Butyrate is a short-chain fatty acid produced by colonic bacteria by fermenting elements from our dietary intake. invariant natural killer T-cell tolerance.86 Additionally, dysbiosis of the microbiome can alter levels of metabolites from the microbiome such as butyrate. Butyrate is usually a short-chain fatty acid produced by colonic bacteria by fermenting elements from our dietary intake. It can induce regulatory T (Treg) cell development to maintain trans-Vaccenic acid immune tolerance and maintain the balance between Th17 and Treg cells.87 This sense of balance is highly important in modulating intestinal inflammation. Finally, the gut microbiome and innate immune trans-Vaccenic acid system are intrinsically linked via many types of pattern recognition receptors (PRRs). TLRs are important in sensing molecular patterns originating from the gut microbiome, such as lipopolysaccharide (LPS), that cause activation of downstream signaling pathways of transcription factor (eg, NF-B) upregulation and pro-inflammatory cytokine release. Chloride Secretion In addition, there is an emerging link between gut microbiome composition and intestinal chloride secretion, particularly via CFTR, which allows exit of chloride ions across the apical membrane. Two studies have investigated this link with lubiprostone, used clinically to treat constipation and known to stimulate electrogenic chloride secretion.88,89 Upregulation of chloride secretion with this agent caused large shifts in the stool microbiome, with an increased abundance of spp in the stool of lubiprostone-treated mice. It was concluded that epithelial chloride secretion may have a key role in influencing bacterial-epithelial interactions. In addition, changes to the CFTR have also shown to cause significant gut microbial changes. In a mouse model, CFTR gene mutations were sufficient to alter the gut microbiome,82 and in a clinical study of 31 patients aged 1 to 6 years with cystic fibrosis (who have mutations in the CFTR), it was suggested that gut microbiota enterophenotypes were direct expressions trans-Vaccenic acid of altered intestinal function.83 These studies show the close links between chloride secretion and the gut microbiome. As extra chloride secretion into the intestinal lumen may cause diarrhea in some SM-TKI treatments, this provides further evidence for SM-TKICinduced diarrhea to be influenced by gut microbial changes. However, while there is some evidence that probiotic bacteria or pathogenic bacteria can alter chloride secretion,90,91 there are low levels of evidence to suggest that the native gut microbiome changes are able to drive chloride channel dysfunction. Future work needs to be done to understand whether microbial dysbiosis is usually a direct driver of diarrhea, or whether the diarrhea itself causes dysbiosis as an outcome. Microbiome Changes Due to Malignancy Treatment Preclinical studies have shown marked changes to overall microbiome composition in the gut following chemotherapy treatment, toward a dysbiotic state. The key obtaining has been a decrease in commensal bacterial species, along with a corresponding increase in pathogenic species.80,81,92-94 These pathogenic species were usually gram-negative species, which can release LPS known to initiate the inflammatory pathways that are key mediators in development of diarrhea.95,96 Clinical studies have shown similar findings, with a decrease in total bacterial abundance and diversity, as well as decreases in commensals Rabbit polyclonal to L2HGDH such as and and were seen following lapatinib treatment. In contrast, chemotherapy studies have shown changes in spp and lower levels of spp.18 However, it was inconclusive whether these microbial changes were simply due to the occurrence of diarrhea, or the drivers of this diarrhea. Probiotics and Fecal Microbiota Transplant Probiotics and dietary modification have also been suggested as a treatment or preventative measure for cancer treatmentCinduced diarrhea. In chemotherapy, probiotics have had varying levels of success in reducing diarrhea.72 While some studies have shown lowered gastrointestinal damage levels and less diarrhea, others have shown no benefit. A meta-analysis recently found insufficient current evidence to support widespread implementation of probiotics after chemotherapy.100 The authors noted the wide variety in probiotic types and dosing schedules, and stressed the need for rationally designed probiotic mixtures and trials. Probiotics are commonly used alongside some forms of SM-TKI.