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This article is part of our special May 2021 issue. Download the full issue here.
Relation
Macnaughtan J, Figorilli F, García-López E, et al. A double-blind, randomized, placebo-controlled trial of probioticsLactobacillus caseiShirota in patients with stable cirrhosis.Nutrients. 2020;12(6):1651.
Study objective
To determine if probioticLactobacillus caseiShirota (LcS) has a positive effect on neutrophil function and infection rates in patients with liver cirrhosis compared to placebo
Draft
A double-blind, randomized, placebo-controlled trial in 2 hospitals in the UK
Participant
Investigators examined 110 patients and included 92 with cirrhosis of any etiology at 2 hospitals. These patients had relevant clinical findings consistent with a diagnosis of cirrhosis and a Child-Pugh score of less than 10. The patients were between 18 and 78 years of age and had abstained from alcohol consumption for 2 weeks before screening. They were randomly assigned (1:1) to either the intervention or placebo group, stratified by alcoholic and nonalcoholic cirrhosis etiology.
The exclusion criteria included:
- Child-Pugh-Score >10
- Aktive Infektion
- Antibiotikabehandlung 7 Tage vor der Einschreibung
- Magen-Darm-Blutung
- Verwendung von immunmodulierenden Mitteln
- Einsatz von Protonenpumpenhemmern
- Verwendung von Prä-, Pro- oder Synbiotika
- Kreatinin >150 mmol/l
- Hepatische Enzephalopathie II-IV
- Pankreatitis
- Organversagen
- Leberkrebs
- Schwangerschaft
Study parameters assessed
Patients in the intervention group received a 65 mL bottle of an LcS drink containing 6.5 billion colony forming units (CFU) bacteria (Yakult Europe) to be taken three times daily for 6 months. The placebo group was given a similar-looking and tasting drink that did not contain bacteria. Patients received 45 bottles every 2 weeks, with empty, used bottles as a measure of compliance. Investigators recorded clinical benchmarks including blood and biochemical tests at screening, days 0 and 14, and months 1, 3, and 6. They collected analytes relevant to intestinal hyperpermeability at months 0, 1, and 6.
Primary outcome measures
One of the primary endpoints in this study was change in neutrophil function. The investigators assessed this using isolation and coincubation methods to measure reactive oxygen species (ROS) production and the prevalence of phagocytosis. The additional primary endpoint included the occurrence of infections assessed by routine clinical blood chemistry.
Secondary endpoints included plasma cytokine profile concentration at various intervals until completion at 6 months. Researchers assessed intestinal hyperpermeability using urinary lactulose-rhamnose ratio, venous endotoxin concentrations, and bacterial DNA identification using polymerase chain reaction (PCR) testing. The final secondary outcome was the quality of life assessment, which was performed using the standardized SF-36 tool.
Key insights
Overall, no significant differences in neutrophil function were observed between the intervention and placebo groups. In patients with atypical neutrophil function at baseline, 6 months of LcS treatment resulted in a significantly higher outcome of ROS production compared to the placebo arm [1403(1214-1821) versus 1168.00(1014-1266),P=0.02]. This suggests improved neutrophil function in this subgroup.
No significant changes in infectious episodes were noted between the randomized groups at the end of the study. Intestinal hyperpermeability was also within the normal range in both groups, with bacterial DNA positivity being 10.1% (placebo group) and 8.1% (LcS group).
The most important result is a positive change in the cytokine profile in all participants in the LcS group of the study.
Results with plasma cytokine concentrations were not significantly different for the vast majority of specific cytokines examined in the study. LcS was observed to increase mean plasma interleukin 1 beta (IL1B;P= 0.04) and monocyte chemotactic protein-1 (MCP-1;P=0.04) concentration in the alcoholic subgroup. Further observations revealed a decreased concentration of interleukin 17A (IL17A) in the non-alcoholic cohort (P=0.02). Macrophage inflammatory protein-1 beta (MIP-1β) levels were decreased throughout the LcS at 6-month intervals (P=0.04).
The 36-item Short Form Health Survey (SF-36) scores assessing quality of life showed no significant differences between the two study arms.
Practice implications
In the ever-evolving landscape of understanding the role of the human gut microbiome, a significant portion of the clinical and scientific dialogue has turned to the role played between the gut and the immune system.1This dialogue extends to the physiological mechanisms of chronic alcohol consumption and the effects it has on the gut microbiome. This in turn brings forward a body of evidence that elucidates the mechanisms of how altered flora contributes to alcohol-related liver disease.2
Given that an imbalance in the gut microbiome has been observed in liver cirrhosis, the progression of this study is logical and intriguing. This logic is now countered by another line of thought that postulates that intestinal dysbiosis can be linked to alcoholic liver disease. The health of the gut microbiome is critical as dysbiosis leads to intestinal inflammation and liver damage, and subsequent restoration of the microbiota with approaches such as promoting the abundance of commensal bacteria could be beneficial to ameliorate disease progression.3
The researchers in this study seek to further determine whether LcS can influence immune function to ultimately provide therapeutic benefit from probiotic use in patients with cirrhosis, both alcoholic and non-alcoholic. This was motivated by previous evidence on LcS in a smaller study suggesting a positive correlation.4While the study concludes that a specific mechanism of action, neutrophil activation, is not noticeably affected, it is important to note that a subset of participants was positively affected. In those who had baseline neutrophil activity below normal, this activity improved to more normal and expected levels. This is consistent with the open label pilot study mentioned above.4No side effects were observed and there was no increase in infections in all 92 participants, supporting the safety of LcS in this patient group.
The most important result is a positive change in the cytokine profile in all participants in the LcS group of the study. This suggests that restoring gut health causes downregulation of inflammatory cytokines; However, the mechanism of action appears to be independent of factors related to intestinal hyperpermeability. This raises further questions for possible studies in the future.
Further questions, both in the area of clinical practice and study design, bring a number of additional questions to the fore. Are all probiotics produced the same quality and does this affect the results? Clinical practitioners will suggest that their patient results are evidence of this concept and that reputable sources of therapeutic probiotics need to be considered. Second, the singularity or diversity of probiotic species should be considered, as increasing evidence suggests that gut microbiome diversity correlates with improved health outcomes.5To this end, methods for gastrointestinal (GI) biome mapping, stool culture, and other objective assessments of the gut microbiome should be considered. Finally, the dose-dependent effect must be taken into account when selecting therapeutic probiotics and their ability to deliver the desired CFU. Clinical observations and case studies suggest that interventions with higher CFU correlate with improved outcomes; However, there are clear precautions and contraindications, and the “more is better” approach has its risks and limitations.6GI mapping also becomes a critical tool in this regard.
Clinicians have several emerging scientific findings and clinical findings that they must balance when implementing probiotics and restoring the gut microbiota. The benefits clearly include, but are not limited to, improved liver health and immune function.