Objective
With this study, we aim to investigate the therapeutic potential of the microbial metabolite 6-BT by increasing its bioavailability in the circulation and distal organs, including pancreas. Specifically, we strive to answer three main questions with this phase- 2 trial:
I) Can 6-BT supplementation restore (residual) beta cell function and improve time in normal glycemic range (TIR) in human T1D patients?
II) Can 6-BT intake dampen immune responses and autoimmunity seen in T1D patients?
III) What are the effects of long-term treatment with 6-BT on safety parameters, gut microbiota structure and other plasma metabolites?
Background Rationale
Evidence from the past decades have shown that aberrant gut microbiota composition and function underpin the development of inflammatory diseases, including type 1 diabetes (T1DS), opening novel therapeutic avenues by targeting the intestinal microbiome or (dietary)-derived microbial metabolites. Indeed, commensal gut microbes constantly engage in a communication with our immune system. This largely occurs through the production of wide range of metabolites, that once absorbed into the circulation, can act as endocrine/immunological signaling molecules in the host. In this regard, we recently discovered that fecal microbiota transplantations stabilized residual beta-cell function (own insulin production) in new-onset T1D patients, and the clinical benefits associated with the plasma abundancy of 6-bromotryphan (6-BT). This is novel microbially modulated metabolite that derives from microbial metabolism of dietary tryptophan in the gut. Strikingly, we discovered that the plasma levels of 6-BT were reduced in cohorts of T1D individuals and associated with preserved beta cell function in both new-onset and long-standing patients with T1D. Further in vitro ivestigations subsequently revealed that that 6-BT (but not tryptophan) exerts significant anti-inflammatory effects on multiple immune cell-types, while it stimulated insulin secretion by beta cells in vitro. Finally, oral 6-BT administration to non-obese diabetic (NOD) mice for 4 weeks improved beta cell function both when given before disease onset stage and after overt diabetes associated hyperglycemia. Moreover, 6-BT markedly limited insulitis, preserved the beta cell mass, and drove the expansion of immunosuppressive regulatory T cells. Therefore In light of these findings, we are currently conducting a double-blinded safety/dose-finding trial in 36 healthy participants and found that orally taken daily 6BT for 4 weeks is safe and well-tolerated up to 8mg/day of 6-BT. While glucose and insulin resistance were reduced in line with the results from the murine studies. In the light of these findings, including safety in humans, and a dual effect on both (systemic) immunity and beta cell function in vivo, we hypothesize that increasing 6-BT plasma levels in new-onset (Stage 3) T1D subjects can stabilize residual beta cell function by halting the autoimmune attack and simultaneously restoring a functional beta cell mass.
Description of Project
We recently identified the immunomodulatory and betacell protective role of a dietary derived endogenous human plasma metabolite tryptophan derivative (6 - bromotryptophan). Based on finalized our human phase 1 dose finding study, we now propose to do a phase 2 trial with 8mg 6BT once daily in a capsule for 12 months can improve residual beta cell function and glycemic control by dampening autoimmune immunological status in new onset type 1 diabetes patients. Endpoints will be next to safety the stabilization of residual beta cell function will be tested by mixed meal tests (NestleSsustacal boost) as well as c-peptide in postprandial morning urinesamples over this period. Glycemic variability will be studied by Continuous glucose monitoring (CGM) to study time in eu/hypo/hyperglycemia and used dosages of exogenous insulin. Secondary endpoints include concentrations of 6BT in blood in relation to its effect on activation/exhaustion state of different T and MAIT as well as frequency of cytotoxic CD8 T cells targeting beta cell antigens. Finally, the effects on plasma metabolite profile (including absolute changes in plasma 6-BT concentrations) and gut microbiota composition will be studied. With this phase 2 trial in 34 new onset T1D subjects, we hope to bring a new (safe) orally and daily taken compound to the arena in order to fight type 1 diabetes.
Anticipated Outcome
T1D remains an incurable disease with a constantly rising prevalence in the past decades. Indeed, epidemiological studies show that the worldwide incidence of T1D is increasing at an alarming rate and the number of T1D cases have tripled in the last 40 years. If this 6BT trial is positive, we will be able to start a large phase 3 trial to test efficacy of this oral medication. Also, we can then further substantiated whether (dietary) tryptophan derivatives can be used to modify course and onset of T1D in humans. Also, provided a positive outcome of this phase 2 trial we could design trials aimed at early intervention (eg in subjects with positive antibodies such as GAD but without clinical diabetes) that is aimed to prevent onset of T1D.Moreover, T1D enhances the risk of developing other autoimmune diseases (e.g. autoimmune thyroid diseases, celiac disease, and autoimmune gastritis) and thus 6BT could also be tested in patients suffering from these other diseases.
Relevance to T1D
Hence, with the rising prevalence of T1D and the lack of an actual cure for T1D, there is an urgent need for translational and clinical studies to unveil novel therapeutic targets and develop strategies to halt aberrant immune responses and reverse the progressive loss of functional beta cells.
This project will not only expand our knowledge on the (environmental) factors determining the course of diabetes, but it will also open up the possibility of using simple nutritional supplements as an adjuvant therapy to insulin replacement, with the ultimate goal of harnessing or at least delaying the progressive course of T1D pathogenesis. With positive results, follow-up studies will include conducting a larger study multi-center trial and investigating dietary regimens that effectively boost endogenous microbial production of 6-BT to "healthy" plasma levels.
Importantly, T1D represents a great financial and societal burden. According to published reports, in USA the cumulative societal burden attributable to T1D is almost 500,000$ on a per-patient lifetime level and an approximate 13 years shorter life expectancy. If our trial data can be translated into a long-term phase 3 clinical trial and dietary interventions, the proposed project will help in reducing the health-care costs by preventing severe diabetic comorbidities, and hospitalization. In addition, the costs of implementing use of this natural metabolite will be relatively low compared to other approaches currently being investigated for T1D treatment (such as stem-cell-based therapy, ex vivo immune cell education and re-infusion, monoclonal antibodies).