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Gut-microbiota manipulation

gut microbiome

Nowadays, some strategies like probiotics, prebiotics, post biotics, synbiotics or fecal microbiota transplantation (FMT) rely on adding individual, several, or a whole consortium of living microbial organisms to exclude disease-causing microbes and provide health-promoting benefits. Moreover, bacteriocins and bacteriophages present another potential strategies to remove specific pathogens associated with the onset of a particular diseases; however, their exploration as therapeutics in humans is still in its infancy.

Gut-microbiota targeted therapeutics in IBD

The therapeutic potential of these agents in inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn’s disease (CD), has been evaluated in a meta-analysis of 32 randomized controlled trials (RCTs). The authors found that these therapeutics considerably increased the number of beneficial intestinal bacteria (particularly Bifidobacterium), induced or maintained IBD remission and lowered UC disease activity index whilst not affecting IBD recurrence. Subgroup analyses showed that combining probiotics and prebiotics with conventional therapies was more effective in reducing these parameters than traditional treatments alone, while synbiotic treatment seemed to be more effective than prebiotics and probiotics alone. Additionally, the study suggested that probiotics containing Bifidobacterium, Lactobacillus, or more than one bacterial strain were more effective as IBD therapeutics and proposed doses from 10۱۰ to 10۱۲ colony forming units (CFU)/day as reference dose. The severity of inflammation and disease activity has also been proposed to influence the effectiveness of microbiota-targeted therapeutics in IBD.

Moreover, the data could suggest that the microbiota-modulatory efficacy of prebiotics decreases going from healthy, at-risk subjects to those with inactive and active IBD, indicating their potential in IBD primary prevention and treatment in a less inflamed gut.

Gut-microbiota targeted therapeutics in diarrhea

The effect of probiotics on chronic diarrhea, associated with different intestinal disorders like irritable bowel syndrome (IBS) and functional diarrhea, was evaluated. Yang et al have shown that intake of Lactiplantibacillus plantarum CCFM1143 for 4 weeks can be effective in managing chronic diarrhea symptoms in patients compared to placebo (maltodextrin). Moreover, it has been demonstrated that prebiotic consumption decreases the abundance of Bacteroides and Eggerthella, increases the abundance of beneficial species like Akkermansia, Terrisporobacter, and Anaerostipes, and stimulates acetic and propionic acid production. These data suggesting the potency of this probiotic strain and prebiotic can improve the microbiota imbalance and clinical symptoms in functional bowel disorders.

Gut-microbiota targeted therapeutics in Helicobacter pylori infection

The therapeutic potential of probiotics alone or in combination with standard treatments has also been evaluated in Helicobacter pylori infection. One study showed that consumption of a probiotic drink containing fermented milk with Lacticaseibacillus paracasei CNCM I-1518 and I-3689, L. rhamnosus CNCM I-3690, and four yogurt strains for 28 days induced faster gut microbiota recovery after H. pylori eradication, reducing the abundance of potentially pathogenic bacteria (e.g., Escherichia-Shigella and Klebsiella) and increasing fecal SCFA generation compared to the control drink. Another study evaluated the therapeutic effects of a probiotic including Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus, provided alone or in combination with quadruple eradication therapy (PPI, bismuth, and two antibiotics) for 2 weeks, on gastric microbiota recovery in H. pylori-infected individuals. Results showed that 2 months after treatment, the quadruple therapy did not restore gastric microbiota of H. pylori-positive subjects to an uninfected state; however, adjuvant probiotic therapy contributed to its recovery by improving microbial diversity, reducing the abundance of potentially harmful bacteria (e.g., Fusobacterium, Campylobacter and Proteobacteria) and increasing the beneficial bacteria (e.g., Lachnospiraceae, Ruminococcaceae, Eubacterium ventriosum). By contrast, probiotic monotherapy was ineffective in H. pylori abolition and failed to restore gastric microbiota, with observed alterations in microbiota structure, increased putative pathogenic bacteria, and no induction of beneficial bacteria.

written by: Dr.Nazila Kassaian

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?What is Paraprobiotic

Paraprobiotics or immobilized probiotics, are kind of postbiotics which when ingested, may have the ability to exert positive biological responses and restore intestinal homeostasis in a similar manner to probiotics. Paraprobiotics are currently being referred to as modified, inactivated, non-viable, para- or ghost probiotics. Paraprobiotics, the immobilized version of probiotics are gaining traction in recent years due to the concerns about the possibility of low tolerance of probiotics, especially in pediatric populations and in severely ill or immunocompromised patients.  Paraprobiotics seem to have similar beneficial properties as live probiotics with fewer of the constraints associated with unstable, diminishing bacteria.

Production of paraprobiotics

Paraprobiotics could be generated using different methods including: Heat-inactivation, Ultraviolet-inactivation, Chemical treatment (e.g. formalin), Gamma-irradiation, and Sonication. In most cases, heat treatment is considered the method of choice for deactivating probiotic strains. The effect that different types of inactivation have on bacterial structure and components as well as the maintenance of probiotic properties requires further research.

Mechanism of action

The mechanisms of action for paraprobiotics is less understood, though the possible mechanisms include immune system regulation and interference with pathogen attachment to host cells. Limited research hypothesizes that immobilized paraprobiotics release key bacterial components, such as lipoteichoic acids, peptidoglycans, or exopolysaccharides which exhibit key immunomodulation effects and antagonizing properties against pathogens.

General paraprobiotics applications

 Emerging clinical and pre-clinical studies have demonstrated that paraprobiotics play a role in general health and well-being and for improving host immune function like that of probiotics. It is proved that paraprobiotics induce changes in the gut microbiome and the altered gut microbial composition is associated with increased levels of innate and acquired immunity biomarkers. Paraprobiotics also seem to exhibit antioxidant effects and has indicated its potential applications in food and pharmaceutical industries.

Paraprobiotics applications in clinical treatment

Paraprobiotics (mostly heat-killed) seem to be beneficial for the following clinical applications:

  • Gastrointestinal diseases; bloating, pediatric disorders, infantile colic, diarrhea, extra-intestinal diseases
  • Upper respiratory tract infections
  • Ocular disorders including eye fatigue
  • Asthma
  • Inflammatory bowel diseases (ulcerative colitis)
  • Colitis-associated colorectal cancer
  • Type 2 Diabetes (improved glycemic parameters)
  • Liver injury
  • Atopic dermatitis
  • Influenza viruses
  • Cardiac injury

Species used as paraprobiotics

Many species of bacteria have been identified to have benefits as paraprobiotic strains including:

Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Enterococcus faecalis,  Lactobacillus acidophilus, , Lactobacillus bulgaricus, Lactobacillus casei , Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillus fermentum, Lactobacillus johnsonii, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri , Lactobacillus salivarius, Lactococcus lactis , Streptococcus salivarius  and subsp. thermophilus.

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Fecal Microbiota Transplant in Pediatric Inflammatory Bowel Disease

FMT in children

This study discusses the results, limitations, and future considerations involved in conducting the first fecal microbiota transplant (FMT) trial for ulcerative colitis (UC) in children. A randomized controlled trial was conducted in 25 pediatric patients with ulcerative colitis (13 in the FMT and 12 in the placebo arms). The composite clinical endpoint of this study was reached in the majority (92%) of the recipients assigned to FMT compared with 50% assigned to placebo at week 6. This trial  highlighted important lessons associated with FMT trials in children.

Indeed, this study offers the first trial evidence that FMT may have a role in pediatric UC management.

The Study on Fecal Microbiota Transplant in Inflammatory Bowel Disease

While drug development continues to focus on modifying dysregulated intestinal immune pathways, targeting enteric microbiota has become increasingly attractive. Four randomized controlled trials of fecal microbiota transplant in UC have been conducted since 2015. Three demonstrated clinical and endoscopic remission in adult patients with active UC, and a 2017 systematic review reported a pooled rate of clinical and endoscopic remission of 27.9%, with a number needed to treat of 5.

Fecal Microbiota Transplant In Pediatric Ulcerative Colitis

Figure ۱. Flow of screened, and randomized patients in the trial. FMT, fecal microbiota transplant; mITT, modified intention to treat; UC, ulcerative colitis.

Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant in pediatric Ulcerative Colitis

In this study, during a 36-month, 48 patients, aged 4 to 17 years, with active UC were referred by the patients’ primary pediatric gastroenterologists for screening across 3 pediatric IBD centers in Canada. Of these, 23 patients were excluded because of medication changes, unable to fulfill trial requirements FMT treatments, unspecified reasons, and remission by trial commencement. Ultimately, 52.1% (n= 25) of referred patients entered the trial. Patients were randomized to FMT (n = 13) or placebo (n = 12) arms. The composite clinical endpoint (improvement in pediatric UC activity index, C-reactive protein, or fecal calprotectin) in 92% (11 of 12) assigned to FMT vs 50% (6 of 12) assigned to placebo at week 6 was seen (risk ratio, 1.8; 95% CI, 1.1–۳.۷). At 12 months, 75% (9 of 12) had maintained clinical response. β-Diversity trended higher from baseline to week 6 in FMT vs placebo arms.

FMT In Pediatric Ulcerative Colitis

Supplementary Figure ۱. Change in microbiota composition between patients receiving fecal microbiota transplant vs placebo from baseline to week 6. The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; the vertical lines mark minimum and maximum of all the data, and the circles indicate individual data points.