CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies.

Immunotherapy utilizing chimeric antigen receptor T cell (CAR-T) therapy holds promise for hematologic malignancies, however, response rates and associated immune-related adverse effects widely vary among patients. Here we show, by comparing diversity and composition of the gut microbiome during different CAR-T therapeutic phases in the clinical trial ChiCTR1800017404, that the gut flora characteristically differs among patients and according to treatment stages, and might also reflect patient response to therapy in relapsed/refractory multiple myeloma (MM; n = 43), acute lympholastic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). We observe significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we find that patients with severe cytokine release syndrome present with higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, which is reproducible in an independent cohort of 38 MM patients. This study has important implications for understanding the biological role of the microbiome in CAR-T treatment responsiveness of hematologic malignancy patients, and may guide therapeutic intervention to increase efficacy. The success rate of CAR-T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here we show that therapeutic response in MM, ALL and NHL, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

Effect of Cigarette Smoke on Gut Microbiota: State of Knowledge.

Cigarette smoke is a representative source of toxic chemical exposures to humans, and the adverse consequences of cigarette smoking are mediated by its effect on both neuronal and immune-inflammatory systems. Cigarette smoking also is a major risk factor for intestinal disorders, such as Crohn's disease and peptic ulcer. On the other hand, cigarette smoking is protective against developing ulcerative colitis. The effects of cigarette smoking on intestinal disorders include changes in intestinal irrigation and microbiome, increases in permeability of the mucosa, and impaired mucosal immune responses. However, the underlying mechanism linking cigarette smoking with intestinal microbiota dysbiosis is largely unknown. In this communication, we first review the current knowledge about the mechanistic interaction between cigarette smoke and intestinal microbiota dysbiosis, which include the likely actions of nicotine, aldehydes, polycyclic aromatic hydrocarbons, heavy metals, volatile organic compounds and toxic gases, and then reveal the potential mechanisms of the lung-gut cross talk and skin-gut cross talk in regulating the balance of intestinal microbiota and the interrelation of intestinal microbiota dysbiosis and systemic disorders.

Clostridiales are predominant microbes that mediate psychiatric disorders.

BACKGROUND: An increasing number of studies have documented associations between psychiatric diseases and the gut microbiome. By taking genetic correlation and comorbidity of different psychiatric diseases into consideration, we hypothesized that different psychiatric diseases might share some similar microbial shift patterns. However, a deep understanding of whether and how those psychiatric disease-associated microbial dysbiosis spectrums are correlated is currently lacking. METHODS: In this study, we analyzed six case-control 16S amplicon sequencing datasets for psychiatric disorders, which included a total of 430 subjects, and compared microbial dysbiosis patterns across these studies. RESULTS: Different psychiatric diseases exhibited similar overall shift patterns. Significant correlations of overall shift patterns existed between schizophrenia and anorexia (p = 0.0008), as well as between schizophrenia and autism (p = 0.028). We identified 6 genera within order Clostridiales (genus Gemmiger, Faecalibacterium, Roseburia, Lachnospira, Anaerostipes, and two unclassified genera from family Lachnopsiraceae and Christensenellaceae) that were significantly depleted in multiple psychiatric diseases. Our further functional analysis revealed that depletion of these Clostridiales was associated with dysfunction in amino acid metabolism and carbohydrate metabolism. Short chain fatty acid (SCFA) producing bacteria Roseburia was the most important contributor for major KEGG (Kyoto Encyclopedia of Genes and Genomes) orthology entries involved in amino acid metabolism. CONCLUSIONS: Our study revealed common microbial shift patterns across psychiatric disorders and found predominant psychiatry-associated intestinal microbes and functions. Depletion of Clostridiales (e.g., Roseburia) probably mediated different psychiatric diseases by dysfunction of intestinal amino acid metabolism and SCFA production. Furthermore, our study indicated that correlations of microbial shift patterns between psychiatric diseases may derived from their genetic associations. Such shared microbial dysbiosis patterns are intriguing for discovering biomarkers and investigating therapeutic targets for treating psychiatric diseases.

Updated review of research on the gut microbiota and their relation to depression in animals and human beings.

The gut microbiota are being called the human "second brain," as they play a key role in the regulation of the central nervous system (CNS). Recent findings provide strong evidence for the presence of bidirectional communication networks between the gut microbiota and the CNS, and such crosstalk has been correlated with alterations in major depressive disorder (MDD) and other psychiatric disorders. Further, germ-free animal models have been used to investigate the effect of the microbiota on MDD and other psychiatric disorders, which have greatly expanded our knowledge of the role of the microbiota in the etiology of MDD and promoted causality studies of this psychiatric disorder and others as well. In this review, we first introduce the methodological approaches used for microbiota research and then provide an overview of current research progress on the modulatory function and composition of the gut microbiota in MDD and the therapeutic effect of probiotics that has been gained using data from human studies as well as animal experiments. Future research should focus on identification and characterization of specific bacterial strains involved in MDD with the hope of applying these findings in the prevention and treatment of MDD.

Engineering Yarrowia lipolytica to Simultaneously Produce Lipase and Single Cell Protein from Agro-industrial Wastes for Feed.

Lipases are scarcely exploited as feed enzymes in hydrolysis of lipids for increasing energy supply and improving nutrient use efficiency. In this work, we performed homologous overexpression, in vitro characterization and in vivo assessment of a lipase from the yeast Yarrowia lipolytica for feed purpose. Simultaneously, a large amount of yeast cell biomass was produced, for use as single cell protein, a potential protein-rich feed resource. Three kinds of low cost agro-industrial wastes were tested as substrates for simultaneous production of lipase and single cell protein (SCP) as feed additives: sugarcane molasses, waste cooking oil and crude glycerol from biodiesel production. Sugarcane molasses appeared as the most effective cheap medium, allowing production of 16420 U/ml of lipase and 151.2 g/L of single cell protein at 10 liter fermentation scale. In vitro characterization by mimicking a gastro-intestinal environment and determination of essential amino acids of the SCP, and in vivo oral feeding test on fish all revealed that lipase, SCP and their combination were excellent feed additives. Such simultaneous production of this lipase and SCP could address two main concerns of feed industry, poor utilization of lipid and shortage of protein resource at the same time.

Improving stability and activity of cross-linked enzyme aggregates based on polyethylenimine in hydrolysis of fish oil for enrichment of polyunsaturated fatty acids.

Cross-linking of enzyme aggregates from recombinant Geotrichum sp. lipase based on polyethylenimine (PEI) was applied to hydrolyze fish oil for enrichment of polyunsaturated fatty acids successfully. Through acetone precipitation and cross-linking of physical aggregates using glutaraldehyde in the presence of PEI, firmly cross-linked enzyme aggregates (PEI-CLEAs) were prepared. They could maintain more than 65% of relative hydrolysis degree after incubation in the range of 50-55 °C for 4 h and maintain more than 85% of relative hydrolysis degree after being treated by acetone, tert-butyl alcohol and octane for 4 h. PEI-CLEAs increased hydrolysis degree to 42% from 12% by free lipase. After five batch reactions, PEI-CLEAs still maintained 72% of relative hydrolysis degree. Hydrolysis of fish oil by PEI-CLEAs produced glycerides containing concentrated EPA and DHA in good yield. PEI-CLEAs had advantages over general CLEAs and free lipase in initial reaction rate, hydrolysis degree, thermostability, organic solvent tolerance and reusability.

Enzymatic enrichment of polyunsaturated fatty acids using novel lipase preparations modified by combination of immobilization and fish oil treatment.

Novel modification methods for lipase biocatalysts effective in hydrolysis of fish oil for enrichment of polyunsaturated fatty acids (PUFAs) were described. Based on conventional immobilization in single aqueous medium, immobilization of lipase in two phase medium composed of buffer and octane was employed. Furthermore, immobilization (in single aqueous or in two phase medium) coupled to fish oil treatment was integrated. Among these, lipase immobilized in two phase medium coupled to fish oil treatment (IMLAOF) had advantages over other modified lipases in initial reaction rate and hydrolysis degree. The hydrolysis degree increased from 12% with the free lipase to 40% with IMLAOF. Strong polar and hydrophobic solvents had negative impact on immobilization-fish oil treatment lipases, while low polar solvents were helpful to maintain the modification effect of immobilization-fish oil treatment. After five cycles of usage, the immobilization-fish oil treatment lipases still maintained more than 80% of relative hydrolysis degree.