Microbiome Therapeutics

Last year, I wrote a short piece on the microbiome that was informational, but not extensive.  Since then, there has been an explosion in work done on this subject, and the American College of Gastroenterology (ACG) has recently produced a monograph on microbiome therapeutics (American College of Gastroenterology Monograph on Microbiome Therapeutics Am J Gastroenterol 2024;119). What follows is a synopsis/summary of this publication.

Non-prescription microbiome-based therapy

  1. Prebiotics: These are substrates that are selectively used by host microorganisms to effect a health benefit. Examples are fermentable dietary fiber, fructosaccharides and galactosaccharides, inulin, human milk oligosaccharides and polyunsaturated fatty acids.
  2. Probiotics: Live organisms which, dosed in adequate amounts, confer a health benefit for the host. Lactobacillus and bifidobacterial species are examples. These are also considered food products; thus, standardization of their viability and efficacy is limited.
  3. Synbiotics: Mixtures of live microorganisms and substrates selectively used by host microorganisms to confer a health benefit on the host.
  4. Postbiotics: Preparation of inanimate microorganisms (inactivated microorganisms but not their microbial metabolites) and/or their components, which confer a health benefit to the host.

The mechanism of action of these non-prescription microbiome-based therapies is beyond the scope of this current piece.

Conditions possibly amenable to non-prescription microbiome-based therapy

  1. Acute infectious gastroenteritis (AGE): Probiotics have mainly been studied in children to reduce the duration and severity of diarrhea in AGE. Probiotics do not seem to reduce duration or severity of AGE/diarrhea in North American children, and cannot be recommended for this condition. Overall, because of limited evidence, probiotics, synbiotics and postbiotics cannot be recommended for treatment in AGE. More studies are needed.
  2. Antibiotic associated diarrhea (AAD): Current literature conditionally supports the use of specific strains of probiotics, including lactobacillus, bifidobacterium species and saccharomyces boulardi, with a modest benefit in preventing or reducing the duration of AAD in adults and children with no serious adverse side effects. Due to limited studies/evidence, prebiotics or synbiotics cannot be recommended.
  3. Clostridium difficile infection (CDI): There has been significant interest in using probiotics to decrease the incidence of CDI in patients on antibiotic therapy. High-quality studies in this area are lacking, leading to little evidence and conflicting opinions. ACG recommends against probiotics for the primary prevention of CDI in patients on antibiotic therapy, and against probiotics for prevention of recurrent CDI. Prebiotic therapy may delay reconstitution of the normal gut flora after antibiotic therapy, potentially contributing to dysbiosis, as seen in recurrent CDI.
  4. Lactose intolerance: Prebiotics and probiotics have been studied. Based on current evidence, neither can be recommended for treatment of lactose intolerance.
  5. Irritable bowel syndrome (IBS): Available studies suggest probiotics may not be effective in global IBS symptoms, but may reduce specific symptoms, such as abdominal pain and bloating. Available studies do not support the use of prebiotics or synbiotics in IBS patients. Further research is needed to better target patients who will most benefit from probiotic therapy.
  6. Chronic constipation (CIC): In pooled analysis of 30 patient trials, bifidobacterium lactis, but not other probiotic strains, may increase stool frequency but not stool consistency. Overall, current evidence does not support the use of probiotics or synbiotics for CIC.
  7. Functional dyspepsia (FD): A few trials have looked at probiotics here. Lactobacillus and bifidobacterial species were studies in small studies. Overall, there is some evidence that certain probiotic combinations may improve post-prandial distress, but given considerable heterogeneity in probiotic products across studies, and the small study sizes, no definitive conclusions about the efficacy of probiotics in FD can be drawn.
  8. Inflammatory bowel disease (IBD): IBD is characterized by gut dysbiosis, and this, in turn, has led to interest in treatment with microbial therapeutics and fecal microbiota transplantation. There have been more studies in Crohn’s disease (CD) than ulcerative colitis (UC). Overall, current evidence does not support the use of prebiotics, probiotics or synbiotics for induction or maintenance therapy in CD or UC. The American Gastroenterology Association (AGA) recommends probiotic use in IBD only in the context of a clinical trial.
  9. Pouchitis (seen in patients who had colectomy with a “J” pouch): An 8-strain probiotic combination has a modest benefit for preventing an initial episode of pouchitis or for maintenance of remission. A small observational study did not demonstrate the probiotic combination to help maintain remission in patients with antibiotic-dependent pouchitis. Presently, practical use of probiotics in pouchitis in mainstream clinical practice is unclear.

Live biotherapeutic products (LBP)

  1. Fecal microbiota transplantation (FMT) restores deficiencies in the microbiota following treatment with antibiotics in patients with recurrent CDI. FMT has evolved from unregulated therapy to FDA-permissible use in cases of recurrent CDI that have not been responsive to standard therapy. lt has faced challenges due to lack of standardization in donor screening, manufacturing, product characterization and administration. Despite these hurdles, two new prescription microbiome therapeutics for recurrent CDI have received FDA approval.
  2. Fecal microbiota live-jslm (RBL, also known as Reybota). RBL is a standardized donor stool-derived microbiota-based rectally administered LBP that was the first live therapy approved by the FDA for prevention of recurrent CDI. RBL is indicated in prevention of recurrent CDI in patients 18 years or older following antibiotic therapy for recurrent CDI. Indications include adults who have had one recurrence (2 episodes) of CDI. RBL is not approved to treat an active infection, and it should be administered (single dose enema bag) after finishing a course of standard antibiotic therapy (vancomycin or fidaxomicin) for recurrent CDI and an antibiotic washout period of 24 to 72 hours.
  3. Fecal microbiota spores, live-BRPK (VOS): Shortly after FDA approval of Reybota, a second LBP was approved. VOS is the first oral LBP. Most patients after treatment with broad spectrum antibiotics have a resulting microbiome deficiency in firmicutes and bacteriodetes species. Firmicutes are prominent and plentiful in a healthy gut, and play a major role in anti-inflammatory activity, fortification of the gut barrier and augmenting gut immunity. When firmicutes species are deficient, the ability of the microbiota to resist infections such as recurrent CDI is weakened. VOS is a narrowed consortium of firmicutes spores encapsulated in a heat stable orally administered capsule. Doses administered, 4 capsules daily for 3 days, are derived from a single donor. These firmicute spores diversify the colonic microbiota and eradicate c. difficile spores. Indications for VOS are identical to Reybota.

Reybota and VOS are the first major successes in microbiome manipulation for specific disease states. Further research will hopefully allow these LBP to be used in non-recurrent CDI indications. From a GI standpoint, IBD and IBS are prime candidates.

Emerging indications for LBP

There has been increasing interest in non-infectious LBP applications in the world of gastroenterology. The interest in clinical trials for non-infectious indications has increased in the last decade. Trials have faced challenges regarding safety and efficacy. Potential long-term effects of LBP are unclear. Emerging indications for LBP in gastroenterology include:

  1. SIBO (small intestinal bacterial overgrowth)
  2. Disorders of gut-brain interaction
  3. IBS
  4. Graft versus host disease
  5. IBD
  6. Immune checkpoint inhibitor colitis


Hippocrates declared over 2,000 years ago that all disease begins in the gut. Dysbiosis may be, at least in part, the cause or enabler of many disease processes. CDI is a product of dysbiosis, and manipulation of the microbiome may be the answer. Microbiome diagnostics could unlock the mechanism of the pathophysiology of many diseases, GI and non-GI alike. Precision medicine using microbiome diagnostics could help chart the course for the proper treatment   of many diseases. Of critical importance to achieving these goals going forward is more research. ObjectiveHealth has 18 gastroenterology research partners who recognize the importance and power of microbial/microbiome modulation in health and disease, and look forward to contributing to the important research necessary to help usher in a new era in medicine.