25 Aug 22
The microbiome has been a potential source of treatment and interest to physicians since the Chinese first documented use of faecal microbiota transplantation (FMT) over 1,700 years ago. Present day research and clinical practice is highlighting the possibility of manipulation of the microbiome to alter disease course and potentially provide a guide to a healthier life.
Our knowledge of the microbiome and its effects has increased greatly over the last 20 years with implications for treatment of a wide range of diverse diseases.
However, it is still the treatment of recurrent C. difficile infection (CDI) that has established proof from randomised controlled studies [1] and is the best understood in terms of changes in the microbiome as a rationale for disease appearance and focus of treatment.
For instance, it has been shown that bile acids in the gastrointestinal tract affect the growth of C. difficile – In vitro primary bile acids stimulate germination, whereas secondary bile acids inhibit germination. Patients with CDI have an altered faecal bile acid composition in the colon, with secondary bile acids in higher concentrations in faecal samples from controls compared to patients with CDI, and primary bile acids elevated in patients with recurrent disease compared to those experiencing a first episode of CDI [2]. The use of FMT redresses the imbalance between bile acids, promoting the levels of secondary bile acids to those seen in healthy subjects and aiding the recovery from recurrent CDIs.
This is not the whole story however – metabolomic analyses using a murine model have shown that gut colonization with C. difficile leads to shifts in detectable metabolites and highlights the importance of increases in specific nutrient availability in the gut for C. difficile colonization and pathogenesis following antibiotic use [3].
Conditioning prior to stem cell transplantation and antibiotic treatment causes gut dysbiosis and is related to an increased incidence (5 to 9-fold) of CDI compared to a hospitalised patient population. Use of the narrow spectrum CDI antibiotic fidaxomicin in the hematopoietic stem cell transplantation (HSCT) population for prevention of CDI has not yet proven conclusive benefit, although it did demonstrate a significant reduction in C. difficile associated diarrhoea (CDAD) at 30- and 60-days post treatment in HSCT patients with confirmed CDAD [4].
FMT is also used successfully for the treatment and/or prevention of CDAD in allogenic HSCT patients. The recent review of studies addressing FMT for allogenic HSCT treatment [5] highlighted the limited number of studies performed and the small numbers of patients evaluated – much like the situation for FMT as treatment for recurrent CDI pre-2000.
Moving on from direct effects on specific bacteria within the microbiome to modulating disease progression via changes in the microbiome.
It is known that 40% to 50% of patients undergoing allogenic HSCT will have Graft versus Host Disease (GvHD) [6]. GvHD is associated with limited gut microbiota diversity, a situation seen in a proportion of patients pre- and post-HSCT treatment due to conditioning and prophylactic use of antimicrobials. Low gut microbiota diversity is associated with lower calorie intake, use of broad-spectrum antibiotics (selective gut decontamination and treatment of infections) and use of high intensity treatment prior to the HSCT procedure. Modulation of gut microbiota could be a potential therapeutic intervention to treat or even prevent GvHD in allogenic HSCT patients. The gut microbiota can be temporarily manipulated by the choice of the antibiotics and the use of probiotics/prebiotics and FMT to repopulate the gut with commensals. FMT has potential to become a treatment for a greater number of allogenic HSCT GvHD patients, but widespread use is limited by lack of large-scale studies to identify the patients who will benefit most and safety concerns of pathogen transmission (bacterial and viral) [5].
The recent article in Nature [7] highlights the potential for FMT to enhance the effects of the novel immunotherapy approaches and alleviate some of the treatment-limiting adverse effects. The Nature article builds on the growing evidence that manipulation of the microbiome can enhance the effects of checkpoint inhibitors (CPIs). Gopalakrishnan showed that the abundance of gut bacteria belonging to the Ruminococcaceae family was associated with the clinical response to anti-PD-1 treatment in patients with melanoma [8]. Katayama performed a retrospective analysis of 40 non-small cell lung cancer (NSCLC) patients to investigate the association between stool abnormalities and CPI efficacy. The disease control rates were found to be significantly lower in NSCLC patients with stool abnormalities (i.e., patients with constipation or use of a laxative) than in those without stool abnormalities. The time to treatment failure with CPI treatment was shorter in NSCLC patients with stool abnormalities [9]. The use of simple markers like stool frequency could provide better guidance to physicians on the appropriate use of CPIs.
In addition, known adverse events (AEs) from CPIs have been shown to be alleviated by concurrent use of FMT, as prior AEs in these patients due to CPI treatment stem from gut dysbiosis.
As with FMT for CDI, there remains the issue of optimal preparation to enhance the efficacy of CPIs for individual patients and the need to screen samples for a wide variety of potential pathogens that may be transmissible form donors to recipients with possible long-lasting deleterious effects.
Studies have shown the link between ulcerative colitis and the gut microbiome. Several studies have validated the approach of manipulating the microbiome composition with freeze dried oral FMT treatment, to achieve clinical remission as reported by Crothers [10].
Influence of microbiome on immunity
Several approaches and approved products have shown the potential for the influence of the microbiome and gut receptors on immunity. Mixtures of bacterial lysates (e.g., Bronco-Vaxom®, OM Pharma) have been used for many years for the prevention of respiratory tract infections in adults and children. Studies with these agents are on-going looking at their use along the atopy march – in atopic dermatitis and wheezing/asthma. It is thought that these lysates act through primary mucosal immune cells in Peyer’s patches by mechanisms involving innate immune mechanisms (Toll-like receptors, TLR-2 and TLR-4). The TLRs activate and cause proliferation of immune cells (B lymphocytes, dendritic cells, macrophages, regulatory T cells) that lead to positive effects in the airways by a number of mechanisms – stimulation of secretory immunoglobulin A; switch of T helper cell 1 (Th1)/Th2 balance towards Th1; increasing Treg control; decreasing infection sensitivity – to prime the immune system without increasing risk of autoimmune reactions [11].
This indirect influence on the immune system has potential for use across a number of diseases all with potential for microbiome influence/effects.
Over the last decade, the gut microbiome has emerged as one of the critical bi-directional regulators of brain function. Known as the gut-brain axis (GBA), it has been shown to impact the central nervous system (CNS)with effects on mood, cognition, and motor and autonomic activity. The mechanisms underlying GBA communications involve neuro-immuno-endocrine mediators.
Both clinical and experimental evidence suggest that microbiota has an important impact on GBA, interacting not only locally with intestinal cells and enteric nervous system, but also directly with CNS through neuroendocrine and metabolic pathways. Evidence show that probiotics and prebiotics beneficially modulate microbial and immune pathways to improve neurological disorders and brain functions [12] that could translate into viable treatments for Alzheimer’s disease and other neurological conditions like stroke.
In July 2022, Seed Health and Axial Therapeutics announced a collaboration to translate breakthrough research into the gut from Sarkis Mazmanian’s lab at California Institute of Technology into novel probiotics for a range of cognitive and neuropsychiatric outcomes including autism and Parkinson’s disease.
Advancements in knowledge of the microbiome and its effects now mean that as Ramnik Xavier said the challenge is that “Microbiome studies need to move from making associations to determining function and causation.” [13].
This plays very much into the current and future approaches that regulatory authorities around the world will need to help companies developing a wide variety of modulators of the microbiome.
The regulatory landscape is still uncertain due to limited guidance from FDA & EMA on development of FMT products and as yet no companies have achieved regulatory approval for natural or synthetic FMT approaches.
Global Data has identified 23 microbiome-targeting pipeline agents in clinical development (Phase 1 through to pre-registration) for the treatment of various infectious diseases in the 7 major markets. The majority of products are focused on CDI, with a number of these at Phase 3 or pre-registration stage. There are a number of companies with products in development for CDI (e.g., Ferring/Rebiotix (RBX2660), Seres (SER109), Finch (CP101)). It is interesting to see that despite regulatory uncertainties for approval, RBX-2660 has achieved orphan and breakthrough therapy status as well as fast track in the United States [14].
The regulatory challenges have historically presented problems for investment, but the increasing clinical data and better understanding of functional aspects of microbiome manipulation mean that this is becoming easier. Recently, Microbiotica raised $67 million (March 2022) to fund their Phase 1b clinical trials in cancer and ulcerative colitis. Microbiotica have in development their Live Bacterial Therapeutic MB310, a mixture of 10 bacterial species, for the treatment of ulcerative colitis.
The small and medium scale microbiome companies focused on CDI and other diseases are now seeing interest from Big Pharma (Pfizer, Janssen, Takeda) and other large companies (Nestle), with partnerships being announced over the last 5 years.
All this movement in basic understanding of the biology through to successful clinical trials for regulatory approval should bode well for the establishment, across a diverse selection of diseases, of microbiome-focused therapeutics in mainstream medicine in the years to come. Novel regulatory pathways and endpoints will need to be discussed with authorities, who are expected to be open to reasoned argument based on supportive pre-clinical/clinical data supported by validated manufacturing processes.
1. van Nood, E., et al., Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med, 2013. 368(5): p. 407-15.
2. Baktash, A., et al., Mechanistic Insights in the Success of Fecal Microbiota Transplants for the Treatment of Clostridium difficile Infections. Front Microbiol, 2018. 9: p. 1242.
3. Fletcher, J.R., et al., Shifts in the Gut Metabolome and Clostridium difficile Transcriptome throughout Colonization and Infection in a Mouse Model. mSphere, 2018. 3(2).
4. Mullane, K.M., et al., A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation. Clin Infect Dis, 2019. 68(2): p. 196-203.
5. Pession, A., et al., Fecal Microbiota Transplantation in Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Systematic Review. J Pers Med, 2021. 11(2).
6. Noor, F., et al., The Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials. J Innate Immun, 2019. 11(5): p. 405-415.
7. Erdmann, J., How gut bacteria could boost cancer treatments. Nature, 2022. 607(7919): p. 436-439.
8. Gopalakrishnan, V., et al., Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2018. 359(6371): p. 97-103.
9. Katayama, Y., et al., Impact of bowel movement condition on immune checkpoint inhibitor efficacy in patients with advanced non-small cell lung cancer. Thorac Cancer, 2019. 10(3): p. 526-532.
10. Crothers, J.W., et al., Daily, oral FMT for long-term maintenance therapy in ulcerative colitis: results of a single-center, prospective, randomized pilot study. BMC Gastroenterol, 2021. 21(1): p. 281.
11. Pasquali, C., et al., Enhanced Mucosal Antibody Production and Protection against Respiratory Infections Following an Orally Administered Bacterial Extract. Front Med (Lausanne), 2014. 1: p. 41.
12. Schachtle, M.A. and S.P. Rosshart, The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research. Front Cell Neurosci, 2021. 15: p. 698172.
13. Emily, H. Researchers unravel how one gut bacterium influences immunity. 2022 [cited 2022 22 August]; Available from: https://www.news-medical.net/news/20220727/Researchers-unravel-how-one-gut-bacterium-influences-immunity.aspx.
14. Global Data, Thematic Research: Microbiome-Targeting Therapeutics in Infectious Diseases May 2022.
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