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The role of the microbiome in immunologic development and its implication for pancreatic cancer immunotherapy.

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PubMed ID: 30768986

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Sethi V, Vitiello GA, Saxena D, Miller G, Dudeja V

Gastroenterology. Feb 2019

COMMENT: Review on the relation of microbiome and the immune system and the importance of it in the context of pacreatic cancer and cancer immunotherapy.

In this review, we start by exploring the dynamic nature of the human microbiome and highlight technological advances enabling microbiome research. We then describe in detail how the microbiome is essential for the development and maturation of the immune system. We then shift our focus on the role of the microbiome in cancer immunity, with a particular focus on pancreatic cancer. Finally, we highlight novel findings of how microbiome-modulating agents, like antibiotics, not only affect pancreatic cancer progression but also open opportunities for successful cancer immunotherapy.

The review starts with a description of the current methodological advances that enable the study of the microbiome and its relations with the host.

Then the authors describe several scenarios where the gut microbiome plays an important role in the development and maturation of the immune system, like the case of the immune system in germ-free animals

These animals (germ-free animals) have a relatively “uneducated” immune system, characterized by hypoplastic lymphoid organs (Peyer’s patches, spleen, mesenteric lymph nodes), deficient IgA production, over-activation of anti-inflammatory Th2 cytokines and decreased expression of pattern recognition receptors (PRR’s) like the toll-like receptors (TLR’s)

The immunomodulatory role of Bacteroides fragilis PSA (bacterial polysaccharide)

Mazmanian et al reported that monocolonization of mouse gut with Bacteroides fragilis leads to systemic immunological maturity of GF mice and increases the splenic CD4+ fraction to that seen in SPF mice53. This expansion was induced by phagocytosis of immunomodulatory bacterial polysaccharide (PSA) via dendritic cells, its MHCII-mediated presentation to Th0 cells and their subsequent Th1 polarization through the IL12/STAT4 signaling. Interestingly, the same bacterium was subsequently found to impact gut LP immune system in a very different way. PSA-producing B fragilis attenuates murine colitis by expanding IL10 producing CD4+ FoxP3+ Tregs at the cost of Th17 cells, thereby highlighting the complex nature and importance of a balanced immune response

Or the importance of the exposure of neonates to certain microbes for the initial change of their immune system

Another factor that contributes in establishing the “core gut microbiome” in early infancy is the breast milk. Exclusive breastfeeding has been associated with decreased risk of asthma later in life and breast milk acts a natural synbiotic rich in indigestible fructans, probiotics as well as short chain fatty acids that select for a bloom of barrier protecting Bifidobacterium in the neonatal gut. The latter has also been associated with increased maturation of innate immune system and protection against necrotizing enterolocolitis and with a shift of Th2-dominated immune response in the fetus to a balanced Th1/Th2 response in the infant.

The authors continue with the implications of the microbiome in the development of colorectal and gastric cancers

Interestingly, ETBF (enterotoxigenic Bacteroides fragilis) and colibactin secreting E coli co-colonize biofilms in adenomas and potentiate each other’s carcinogenic potential through a combination of immunosuppressive and genotoxic effects.

Similarly, Fusobacterium nucleatum, a gram negative periodontitis-associated oral commensal, has long been isolated from colon cancer biopsies (right sided > left sided tumors, recurrent >initial tumors). Kostic et al reported that F. nucleatum gavaged to ApcMin/+ mice invades cancerous tissue, accelerates tumorigenesis, enriches tumors for CD11b+ myeloid cells and induceds a human-like inflammatory gene rich signature in murine tumors. It is also becoming increasingly clear that this bacterium lives in a symbiosis with colon cancer. (...) In summary, it is clear that microbes not only directly contribute to oncogenesis, in the form of DNA damage and toxic metabolites, but also subvert the immune system to create a cancer-promoting environment.

The review finally highlights how the microbiome modulates the cancer immunotherapy response, in particular in the case of pancreatic cancer.

A putative link between the microbiome and pancreatic oncogenesis could perhaps have been predicted. A host of pattern recognition receptors (PRR’s), their ligands (e.g., microbe-associated molecular patterns, and damage-associated molecular patterns) and their downstream targets (e.g., NF-κB pathway) have been previously linked to the development of pancreatic disease in mouse models. We and others previously reported that ligation of bacterial sensors, TLR4, NOD and NLRP3 inflammasome increases the severity of acute pancreatitis in mice and oral antibiotics ameliorate it.

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Marina Manrique