Definitions used in the study of microbiome

Evolution of Microbiome

After birth, the body is essentially sterile, that is, no microorganisms are present in the body. Afterward, the growth of facultative aerobes bacteria (Enterobacteriaceae) occurs in the gut. It is followed by growth of anaerobic species (Clostridia?spp.). By the end of third year of life, the microbiome increases in composition and diversification and attains adult-type characteristics.?Firmicutes?and?Bacteroidetes?are the two most dominant bacterial phyla.[3] [4] The composition of microbiome is influenced by the following factors.

Mode of Delivery of a Child

Children delivered by cesarean have largely different microbiome than those born vaginally.

Environmental Factors

The microbiome varies with race, gender, ethnicity, geography, diet, etc. For instance, Western lifestyle hampers the normal composition of the microbiome. Similarly, excessive use of antibiotics in neonates also prevents microbiome. Microbial biodiversity varies with various exogenous variables such as sex, race, and weight.

Race

Around 400 different genes have been described that distinguish the microbiome of people from different continents.[5]

Carcinogenesis Pathways Involved in Microbiome

Cellular DNA Damage

Gram-negative bacilli produce toxins (colibactin) or free radicals that cause lethal damage to normal DNA.[6]

Cancer Cell Proliferation

Escherichia coli?induce growth factors that trigger cell growth.[7]

Chronic Inflammation

Helicobacter pylori?infection leads to chronic inflammation (gastritis) and predisposes to gastric adenocarcinoma and gastric MALToma.[8]

Immune Dysregulation

Bacteroides fragilis?influences T-helper cells (CD 4 cells) and triggers interleukin-mediated signals. Microbes hamper natural killer cell activity and reduce ability to kill cancer cells.[9]

Inducing Host Cell Proliferation

Human papillomavirus enters the host cell nucleus and takes control of DNA replication (by E 6 and E 7 genes) causing oncogenesis.[10]

Epithelial to Mesenchymal Transition

B. fragilis?and?Fusobacterium nucleatum?cause damage to adhesion molecules between host cells, thus attaining invasive properties.[11]

Metastasis

Microbes produce special molecules that can influence gene expression with change in cell density. Gram-positive bacteria secrete small peptides and Gram-negative bacteria secrete lactones that contribute to metastasis.[12]

Alteration of Cell Epigenetics

• F. nucleatum?possesses virulence factors that drive cell proliferation (WNT/?-catenin pathway).

• Porphyromonas?sp. produces reactive oxygen species and?Bilophila?and?Fusobacterium?produce hydrogen sulfide that is linked with colorectal neoplasia.

• Enterotoxigenic?B. fragilis?secretes toxins that cause colon cancer (TH-17/IL-17 pathway).

• E. coli?and?Campylobacter jejuni?produce genotoxins such as cytolethal distending toxin and colibactin that cause DNA damage.[13] [14]

Microbiome and Cancer

• Esophageal and gastric cancers:?H. pylori?infection results in gastric inflammation, achlorhydria, dysplasia, gastric cancer, and gastric lymphoma (MALToma).?H. pylori?reduces acid secretion that reduces acid reflux and decreases the chances of developing esophageal adenocarcinoma.

• Gallbladder cancer: Salmonellosis predisposes to gallbladder cancer.

• Hepatocellular carcinoma: Hepatitis B virus and Hepatitis C virus can infect the liver and cause cancer. In animal models, Gram-negative bacteria via inflammation pathway promote hepatocarcinogenesis.

• Lung cancer: Various pulmonary infections such as?Mycobacterium tuberculosis?predispose to it.

• Breast cancer: Various subtypes have a different composition of the microbiome. Furthermore, microbial variation is seen with different grades of breast cancer.

• Lymphomas:?H. pylori, a commensal in human stomach, has been incriminated in gastric marginal zone lymphoma and gastric adenocarcinoma.

• Kaposi sarcoma-associated herpesvirus being the etiologic factor for Kaposi sarcoma and primary effusion lymphomas.

• Other cancers: Human polyomaviruses?Merkel cell polyomavirus?leads to Merkel cell carcinoma and skin cancer. Simian Virus 40 (SV40) leads to mesothelioma.

Microbiome and Hallmarks of Cancer

Microbiome affects all hallmarks of cancer as described in [Table 2].

Microbiome and hallmarks of cancer[19]

Microbiome and Food

High-Fiber Diet

Plant-based diet is difficult to digest. Microorganisms present in gastrointestinal tract convert these poorly digestible into small fatty acids (butyrate and propionate) and other small compounds (phytochemicals, polyphenols, flavonoids, and glucosinolates). Butyrate and propionate favor cell differentiation, apoptosis, and regulation of glucose and lipid metabolism. It results in inhibition of tumorigenesis.[15] Microbes (e.g.,?Eggerthella) metabolize glucosinolates into isothiocyanates that have anticancer properties. Isoflavonoids also have anticancer properties.[16]

Protein- and Fat-Containing Foods

Consumption of protein- and fat-rich diets inhibits the content of beneficial microbes such as?Roseburia?and?Eubacterium rectale?and favors the production of carcinogens such as secondary bile acids and N-nitroso compounds. Animal-rich diets promote the production of bile-tolerant microbes and inhibit polysaccharide-metabolizing microbes that possibly increase the risk of cancer ([Table 3]).[17]

Relationship between diet and microbiome

Microbiome and Chemotherapy and Immunotherapy Drugs

There occur interactions between the microbiome and anticancer treatment at several levels, for example, by modulating the immune system and by metabolizing the chemotherapeutic drugs.[18] The effect of various anticancer drugs is given in [Table 4].

Anticancer drugs and microbiome

Abbreviations: 5-FU, fluorouracil; anti-CTLA4, anti-cytotoxic T lymphocyte-associated protein 4; LPS, lipopolysaccharides; PARP, poly ADP ribose polymerase; PD-L1, programmed death ligand 1; PD, programmed death; SERM, selective estrogen receptor modulator.

Microbiome in HSCT and GVHD

The association between microbiome in hematopoietic stem cell transplant (HSCT) and graft versus host disease (GVHD) is now well established. The use of antibiotic prophylaxis reduces microbiome diversity within first 2 weeks after HSCT. Researchers have shown that certain microbial products such as short-chain fatty acids and indole-based derivatives play a role in the prevention of GVHD.

Cancer-related infections have direct bearing with microbial diversity. In patients of Acute Myeloid Leukemia, greater baseline diversity was associated with acquiring less chances of infections. Similarly, in Hodgkin lymphoma, bloodstream infection was worse in those with less microbial diversity. Some data are also accumulating regarding relationship between anti-vascular endothelial growth factor (VEGF) and type of microorganisms: higher?Bacteroides?being deleterious and higher?Prevotella?beneficial for anti-VEGF-related diarrhea.

Immunotherapy is new talk of the town in different end-stage cancers. Studies have proven that higher patients with higher microbial diversity show better response to immunotherapy.

Future Directions

The connection between cancer and microbiome is evolving and future studies are pipelined to discern causality and influence on therapeutics. Key directions for the future are as follows:

• Multicenter international longitudinal cohort studies.

• Uniformity in reporting microbiome research.

• Human microbe?inoculation studies.

• Implementation of data in various oncology fields.

Conflicts of Interest

There are no conflicts of interest.

• References