Anukriti Sharma

Background: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage. Methods: The plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage. Results: Here we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity). Conclusions: Plasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies.

Background: Reports indicate that COVID-19 may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA). Methods: We compared pre- and post-COVID-19 HbA1c, and risk of developing T2D in a large real-world clinical cohort of 8,755 COVID-19(+) patients and a matched control cohort of 11,998 COVID-19(-) patients. We investigated if DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N=704) or T2D (N=22,904), or by race and sex. Findings: We observed a statistically significant, albeit clinically insignificant, HbA1c increase post-COVID-19 (all patients ΔHbA1c=0.06%, P <.001; with T2D ΔHbA1c=0.1%; P <.001), and no increase among COVID-19(-) patients ( P >.05). COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared to COVID-19(-) patients ( P <.001) and 28% more likely to be diagnosed with T2D for the same HbA1c change as COVID-19(-) patients ( P <.001). COVID-19(+) patients with T2D on insulin were 34% more likely to develop DKA compared to COVID-19(-) patients on insulin ( P <.05), and COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (HR:1.63, P =.007). There was no significant difference in DKA risk between COVID-19(+) and COVID-19(-) patients with T1D. Interpretation: DKA risk is increased in T2D patients on insulin and in Black patients with T2D after COVID-19 infection.T2D risk is greater in COVID-19(+) patients for the same HbA1c increase in COVID-19(-) patients, indicating that T2D risk attributed to COVID-19 may be due to increased recognition during COVID-19 management. Funding: No funding to report.

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.

We present here the draft genome sequence of a pyridine-degrading bacterium, Micrococcus luteus ATCC 49442, which was reclassified as Pseudarthrobacter sp. strain ATCC 49442 based on its draft genome sequence. Its genome length is 4.98 Mbp, with 64.81% GC content.

Background: Both obesity and the presence of collagenolytic bacterial strains (Enterococcus faecalis) can increase the risk of anastomotic leak. The aim of this study was to determine whether mice chronically fed a high-fat Western-type diet (WD) develop anastomotic leak in association with altered microbiota, and whether this can be mitigated by a short course of standard chow diet (SD; low fat/high fibre) before surgery. Methods: Male C57BL/6 mice were assigned to either SD or an obesogenic WD for 6 weeks followed by preoperative antibiotics and colonic anastomosis. Microbiota were analysed longitudinally after operation and correlated with healing using an established anastomotic healing score. In reiterative experiments, mice fed a WD for 6 weeks were exposed to a SD for 2, 4 and 6 days before colonic surgery, and anastomotic healing and colonic microbiota analysed. Results: Compared with SD-fed mice, WD-fed mice demonstrated an increased risk of anastomotic leak, with a bloom in the abundance of Enterococcus in lumen and expelled stool (65–90 per cent for WD versus 4–15 per cent for SD; P = 0·010 for lumen, P = 0·013 for stool). Microbiota of SD-fed mice, but not those fed WD, were restored to their preoperative composition after surgery. Anastomotic healing was significantly improved when WD-fed mice were exposed to a SD diet for 2 days before antibiotics and surgery (P < 0·001). Conclusion: The adverse effects of chronic feeding of a WD on the microbiota and anastomotic healing can be prevented by a short course of SD in mice. Surgical relevanceWorldwide, enhanced recovery programmes have developed into standards of care that reduce major complications after surgery, such as surgical-site infections and anastomotic leak. A complementary effort termed prehabilitation includes preoperative approaches such as smoking cessation, exercise and dietary modification.This study investigated whether a short course of dietary prehabilitation in the form of a low-fat/high-fibre composition can reverse the adverse effect of a high-fat Western-type diet on anastomotic healing in mice.Intake of a Western-type diet had a major adverse effect on both the intestinal microbiome and anastomotic healing following colonic anastomosis in mice. This could be reversed when mice received a low-fat/high-fibre diet before operation.Taken together, these data suggest that dietary modifications before major surgery can improve surgical outcomes via their effects on the intestinal microbiome.

Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1β positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.

The microbiome, a collection of microorganisms, their genomes, and the surrounding environmental conditions, is akin to a human organ, and knowledge is emerging on its role in human health and diseases. The influence of the microbiome in drug response has only been investigated in detail for the last 10 years. The human microbiome is a complex and highly dynamic system, which varies dramatically between individuals, yet there exists a common core microbiome that is heritable and can be transmitted to progeny. Here, we review the role of the human microbiome, which is now widely accepted as a major factor that drives the interpersonal variation in therapeutic response. We describe examples in which the microbiome modifies drug action. Despite its complexity, the microbiome can be readily altered, with the potential to increase the benefits and reduce the toxicity and side effects associated with pharmaceutical drugs. The potential of new microbiome‐based strategies, such as fecal microbiota transplant, probiotics, and phage therapy, as promising medical therapeutics are outlined. We also suggest a combination reductionist and system‐level approaches that could be applied to further investigate the role of microbiota in drug metabolism modulation of drug response. Finally, we emphasize the importance of combining microbiome and pharmacology studies as a novel means to treat disease and reduce side effects.

Obesity remains a prevalent and independent risk factor for life-threatening infection following major surgery. Here, we demonstrate that when mice are fed an obesogenic Western diet (WD), they become susceptible to lethal sepsis with multiple organ damage after exposure to antibiotics and an otherwise-recoverable surgical injury. Analysis of the gut microbiota in this model demonstrates that WD alone leads to loss of Bacteroidetes , a bloom of Proteobacteria , and evidence of antibiotic resistance development even before antibiotics are administered. After antibiotics and surgery, lethal sepsis with organ damage developed in in mice fed a WD with the appearance of multidrug-resistant pathogens in the liver, spleen, and blood. The importance of these findings lies in exposing how the selective pressures of diet, antibiotic exposure, and surgical injury can converge on the microbiome, resulting in lethal sepsis and organ damage without the introduction of an exogenous pathogen.