Cancer Immunotherapy with Immune Checkpoint Inhibitors-Biomarkers of Response and Toxicity; Current Limitations and Future Promise

Immune checkpoint inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and tumour mutational burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

Cancer Immunotherapy Biomarkers of Response and Toxicity; Current Limitations and Future Promise

Immune Checkpoint Inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and Tumour Mutational Burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

Correlation between faecal microbial taxa and ulcerative colitis in different phases of disease activity in a north Indian cohort

Objective: A link between gut microbiota and Ulcerative Colitis (UC) has been established in several studies. However, a few studies have examined specific changes in microbiota associated with different phases of disease activity in UC. In this study, we investigated phenotypic variability underlying genetically distinct north Indian (NI) UC patients by identifying differentially abundant taxa between (i) UC patients and healthy controls and (ii) different disease phases of disease activity. Design: 16S rRNA (V3,V4) sequencing of 105 patients with UC [newly diagnosed (n=14); patients in remission (n=36) and active disease (relapse, n=55)]; and 36 healthy controls was performed. The faecal microbiota composition in different phases of UC disease activity and healthy controls was analysed. Results: Lower gut microbial diversity; enrichment of lactate-producing bacteria namely Streptococcus, Bifidobacterium and Lactobacillus; and depletion of butyrate-producing bacteria (e.g., Lachnospiraceae and Ruminococcaceae), was observed among UC patients. Subgroup analysis revealed differential abundance of Escherichia-Shigella, Streptococcus, Enterococcus and Faecalibacterium in newly diagnosed UC patients. No discrete microbial features were observed between patients in remission and those with active disease. Co-occurrence network analysis revealed a mutualistic association between opportunistic pathogens and Bifidobacterium and Lactobacillus and antagonistic relationship with butyrate-producers. Conclusion: This first faecal microbiome study elucidated dysanaerobiosis; loss of short chain fatty acid producers and enrichment of inflammation associated microbes; population specific differential microbial genera; and microbial signature for early dysbiosis, among NI UC cohort.

Effects of ShenLing BaiZhu San Supplementation on Gut Microbiota and Oxidative Stress in Rats with Ulcerative Colitis

The aim of this study was to evaluate the effect of gut microbiota and antioxidation of Shenling Baizhu San (SLBZS) as a supplement in a rat model of ulcerative colitis (UC) induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Acute intestinal inflammation was induced in 40 male SD rats aged 4 weeks with 100 mg/kg TNBS, and then three dosages of SLBZS (0.5 g/kg, 1 g/kg, and 1.5 g/kg) were administered for eight days, respectively. Faecal microbiome composition was assessed by 16S rRNA high-throughput sequencing. The result indicated that SLBZS could reduce the diversity of gut microbiota and increased its abundance. At the genus level, the relative abundance of SCFAs producing bacteria including Prevotella and Oscillospira increased, while the relative abundance of opportunistic pathogens including Desulfovibrio and Bilophila decreased. Meanwhile, SLBZS could improve the lesions of colon and significantly reduce the level of MPO, increase the levels of SOD and CAT in rats’ serum. These findings revealed that SLBZS was effective and possessed anticolitic activities in a rat model of UC by reducing macroscopical and microscopical colon injury, enhancing antioxidant capacity, and regulating gut microbiota.

The Healthy Female Microbiome Across Body Sites: Effect of Hormonal Contraceptives and the Menstrual Cycle

Background: There is increasing evidence that the vaginal microbiome influences women’s health. V agina l dysbiosis with a low abundance of L actobacillus h as been connected to gynaecological and obstetric complications. However, the interplay between the vaginal microbiome and the microbiome in other body sites is not yet described. In addition, fluctuating endogenous sex hormones may exert an effect on microbiome composition and are markedly changed by hormonal contraception . This study includes a cohort of 160 healthy young Caucasian women using three different contraceptive regimens: non-hormonal methods, combined oral contraceptive (COC) or levonorgestrel intra-uterine system (LNG-IUS ) . The oral, vaginal, rectal and faecal microbiome s are characterized by shot gun sequencing during each phase of the menstrual cycle (menses, follicular and luteal phases). Results: The use of COC and LNG-IUS do not affect the microbiome composition or diversity . However , an increased diversity in the vaginal microbiome is observed during menses , followed by a subsequent expansion of Lactobacillus during the follicular and luteal phase s which correlate s with measured serum oestradiol levels (r = 0.11, p<0.001) . During menses 89 women (58%) ha ve a dysbiotic vaginal microbiome with less than 60% Lactobacillus spp . This decline s to 49 (32%) in the follicular phase (p = 1.3E-5) and 44 (29%) in the luteal phase (p = 4.6E-7) . During menses, bacterial richness and diversity in saliva reach its lowest while no difference is observed in the faecal microbiome . T he microbiome in different body sites is on average more similar within the same individual than between individuals , despite phase or hormonal treatment . Only the vagina present s a clear cluster structure with dominance of either Lactobacillus crispatus , Lactobacillus iners , Gardnerella vaginalis or Prevotella spp. Conclusions: The use of COC or LNG-IUS is not associated with changes of the healthy female microbiome except for increased stability in the vagina in LNG-IUS users . Body site is the main driver of the microbiome, including a clear difference between faecal and rectal samples. The menstrual cycle is a confounding factor for microbiome composition in both saliva and the vagina and should be considered when analysing the microbiome in women of reproductive age.