Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(3), P. e003725 - e003725

Published: March 1, 2022

Background Despite the great success, therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel strategies that provide manageable side to existing ICIs would enhance and expand their efficacy application. Due its proven role development regulation, gut microbiome has gained increasing expectation as a potential armamentarium optimize with ICI. However, much be learned fully harness for clinical applicability. Here we have assessed whether microbial metabolites working at interface between microbes host system may ICI therapy. Methods To this purpose, tested indole-3-carboxaldehyde (3-IAld), tryptophan catabolite known contribute epithelial barrier function homeostasis via aryl hydrocarbon receptor (AhR), different murine models ICI-induced colitis. Epithelial integrity, inflammation changes composition were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 IL-22 knockout mice used investigate mechanism 3-IAld activity. The induced was evaluated on fecal transplantation (FMT). Finally, tumor assess effect treatment antitumor activity Results On administration colitis, protected from intestinal damage dual action both microbes. Indeed, paralleling activation AhR/IL-22-dependent pathway, also affected microbiota such FMT 3-IAld-treated against colitis contribution butyrate-producing bacteria. Importantly, while preventing damage, did not impair Conclusions This study provides proof-of-concept demonstration moving past bacterial phylogeny focusing metabolome lead new class discrete molecules,

Language: Английский

---

Ginsenoside Rg1 Alleviates Acute Ulcerative Colitis by Modulating Gut Microbiota and Microbial Tryptophan Metabolism

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 17, 2022

Ulcerative colitis (UC) is a chronic and recurrent inflammatory disorder in the gastrointestinal tract. Here, we examined pharmacological effects of ginsenoside Rg1, natural compound with low bioavailability, on acute experimental mice induced by dextran sulfate sodium (DSS) explored underlying mechanisms. Acute UC was C57BL/6 2.5% DSS for 7 days, meanwhile, 2 mg/10 g b.w. Rg1 administrated to treat mice. Body weight, colon length, tissue pathology, cytokines were assessed. The composition structure gut microbiota profiled using 16s rRNA sequencing. Global metabolomic profiling feces performed, tryptophan its metabolites serum detected. results showed that significantly ameliorated DSS-induced colonic injury inflammation. In addition, also partly reversed imbalance caused DSS. intervention can regulate various metabolic pathways such as valine, leucine, isoleucine biosynthesis vitamin B6 metabolism most prominent alteration metabolism. decreased levels serum, including indole-3-carboxaldehyde, indole-3-lactic acid, 3-indolepropionic niacinamide increase these metabolites. conclusion, study discovered protect intestinal barrier alleviate inflammation mice, mechanism closely related regulation microbial

Language: Английский

---

Metabolite interactions between host and microbiota during health and disease: Which feeds the other?

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 160, P. 114295 - 114295

Published: Jan. 27, 2023

Metabolites produced by the host and microbiota play a crucial role in how human bodies develop remain healthy. Most of these metabolites are hosts digestive tract. gut have important roles energy metabolism, cellular communication, immunity, among other physiological activities. Although numerous metabolites, such as free fatty acids, amino vitamins, found intestine, generated equally vital for intestinal homeostasis. Furthermore, is sole source some including short-chain acids (SCFAs). microbiota, neurotransmitters hormones, may modulate significantly affect metabolism. The becoming recognized second endocrine system. A variety chronic inflammatory disorders been linked to aberrant host-microbiota interplays, but precise mechanisms underpinning disturbances they might lead diseases be fully elucidated. Microbiome-modulated promising targets new drug discovery due their function various complex disorders. In humans, metabolotherapy prevention or treatment will possible if we better understand metabolic preferences bacteria specific tissues organs. Better disease treatments with help novel complementary therapies that target bacterial consequences, functional interplays highlighted, summarized, discussed this overview.

Language: Английский

---

Production of Indole and Indole-Related Compounds by the Intestinal Microbiota and Consequences for the Host: The Good, the Bad, and the Ugly

Microorganisms, Journal Year: 2022, Volume and Issue: 10(5), P. 930 - 930

Published: April 28, 2022

The intestinal microbiota metabolic activity towards the available substrates generates myriad bacterial metabolites that may accumulate in luminal fluid. Among them, indole and indole-related compounds are produced by specific species from tryptophan. Although are, first, involved microbial community communication, these molecules also active on mucosa, exerting generally beneficial effects different experimental situations. After absorption, is partly metabolized liver into co-metabolite indoxyl sulfate. some anti-inflammatory actions of cells have been shown, sulfate a well-known uremic toxin aggravates chronic kidney disease, through deleterious cells. Indoxyl known to provoke endothelial dysfunction. Regarding central nervous system, emerging research indicates at excessive concentrations displays negative impact emotional behavior. indole-derived isatin appears, pre-clinical studies, brain, modulating brain function either positively or negatively, depending doses used. Oxindole, metabolite enters has shown system studies. Lastly, recent studies performed with report once again dose used, missing information physiological reaching system. Any intervention aiming compound biological fluids should crucially take account dual according host tissues considered.

Language: Английский

---

Nutrition, Immunosenescence, and Infectious Disease: An Overview of the Scientific Evidence on Micronutrients and on Modulation of the Gut Microbiota

Advances in Nutrition, Journal Year: 2022, Volume and Issue: 13(5), P. S1 - S26

Published: May 6, 2022

The immune system is key to host defense against pathogenic organisms. Aging associated with changes in the system, a decline protective components (immunosenescence), increasing susceptibility infectious disease, and chronic elevation low-grade inflammation (inflammaging), risk of multiple noncommunicable diseases. Nutrition determinant cell function gut microbiota. In turn, microbiota shapes controls inflammatory responses. Many older people show Age-related competence, inflammation, dysbiosis may be interlinked relate, at least part, age-related nutrition. A number micronutrients (vitamins C, D, E zinc selenium) play roles supporting many types. Some trials report that providing these as individual supplements can reverse deficits and/or those insufficient intakes. There inconsistent evidence this will reduce or severity infections including respiratory infections. Probiotic, prebiotic, synbiotic strategies modulate microbiota, especially by promoting colonization lactobacilli bifidobacteria, have been demonstrated some biomarkers and, cases, gastrointestinal infections, although, again, inconsistent. Further research well-designed well-powered at-risk populations required more certain about role modify microbiota-host relationship protecting infection, infection.

Language: Английский

---