes used as a sweetener. Inulin, which made up the majority of the prebiotic used in this study, is a fructan. A subset of persons may not tolerate these fermentable carbohydrates, such as those with small intestinal bacterial overgrowth (SIBO) or irritable bowel syndrome (IBS). While practitioners must be cautious recommending fibers in this population, the ultimate goal is for complete tolerance to all prebiotics as a part of a healthy, diverse plant-based diet. Tolerance of fermentable carbohydrates, including all FODMAP (fermentable oligo-, di-, monosaccharides, and polyols) foods, should always be the goal. Removal or permanent avoidance of prebiotic foods, which may be required to relieve acute intestinal symptoms, should not be done long term. As this study implies, and clinical trials support, the ingestion of a broad array of prebiotics/soluble fibers is essential to overall health and disease prevention.
- Schumann RR. Old and new findings on lipopolysaccharide-binding protein: a soluble pattern-recognition molecule. Biochem Soc Trans. 2011;39(4):989-993.
- Zweigner J, Schumann RR, Weber JR. The role of lipopolysaccharide-binding protein in modulating the innate immune response. Microbes Infect. 2006;8(3):946-95
- Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem. 1999;274(16):10689-10692.