Prebiotic relieves constipation and alters the microbiota

Relation

Chu JR, Kang SY, Kim SE, Lee SJ, Lee YC, Sung MK. The prebiotic UG1601 alleviates constipation-related events associated with gut microbiota: a randomized placebo-controlled intervention trial.World J Gastroenterol. 2019;25(40):6129-6144.

Study objective

To evaluate the effectiveness of a specific prebiotic (UG1601) on symptoms of mild constipation and microbiota composition.

Draft

Randomized, double-blind, placebo-controlled trial.

Participant

The researchers divided 40 participants into either an intervention arm or a placebo arm (n=20). Participants consisted of 10 men (mean age 25 years; mean body mass index (BMI) = 23.43) and 30 women (mean age 24 years; mean BMI = 21.33).

Inclusion criteria were 1 or more of the following for more than 3 months and less than 6 months:

• Gefühl einer unvollständigen Evakuierung > 25 % der Zeit
• Stuhlfrequenz < 3 Mal pro Woche
• Pressen beim Stuhlgang > 25 % der Zeit

Exclusion criteria included the presence of intestinal disease, history of major surgery, use of probiotics, prebiotics, or synbiotics within the last month, and use of antibiotics during the 3 months prior to study entry. The study also excluded volunteers who smoked, were pregnant or breastfeeding.

intervention

Participants received either a prebiotic (UG1601) consisting of 61.5% inulin, 34.6% lactitol, and 3.9% aloe vera gel, or an identical-looking placebo containing maltodextrin. Participants took 13 grams of either the prebiotic or placebo dissolved in water daily for 4 weeks (the researchers did not specify the time of day).

Primary outcome measures

Time points for data collection were baseline, 4 weeks and 2 weeks post-intervention (6 weeks from baseline). Participants completed a food log 3 days per week. Blood and stool samples were collected at baseline and at the end of the intervention period (4 weeks).

Bowel movements have always been an essential part of well-being, and this study provides further evidence that they are indeed central to health.

Bowel movement (BM) frequency was recorded 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.

Assessment of gastrointestinal (GI) symptoms

Participants reported the following parameters as worsened, unchanged, or improved:

• Stuhlkonsistenz
• Gefühl der unvollständigen Entleerung
• Für die Evakuierung benötigte Zeit
• Blähung

The researchers 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. The researchers determined the relative abundance of SCFA-producing bacteria using 11 representative bacteria:

• Acetat produzierende Bakterien Bifidobacterium longum, Bifidobacterium adolescentis (B. adolescentis), und Bifidobacterium catenulatum (B. catenulatum);
• Propionat produzierende Bakterien Prevotella ruminicola (P. ruminicola), Propionibacterium acidipropionici (P. acidipropionici), und Propionibacterium freudenreichii (P. freudenreichii);
• Butyrat-produzierende Bakterien Faecalibacterium prausnitzii (F. prausnitzii), Clostridium leptum (C. leptum), und Roseburia hominis (R. hominis);
• Präbiotika-empfindliche Bakterien Bifidobacterium lactis (B. lactis) und Lactobacillus acidophilus (L. acidophilus)

Key insights

The stool frequency score improved with both the prebiotic (P=0.001) and the placebo (P=0.002) groups after 4 weeks of intervention compared to baseline. While the prebiotic group had fewer GI symptoms, this did not reach statistical significance between groups.

The serum LPS concentration and the CD14 concentration decreased in both groups over the 4-week study, but reached 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 compared to the reduction in the placebo group (P<0.001).

SCFA concentrations did not differ between the two groups after 4 weeks. The only bacterial species that increased significantly was the butyrate-producing speciesR. hominis(which increased by 15.3%) after 4 weeks in those who received the prebiotic. This increase was significantly greater than that 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 reduction in their evacuation time and whose serum CD14 concentration decreased by >10%. Subgroup analysis of responders compared to nonresponders revealed many differences in minor taxa between groups, such as: B. a decrease in the trunkFirmicutes(P=0.031), the classClostridia(P=0.058) and the orderClostridia(P=0.058) and increases in several other bacteria includingPrevotella stercorea,Bacteroides plebeiusandBacteroides stercoris.

Practice implications

In this study, there were measurable changes in microbiota and bowel movement frequency after just 4 weeks of soluble fiber supplementation. A change in gut function with 13 grams of supplemental fiber may not be surprising to practitioners. The net effect of more frequent evacuations and microbial population shifts reduced endotoxemia (i.e., LPS and its receptor, CD14, in the circulation). This result is the most fascinating aspect of the study. A reduction in endotoxemia is likely to have effects throughout the body. Bowel movements have always been an essential part of well-being, and this study provides further evidence that they are indeed central to health.

Lipopolysaccharides (LPS), which are a component of the cell membranes of gram-negative bacteria, are often synonymous with endotoxins. Once the bacteria are damaged (i.e., lysed), LPS is recognized as a pathogen-associated molecule responsible for initiating host defense against these bacteria.¹The immune response is stimulated when LPS binds Toll-like receptors (TLRs), a class of proteins that trigger inflammation. In bacterial infections, acute inflammation is necessary to eliminate the pathogen and eliminate 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 the circulation? The presence of endotoxins (i.e. LPS) in the blood is the definition of endotoxemia. Not surprisingly, LPS is higher when voiding frequency is lower, due to the absorption of intestinal bacterial components, including LPS, as bacteria go through their life cycle in the intestine. 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 bacterial species in the gut or the adsorption of LPS to soluble fiber that led to a reduction in circulating LPS is a matter of science. From a clinical perspective, this combination of soluble fiber achieved a desirable effect, reducing endotoxemia.

LPS is a remarkably reliable stimulator of the inflammatory process, as suggested by its extensive use in experimental animal models of systemic inflammation. The cascade is as follows: LPS binds TLR-4, which is the mediator in the activation of NF-κB (nuclear factor kappa light chain enhancer of activated B cells) and AP-1 (activator protein 1), both master cell cells. switches” that lead to the expression of hundreds of genes involved in inflammation.³Ultimately, 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. When LPS is continuously present, inflammation becomes chronic, and chronic inflammation underlies many disease processes.

A limitation of the current study was that the duration was only 4 weeks. If the changes observed in the prebiotic group persist over time and the hypothesized reduction in systemic inflammation occurs, then one would expect many chronic inflammatory conditions to resolve. These can 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 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 people cannot tolerate these fermentable carbohydrates, such as: B. People with small intestinal bacterial overgrowth (SIBO) or irritable bowel syndrome (IBS). While practitioners must be cautious about recommending fiber in this population, the ultimate goal is complete tolerance to all prebiotics as part of a healthy, diverse plant-based diet. Tolerance to fermentable carbohydrates, including all FODMAP foods (fermentable oligo-, di-, monosaccharides and polyols), should always be the goal. Removal or long-term avoidance of prebiotic foods, which may be necessary to relieve acute intestinal distress, should not be done long-term. As this study suggests and clinical trials demonstrate, consuming a broad spectrum of prebiotics/soluble fiber is essential for overall health and disease prevention.