From Unknown Unknowns to Known Unknowns: Intestinal Microbiota As a Previously Unappreciated Contributor to Cytokine Networks

The increasing availability and decreasing cost of sequencing technology has facilitated a rapid increase in the number of associative studies linking the intestinal microbiome with clinical outcomes (for more, see Diffusion article in this issue by Dr. Loretta Nastoupil). Bacterial communities within the intestinal tract, commonly measured using 16S rRNA sequencing of stool samples, have been linked with numerous important outcomes for hematology-oncology patients. In particular, preservation of diverse microbial communities is linked with improvements in overall survival post–allo- and autologous stem cell transplantation (SCT).^1,2  Specific community compositions have been linked with bacterial and fungal infection after chemotherapy and transplantation,^3,4  immune recovery after SCT,^5,6  and relapse after AML therapy or transplantation. Furthermore, a number of groups have linked microbial composition with acute and chronic graft-versus-host disease (GVHD).^7–9  GVHD is characterized by a highly inflammatory cytokine milieu, where cytokines are capable of direct tissue apoptosis as well as modulation of T-cell function, which is critical for response to therapies and long-term outcomes.¹⁰  Regulatory T cells are thought to provide an important counter to the pro-inflammatory T cells, and much effort has gone into strategies to harness this population for therapeutic benefit.¹¹ 

Primary bile acids are host-derived steroidal products that are secreted into the gastrointestinal tract postprandially, and secondary bile acids are produced by intestinal bacteria and are increasingly recognized as immunomodulators.^12–14  With their recent study, Dr. Donggi Paik and colleagues have offered new insight into the microbiome-dependent regulation of cytokine networks, demonstrating that secondary bile acids (i.e., 3-oxo-lithocolic acid and isolithocolic acid) control Th17 differentiation via inhibition of the canonical Th17 transcription factor, Rorgt. The authors used elegant mouse models combined with microbiological approaches to explore the mechanism and paired this with correlative data from patient fecal samples.

The clinical data confirmed a relative loss of 3-oxo-lithocolic acid and isolithocolic acid in patients with inflammatory bowel disease compared with control subjects. Furthermore, numerous studies have also linked secondary bile acids with the development of regulatory T cells.^15,16  Importantly, bile acids represent just one immunomodulatory product of the microbiome, and others include the short-chain fatty acids (e.g., acetate, butyrate, and propionate) and metabolites of the tryptophan catabolic pathway. These new mechanistic studies, which seem to place microbes and their metabolites upstream of the cytokine networks as we currently understand them, add a new dimension to our understanding of how cytokine production is controlled in vivo. The influence of the microbiome and its metabolites on the cytokine milieu and/or T-cell functional status has not been a routine consideration in mouse studies or in clinical analyses of patient samples to date, but considering these new “knowns,” it seems prudent to consider the contribution of the microbiome to these immunological parameters. Furthermore, studies integrating microbial composition and functional capacity with immunophenotype and disease outcomes (in mice and in humans) are key for moving the field forward.