Gut Bacteria Provide Genetic and Molecular Reporter Systems to Identify Specific Diseases

Abstract

With genetic information gained from next-generation sequencing (NGS) and genome-wide association studies (GWAS), it is now possible to select for genes that encode reporter molecules that may be used to detect abnormalities such as alcohol-related liver disease (ARLD), cancer, cognitive impairment, multiple sclerosis (MS), diabesity, and ischemic stroke (IS). This, however, requires a thorough understanding of the gut-brain axis (GBA), the effect diets have on the selection of gut microbiota, conditions that influence the expression of microbial genes, and human physiology. Bacterial metabolites such as short-chain fatty acids (SCFAs) play a major role in gut homeostasis, maintain intestinal epithelial cells (IECs), and regulate the immune system, neurological, and endocrine functions. Changes in butyrate levels may serve as an early warning of colon cancer. Other cancer-reporting molecules are colibactin, a genotoxin produced by polyketide synthetase-positive Escherichia coli strains, and spermine oxidase (SMO). Increased butyrate levels are also associated with inflammation and impaired cognition. Dysbiosis may lead to increased production of oxidized low-density lipoproteins (OX-LDLs), known to restrict blood vessels and cause hypertension. Sudden changes in SCFA levels may also serve as a warning of IS. Early signs of ARLD may be detected by an increase in regenerating islet-derived 3 gamma (REG3G), which is associated with changes in the secretion of mucin-2 (Muc2). Pro-inflammatory molecules such as cytokines, interferons, and TNF may serve as early reporters of MS. Other examples of microbial enzymes and metabolites that may be used as reporters in the early detection of life-threatening diseases are reviewed.

Keywords: diseases; gut microbiota; reporter systems.

Figure 1

Biomarkers that are normally used in liver function tests. ALP = alkaline phosphatase, PT = prothrombin time, GGT = gamma-glutamyl transferase, AST = aspartate aminotransferase, ALT = alanine aminotransferase. An AST:ALT ratio above 2 is normally considered a reliable indication of ARLD. The red cross denotes a loss in liver tissue. Constructed using Biorender.com (25 March 2024).

Figure 2

Changes in some bacterial populations when alcohol is consumed. GIT = gastrointestinal tract, ARLD = alcohol-related liver disease. Changes in cell numbers of some genera may be symptomatic of ARLD. Red arrows denote an increase in cell numbers and black arrows a decrease. Constructed using Biorender.com (25 March 2024).

Figure 3

Damage caused by high alcohol consumption. An elevation in CYP2E1 and NADPH oxidases (NOXs) increases oxidative stress. Gut dysbiosis alters gut metabolism and damages the intestinal barrier (epithelial cells) through various mechanisms, including oxidative stress-mediated post-translational modifications (PTMs) that decrease the interactions between tight junction proteins (TJPs). The release of fibroblast growth factor 19 (FGF-19) into the portal vein inhibits the synthesis of hepatic bile acid (BA) in the liver. Per2 = period circadian regulator, LCA = lithocholic acid, LPS = lipopolysaccharide, TNF-α = tumor necrosis factor alpha, IL-1β = isoleucine 1 beta (a pro-inflammatory cytokine), NLRP-3 = Nod-like receptor protein 3, α-SMA = alpha smooth muscle actin, TFG-β = transforming growth factor beta, CYP2E1 = cytochrome P450 2E, ROS = reactive oxygen species. Created using Biorender.com (25 March 2024).

Figure 4

Some biomarkers currently used to detect prevalent cancers. Created using Biorender.com (11 April 2024).

Figure 5

Cognitive functions are influenced by metabolites produced by gut microbiota. A few of these metabolic compounds are listed here. SCFA = short-chain fatty acids, LPS = lipopolysaccharides, PPG = peptidoglycans, GABA = γ-amino butyric acid, GPCR = G protein-coupled receptor, AD = Alzheimer’s disease, GABARs = GABA receptors, BDNF = brain-derived neurotrophic factor, L-Glu = L-glutamine, D-Glu = D-glutamine. Dysbiosis can be caused by stress that may alter tryptophan levels, SCFA levels, the immune system, and gut permeability. The release of cytokines and chemokines (IL-6, IL-1β, IL-8) can lead to neuroinflammation and activation of the hypothalamic–pituitary–adrenal (HPA) axis. Created using Biorender.com (11 April 2024).

Figure 6

A summary of reactions that cause multiple sclerosis (MS). CNS = central nervous system, CCR6 = chemokine receptor 6, BBB = blood–brain barrier, GM-CSF = granulocyte-macrophage-colony-stimulating factor, ROS = reactive oxygen species, IEC = intestinal epithelial cell. The red cross denotes dysfunctional mitochondria. Created using Biorender.com (12 April 2024).

Figure 7

Diabesity, described as a strong pathophysiological link between diabetes and excess body weight, is regulated by gut microbiota. Created using Biorender.com (12 April 2024).

Figure 8

Complications associated with ischemic stroke (IS). TMA = trimethylamine, TLRs = Toll-like receptors, NF-κB = nuclear factor kappa B, IL-17 = isoleucine 17. Created using Biorender.com (12 April 2024).