Impact of Immunosuppression on the Metagenomic Composition of the Intestinal Microbiome: a Systems Biology Approach to Post-Transplant Diabetes

Abstract

Solid organ transplantation (SOT) outcomes have continued to improve, although long-term use of immunosuppressants can lead to complications such as diabetes, compromising post-transplant outcomes. In this study, we have characterized the intestinal microbiome (IM) composition at the metagenomic level in the context of hyperglycemia induced by immunosuppressants. Sprague-Dawley rats were subjected to doses of tacrolimus and sirolimus that reliably induce hyperglycemia and an insulin-resistant state. Subsequent exposure to probiotics resulted in reversal of hyperglycemia. 16S rRNA and metagenomic sequencing of stool were done to identify the bacterial genes and pathways enriched in immunosuppression. Bacterial diversity was significantly decreased in sirolimus-treated rats, with 9 taxa significantly less present in both immunosuppression groups: Roseburia, Oscillospira, Mollicutes, Rothia, Micrococcaceae, Actinomycetales and Staphylococcus. Following probiotics, these changes were reversed to baseline. At the metagenomic level, the balance of metabolism was shifted towards the catabolic side with an increase of genes involved in sucrose degradation, similar to diabetes. Conversely, the control rats had greater abundance of anabolic processes and genes involved in starch degradation. Immunosuppression leads to a more catabolic microbial profile, which may influence development of diabetes after SOT. Modulation of the microbiome with probiotics may help in minimizing adverse long-term effects of immunosuppression.

Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent

“…There is a known association between GERD reflux and IPF. Many patients are on PPI which have been linked to an increased risk of pneumonia [21,39]. While we did not set out to address this issue prospectively, we demonstrated no association between GERD or PPI use and bacterial burden.…”

“…The mean score between radiologists, following arbitration, was used as the final score for analysis. In general, there was a reasonable agreement between radiologists (Supplementary Table 3) [20,21]. Over half of the cohort had probable or definite UIP (57.7%) according to the current ATS/ERA/JRS/ALAT guidelines [13].…”

Butyric acid normalizes hyperglycemia caused by the tacrolimus-induced gut microbiota

“…Several studies have indicated their beneficial role in glucose homeostasis 14,17,18 . SCFAs activate de novo–synthesized glucose from the gut epithelium, which is sensed in the portal vein and participates in signaling through a gut–brain neural circuit to increase insulin sensitivity and glucose tolerance 19,20 . Furthermore, SCFAs promote the release of insulinotropic peptide hormones, including glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY) secreted from enteroendocrine mucosal L cells, thereby restoring β‐cell insulin secretion and glucagon suppression 21‐23 .…”

The vaginal microbiome in uterine transplantation

“…MMF is stopped prior to embryo transfer because of its potential teratogenic impact, at which time it is usually replaced with azathioprine. Although there are no published data evaluating the VM following the induction of an immunosuppressed state, various studies have identified that the use of immunosuppression alters the intestinal microbiome in animals and humans, with subsequent normalisation of the intestinal microbiome seen following the administration of probiotics in the animal model . The currently accepted method of detecting rejection following UTx is by histological evaluation of cervical biopsies, which have been demonstrated to be consistent with rejection throughout the graft .…”