Is there a place for faecal microbiota transplantation in chronic kidney disease?

Nicolas Benech, Laetitia Koppe · 2022 · 13 citationsRead the paper

The gut microbiota is a complex ecosystem composed of all the microorganisms that inhabit the digestive tract, including bacteria, viruses, parasites, archaea and fungi. It is identified as an essential cofactor in the pathophysiology of many diseases, some of which can lead to kidney damage, such as autoimmune diseases, diabetes and metabolic syndrome. Indeed, alterations of both gut microbiota composition and function have been described in patients with chronic kidney disease (CKD) [1, 2]. Most reliable changes described among various cohorts of CKD patients identify a decrease in bacterial diversity and a low microbial gene richness. This dysbiosis is characterized by an increase in pro-inflammatory and uraemic metabolite-producing bacteria belonging to the Proteobacteria and Fusobacteria phyla and Enterobacteriaceae family, and a decrease in anti-inflammatory and short-chain fatty acid (SCFA)-producing bacteria, including bacteria of the genus Faecalibacterium, Prevotella and Roseburia [2]. These compositional changes are also driven by multiple factors such as repetitive antibiotic treatments, phosphate- and potassium-binding agents, hospitalization and biochemical changes of the intestinal mucosal environment due to kidney failure. The CKD-associated dysbiosis leads to pathological host–microbial interactions that can contribute to disease progression and CKD-associated complications such as infection, cardiovascular events and metabolic complications and increase drugs toxicity and possibly kidney transplantation rejection [3]. Indeed, CKD patients have an increase in gut microbiota–derived uraemic toxins such as trimethylamine N‑oxide (TMAO), p-cresyl sulphate (PCS) and indoxyl sulphate (IS), whose elevated concentrations are associated with poor outcomes [4]. As several of these metabolites are poorly dialyzable and dialysis cannot be used in the majority of CKD patients, new therapeutic options are needed to reduce their production and accumulation. However, the consequences of intestinal dysbiosis in CKD are not limited to uraemic toxins accumulation. Bacterial fragments from the intestinal microbiota, such as lipopolysaccharides (LPSs), could have a negative impact in CKD. Recent developments in metagenomics, metatranscriptomics and metabolomics have successfully discovered thousands of microbial metabolites, such as secondary bile acids and SCFAs, that show differential expressions in CKD with potential deleterious effects. Strong data have demonstrated that intestinal microbiota–generated production (e.g. an increase in ammonium, thiols or trimethylamine or a decrease in SFCAs and succinate) have the potential to further damage muscle, kidney, hepatic and visceral adipose tissue through inflammatory, oxidative and fibrotic pathways [5]. Also, the imbalance of bile acid composition observed in CKD [1] can decrease the secretion of glucagon-like peptide-1, a key mediator in the gut–kidney axis with potential nephroprotective properties [6]. Furthermore, the increased incidence of intestinal infections, particularly Clostridioides difficile infection (CDI), in patients with CKD suggests a loss of the protective barrier function of the gut microbiota [7]. Indeed, according to various studies, CKD patients have a 2-fold increased risk of developing CDI, with a higher morbidity and mortality rate, compared with non-CKD patients [8]. By occupying nutrient and spatial niches within the intestine, host gut microbiota constitutes, in a healthy state, a true microbiological barrier to C. difficile colonization and infection that is impaired in CKD for various reasons (frequent hospitalization, antibiotics exposure, altered bile acid intestinal metabolism etc.). Similarly, increased permeability of the intestinal barrier (leaky gut) contributes to the development of subclinical inflammation and diabetic nephropathies through translocation of LPSs or specific bacteria (e.g. Klebsiella oxytoca) [9]. Finally, distinct gut microbiota compositions have been described in patients with acute or chronic rejection after solid organ transplantation. Preclinical models with germ-free and antibiotics-treated mice suggest that the presence of a complex gut microbiota can fuel autoimmunity after transplantation. The metabolism of drugs by the gut microbiota may also support various post-transplantation dosages of immunosuppressive drugs, as shown by the association between faecal abundance of Faecalibacterium prausnitzii in kidney transplant patients and the dose of tacrolimus needed to reach a therapeutic serum concentration [3]. Thus, targeting the gut microbiota at all stages of CKD appears to be a promising approach to restore the host–microbial symbiosis with potential benefit at numerous levels by improving immunity, cardiovascular risk and kidney function. FMT is defined as the transfer of the faecal ecosystem of a healthy donor to the gastrointestinal tract of a recipient to induce therapeutic effects. Currently it is the most efficient treatment to cure multiple recurrent CDIs and restore the microbial protective function to prevent CDI relapse. Stools preparations are usually administrated through enema, frozen capsule, colonoscopy or gastric/duodenal infusion, with a very good safety profile (mostly mild and transient gastrointestinal symptoms) [10]. Today, it is the only microbe-based therapy allowing the transfer of a complex ecosystem in the gut. Indeed, other microbes-targeting strategies are not able to induce a comparable global compositional switch with bacterial, fungal and virus engraftment. For example, broad-spectrum antibiotics can lower the plasmatic uraemic toxins level but result in a global decrease in the gut bacteria richness and diversity. In the same line, probiotics and genetically engineered bacteria intake are associated with partial gut microbial compositional switch, with variable effects from one subject to another ranging from no engraftment to sustained bacterial strains replacement [11]. Potential benefits of using FMT in the therapeutic arsenal for the prevention and treatment of CKD has been suggested by FMT experiments in rodents, highlighting the contribution of the gut microbiota in worsening uraemic toxins production, metabolic complications and kidney function. The transplantation of faeces from a CKD patient into antibiotic-treated rodents or germ-free mice has resulted in higher production of several uraemic toxins (i.e. PCS, IS and TMAO) and worsening of kidney fibrosis [1]. Similarly, germ-free mice transplanted with CKD mice faeces had increased concentrations of serum uraemic toxins (PCS and IS) and induced insulin resistance and sarcopenia [12]. More convincing from a therapeutic perspective, FMT from healthy mice to CKD mice was able to decrease serum PCS and improve glucose tolerance [13]. Thus all these preclinical data suggest that CKD-related toxins are at least partially mediated by the gut microbiota, and targeting its composition through FMT can tune their plasma levels with potential therapeutic effects. Despite many unknowns on its precise mode of action and its long-term safety, FMT has been used in daily practice for many years and promising results have been seen in an increasing number of indications, including inflammatory bowel disease and metabolic disorders. However, as the role of the gut microbiota varies depending the disease, a disease-specific approach may be needed for donor selection and FMT to ensure therapeutic benefits. When designing FMT trials in CKD patients, one will face many practical questions for which there has been no evidence-based answer until now: ‘At which stage of CKD would FMT be the most relevant?’ ‘Would it be at a later stage when uraemic toxins are the highest and/or before severe kidney disease to favour CKD prognosis?’ ‘How many FMTs should be performed to ensure a sustainable therapeutic effect?’ As described in other multifactorial diseases, repetitive FMT should be needed. ‘Should we propose a specific diet for the patients, such as high fibre intake and modification of the quality of protein?’ The properties provided by fibres (increased SCFA production; increased microbiota-produced succinate, which is a major intermediary in the citric acid cycle and involved in improvement of glucose homeostasis and intestinal function [14]; reduced proteolytic bacteria; improved constipation) could strongly influence the engraftment of an FMT in the gut uraemic environment as recently demonstrated in obesity [15]. A high-sulphur amino acid–containing diet increases bacterial production of hydrogen sulphide (H2S) in CKD, and H2S can directly reduce the activity of tryptophanase activity and improve kidney function [16]. ‘Does the aetiology of kidney disease play a role in microbiota modulation and the potential benefits of FMT?’ Because the intestinal immune system ensures protection against pathogens through the production of immunoglobulin A (IgA), recent data suggest that FMT could improve IgA nephropathy [17]. ‘What are the best surrogate markers of a successful FMT for CKD patients?’ It is important to not only demonstrate that these interventions reduce the levels of uraemic toxins and increase SCFA, succinate and H2S production, but also that FMT leads to a decrease in morbidity and mortality or/and improves kidney function and/or proteinuria, or at least patient-centred outcomes such as insulin resistance, control of blood pressure, quality of life, fatigue or other functional symptoms related to advanced CKD. ‘What should be the characteristic of a good donor of stools for FMT in CKD?’ A healthy adult donor (usually <65 years of age), selected on the basis of a thorough clinical and biological examination to prevent transmission of infectious disease, is now the gold standard in FMT studies. However, the donor characteristics that are associated with better outcomes of FMT in CKD patients are unknown. One can presume that the transplant composition should carry a low abundance of uraemic metabolite–producing bacteria in combination with a high abundance of SCFA-producing bacteria. However, such simplistic approaches may miss beneficial complex microbial and interkingdom interdependences such as fungi–bacteria or bacteriophage–bacteria interactions. Recently, new insights from FMT studies were gained regarding precise conditions and protocols that may potentiate microbial engraftment and therapeutics. In particular, there is increasing evidence that the complementarity and similarity of the donor and recipient microbiota are key determinants of donor bacterial strain engraftment and FMT outcomes in various diseases such as metabolic syndrome, inflammatory bowel disease or recurrent CDI [18]. Future clinical trials evaluating FMT in CKD patients should be designed according to recently available data. In the case of CKD, to ensure a durable beneficial effect on chronic complications, FMT should allow a sustainable shift in the gut microbiota metabolism and composition. As CKD is a permanent and multifactorial disease where environmental and host factors are usually at an equilibrium state, shifting the intestinal niche to a new equilibrium would require the use of destabilizing factors in combination with FMT to ensure microbial engraftment. In analogy in what is actually performed for FMT in recurrent CDI and what recent interventional studies have shown, a previous antibiotic regimen using broad-spectrum antibiotics such as oral vancomycin would open the colonic ecological niche [10]. At the same time, the use of cleansing bowel preparations will permit physical wash-out of gut microbial spores and species and leave the space and available nutritional resources to new microbial communities. The route of FMT administration may also be important because each route (enema, capsules, colonoscopy, duodenal/gastric infusion) would be associated with differences in the amount of stool administered and the biogeography and kinetics of intestinal FMT exposure. FMT can appear as a primitive approach when targeting the gut microbiota. New microbiota-derived therapies (such as a personalized cocktail of pre-/pro-/post-biotics) are being tested to increase reproducibility of the treatment composition while minimizing infectious risks. However, such products have not yet proven their efficacy compared with conventional FMT, especially in complex multifactorial diseases as shown by the limited efficacy to induce disease remission in ulcerative colitis of a recently evaluated oral formulation of Firmicutes spores compared with what has been demonstrated with conventional FMT [19, 20]. Thus, as crude as it might appear, FMT remains the most powerful approach to global reprogramming of the gut microbiota composition, with a well-known and reassuring safety profile even in CKD or frail patients [10]. FMT or microbial-based therapy alone might not be able to cure CKD complications. However, combining conventional therapies such as dietary modulation and pharmacological treatments with microbiota-targeted treatment constitutes a promising approach that considers the human body as it is, a symbiosis between a host and its microbial compartment (Fig. 1). Convincing preclinical data are now available suggesting that FMT could be efficient in restoring beneficial host–microbial interactions in CKD. The time has come for clinical studies to evaluate the relevance of FMT in CKD in humans. However, at the time of writing, only two FMT clinical trials in CKD are registered in ClinicalTrials.gov (NCT04361097, NCT04222153), until now without preliminary results. Combining gut microbiota–targeting treatment, diet and conventional interventions that include aetiological treatment and management of complications of CKD, strict control of blood pressure and nephroprotective treatments such as sodium–glucose cotransporter type 2 inhibitors and renin–angiotensin–aldosterone system inhibitors to improve clinical and biological outcomes in patients with CKD. In addition to demonstrating potential therapeutic efficacy, FMT studies in CKD will provide data on host–microbial interactions in this context. These trials, by the potential identification of relevant pathophysiological pathways with new therapeutic targets, will pave the way for innovative microbiota and non-microbiota targeted interventions. N.B. received lecture fees from Tillots and travel grants from Pfizer. L.K. received lecture fees and travel grants from Fresenus Kabi, AstraZeneca, Bayer and Dr Shäre. No conflicts of interest are declared.

1 idea Seedlabs derived from this research