Influence of immunomodulatory drugs on the gut microbiota

Abstract

Immunomodulatory medications are a mainstay of treatment for autoimmune diseases and malignancies. In addition to their direct effects on immune cells, these medications also impact the gut microbiota. Drug-induced shifts in commensal microbes can lead to indirect but important changes in the immune response. We performed a comprehensive literature search focusing on immunotherapy/microbe interactions. Immunotherapies were categorized into 5 subtypes based on their mechanisms of action: cell trafficking inhibitors, immune checkpoint inhibitors, immunomodulators, antiproliferative drugs, and inflammatory cytokine inhibitors. Although no consistent relationships were observed between types of immunotherapy and microbiota, most immunotherapies were associated with shifts in specific colonizing bacterial taxa. The relationships between colonizing microbes and drug efficacy were not well-studied for autoimmune diseases. In contrast, the efficacy of immune checkpoint inhibitors for cancer was tied to the baseline composition of the gut microbiota. There was a paucity of high-quality data; existing data were generated using heterogeneous sampling and analytic techniques, and most studies involved small numbers of participants. Further work is needed to elucidate the extent and clinical significance of immunotherapy effects on the human microbiome.

Figure 1.. Host-Drug-Microbiota Interactions.

The interface between microorganisms and the immune is complex and multidirectional, and it is further influenced by immunomodulatory medications. Commensal organisms at mucosal/epithelial surfaces influence immune education and modulation both locally and systemically. These microbes also influence drug metabolism and efficacy. Inversely, the immune system shapes the composition of the microbiome. Immunomodulatory medications impact circulating immune cells directly, via a variety of mechanisms. Emerging data suggest that these medications also function indirectly, by shifting the composition of the microbiome. These multi-directional relationships are complex and remain poorly understood. Figure created with BioRender.com

Figure 2.. Microbiome Study Design.

Human microbiome studies require identifying the anatomic region of interest, selecting a sampling methodology, and isolating the specimen. Analytic assays will be targeted to the research question and may include microbial characterization at the cellular, DNA, RNA, or metabolic level. Human microbiome studies require subject-level characterization to adequately control for environmental variables known to impact the microbiome. NSAIDs: non-steroidal anti-inflammatory drugs. PPIs: proton pump inhibitors. Figure created with BioRender.com