Fecal Microbiota Transplantation for The Early-Onset Type 1 Diabetes. Could It Be a Promising Solution?

Abstract from de Groot P, Nikolic T, Pellegrini S, et al.: Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial. Gut. 2021;70(1):92–105.

Type 1 diabetes mellitus (T1D) is an autoimmune disease whose pathophysiology recently has been linked with intestinal dysbiosis. Preclinical studies in non-obese diabetic (NOD) mice showed that interaction between commensal flora and the innate immune system is the cornerstone for the development of T1D. It is considered that the development of T1D is related to an increased intestinal permeability, induced by an impaired intestinal short-chain fatty acid (SCFA) production (end products of fiber fermentation). In this framework, fecal microbiota transplantation (FMT) could be a solution in improving the small intestinal immune system.

The study by de Groot P et al. [1] was published in Gut in October 2020. It was the first exploratory randomized controlled trial that highlighted the effect of FMT – autologous (their own) or allogenic (from healthy donors) – on residual beta-cell function in patients with new-onset T1D in the Amsterdam region. Lack of funding led to a limited sample size of 20 patients who underwent FMT by nasoduodenal tube at 0, 2, and 4 months. The researchers studied the differences between the two groups (N₁ = 10 with autologous FMT and N₂ = 10 with allogenic FMT) in fasting plasma C peptide and HbA1c at 6 and 12 months. All patients had a normal body mass index (18.5–25 kg/m²) and were given mixed meals and similar amounts of exogenous insulin. At baseline, fasting plasma C peptide was similar between groups. Twelve months later, C peptide levels were preserved in the autologous FMT group but exacerbat-ed in the allogenic FMT group (Fig. 1). Similar results were observed for residual beta-cell function as expressed by the response of stimulated C peptide area under the curve (AUC), which was equal at baseline (p value 0.92); however, one year later after autologous FMT their function was significantly preserved (p value 0.033). Glycaemic control as expressed by HbA1c showed no significant differ-ence between groups. HbA1c levels decreased after insulin treatment but did so in both groups (Fig. 2). Analyses of secondary endpoints included immunological assays like fluorescent-activated cell sorting, lymphocyte stimulation assays, and human leucocyte antigen multimer analyses to enumerate CD8 T cell autoimmunity to islet autoantigens (CD8 Quantum dot) at 0, 2, 6, 9, and 12 months. Furthermore, targeted plasma metabolites were measured at 0, 6, and 12 months; gastroduodenoscopy with duodenal biopsies was performed at 0 and 6 months to assess small intestinal microbiota and perform quantitative reverse transcription PCR to assess duodenal gene expression.

Multiomics analysis identified a significant bacterial strain named Desulfovibrio piger, which was associated with a change in stimulat-ed C peptide responses on FMT and increased amounts in the autologous group. D. Piger correlated positively with levels of plasma 1-arachidonoyl-GPC, a beneficial glycerophospholipid.

Unexpectedly, autologous FMT had better results than healthy donor FMT. Researchers speculate that allogenic FMT increases the inflammatory status which is already present at the time of T1D diagnosis because donor gut microbiota is not compatible with the host. Thus, foreign microbiota is less tolerated by the immune system and specifically by T cells which are located in the epithelium of the small intestine.

This is the first time that FMT is applied in humans with recent onset of T1D. In spite of the small sample size the results are promising, showing prolonged residual beta-cell function. Increased plasma phospholipids and tryptophan derivatives (1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC) after FMT were associated with beneficial changes in immune cell subsets such as CD4+ T cells. FMT could be a potential therapeutic solution due to the perception of ‘natural’ treatment and its relatively inexpensive implementation.

I hereby confirm that there are no conflicts of interest pertaining to this commentary.