The Gut Microbiota: More Important Than You Thought

Medically reviewed by Onikepe Adegbola, MD, PhD

Abstract

The gut microbiota is often regarded as the most important regulator of host health. Microbes practically infest every part of our body, implying various interactions with our organs.

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Defects in the gut microbiota are now related to various disorders, including obesity, type 2 diabetes, hepatic steatosis, inflammatory bowel diseases (IBDs), and cancer. As a result, various immune, energy, lipid, and glucose metabolic pathways are thought to be impacted.

Several biological mechanisms show how gut bacteria may be linked to the prevention or onset of sickness. We look at both well-known and freshly found metabolites (such as short-chain fatty acids, bile acids, and trimethylamine N-oxide).

Understanding the complexities and molecular elements of the link between gut microorganisms and health will aid in the development of innovative therapeutics.

The human gut microbiome

The human microbiome is a collection of microbes, their genes, and their chemicals that occupy our bodies and are passed down vertically from generation to generation. While all body regions are colonized, the gut has the highest microbial numbers, which have been extensively studied. The most essential and recent study on how gut microbes, their activity, and the mediating role of chemicals can affect our health is discussed here.

In the oral and saliva microbiomes of healthy persons, millions of bacteria consume our food daily. Many factors, including stomach acidity, bile acid generation, digesting enzymes, and antimicrobial enzymes in the duodenum and beyond, limit their lifetime in the gut. Chemical variables like pH, oxygen content, reductive position, the natural production of mucus, bile, and antigens, and natural elements like gut design approach, muscular contractions, and transit times influence further downstream microorganism growth.

Per unit system, the small intestine generates tens of millions to hundreds of millions of partly oxygen-tolerant cells. Because colon transit is over a dozen times faster than small intestine transit, maximal groupings of up to 100 billion cells per gram can be detected in the lower gut for only a few days.

This biomass, excreted as feces, forms the gut microbiome linked to various disorders and is highly adaptable to food and medicines. (see table 1 for an overview).

It’s important to note that, while we may live without a colon, we can’t live without a small intestine, which has the most mucosal regions of any organ in our body. It contains the bulk of gut synapses, immune and nerve cells, and is implicated in many crucial microbe-host interactions. Various innovative technologies, such as catheters or capsules for sampling, delivery, or inspection, have been developed recently, despite being difficult to test experimentally.

The gut microbiome and various intestinal and extraintestinal diseases.

The gut microbiota has been related to various intestinal and duodenal ulcers. Much significant research has been carried out in specific gastrointestinal (GI) conditions such as IBDs, celiac disease, irritable bowel syndrome (IBS), colorectal cancer (CRC), chronic liver ailments, or pancreatic ailments to investigate the gut microbiota and its implications.

Microbial imbalance is seen in chronic liver illnesses and severe liver ailments such as liver cirrhosis. The gut microbiota plays a critical role in several metabolic diseases, according to research using prebiotics, probiotics, and antibiotics.

Reduced gut microbiota has also been linked to pancreatic adenocarcinoma, a growing public health concern. The makeup of the intratumoral microbiota affects the immune system and the natural course of human illness.

The gut bacterial axis appears to play a role in NAFLD, particularly in cases of fibrosis and advancement to more severe stages of the disease like non-alcoholic hepatic steatosis. The gut microbiota has been investigated in various gastrointestinal and metabolic disorders. (see table 1 for an overview).

Table 1. PubMed-listed articles regarding topics, “microbiome and diseases”

PubMed search 15 December 2021.

Gut microbes and metabolic disorders: molecular actors

The gut microbes influence various metabolic illnesses. This regulation is based on the microbiota’s synthesis of various chemicals and their interactions with receptors on the human host, which may activate or inhibit signaling pathways and be beneficial or destructive to the host’s health.

These interactions affect various bacterial metabolites, ranging from tiny molecules to large macromolecules. They contain metabolic byproducts like SCFAs and diverse molecules like peptidoglycan and lipopolysaccharides (LPS) essential for bacterial preservation.

Microorganism composition and food and lifestyle variables affect the amount and availability of these metabolites.

Short-chain fatty acids and impact host health: molecular mechanisms

Because the intestinal system is highly specialized for indigestion, emulsification, and nutrient absorption, most nutrients will bypass the digestive process. Most proteins (reduced to amino acids) and simple carbohydrates (divided into sugar units) are digested and absorbed in the same way.

The body requires enzymes to break them down, allowing them to pass undigested through the small intestine. Variety of gut microbes aid in the metabolization of these non-digestible complex carbohydrates into various SCFA molecules.

These chemicals impact the liver, adipose tissue, muscles, and the brain, among other metabolic processes in the gut and elsewhere.

A fermentable dietary fiber-rich diet has found molecular approaches that might lower body weight gain, fat mass development, insulin resistance, and energy absorption, according to the researchers.

Other functionalities linked to their fundamental roles and action mechanisms may be present in certain SCFAs. In several instances, butyrate has been found as a critical source of energy for colonic cells to extend and defend the gut boundary.

Lipopolysaccharides/Pathogen-associated molecular patterns

The gut barrier is a complex system of physical and chemical components that monitor and protect the host against microbial invasion and harmful stimuli. Some of these hazardous substances from the environment are pathogen-associated molecular patterns (PAMPs), bacteria of which LPS is the archetypal family.

To resist microbial invaders or mend wounded tissue, antigen-presenting cells are activated, joining the innate immune system, and signaling pathways are boosted.

Different microorganisms produce different amounts of LPS, which affects gut barrier function, adipose inflammation, intestinal glucose absorption, blood glucose, insulin, and incretins, implying that the overall outcome of metabolic endotoxemia stages on host metabolism can differ depending on the microbial community composition.

Bioactive lipids

Endocannabinoid system

The eCB signaling system plays a key role in regulating energy, glucose, and lipid metabolism and in immunity, inflammation, and microbiota-host interactions. Among its various pleiotropic effects, the eCB has been associated with immune responses and a range of other physiological processes.

It changes after obesity and diabetes, with a rise in AEA levels that causes intestinal permeability through CB1-dependent pathways. Changes in the gut microbiota composition are linked to an increase in AEA.

This is the first research to present that NAEs may play a role in metabolic diseases and alterations in gut flora.

Bile Acids

Primary BAs are amphipathic compounds generated in the liver from cholesterol, such as cholic acid (CA) and chenodeoxycholic acid (CDCA) in humans (and muricholic acid (MCA) in rodents). When food is swallowed, it is released into the small intestine, where it aids in the breakdown and absorption of dietary fat. Around 95% of intestinal BAs are absorbed in the ileum before the liver re-secrets it. BAs circulate through the enterohepatic system multiple times per day. It’s a crucial physiological mechanism for preventing hyperglycemia, dyslipidemia, and obesity by maintaining whole-body glucose, lipid, and energy homeostasis. It protects the gut and cardiovascular systems against inflammatory and metabolic illnesses.

Although BAs’ principal role is to control cholesterol, triglycerides, and fat-soluble vitamins digestion and absorption, they have recently been discovered to have an endocrine function as signaling molecules. Bile acids (BA) activate numerous receptors that regulate epithelial cell proliferation, gene expression, lipid, glucose, and energy metabolism.

Aryl hydrocarbon receptor: a link to energy metabolism, inflammation, and gut microbiome

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated following ligand interaction. It is found in all vertebrate cells. Because there is a diminished ability to metabolize tryptophan into AhR binding derivatives in both preclinical and clinical contexts, AhR has been connected to energy metabolism and metabolic syndrome. By upregulating Lactobacillus spp. and the critical barrier cytokines interleukin (IL)-10 and IL-22, Indigo, a naturally occurring AhR ligand with powerful anti-inflammatory properties, protects against high-fat diet-induced obesity and metabolic abnormalities.

The AhR route is a model pathway that connects microbiota, epithelial barrier, metabolism, and immunological activities. In simulated alcoholic liver illness, stimulation of AhR ligands and administration of 6-formylindolo (3,2-b) carbazole (Ficz) eased alcoholic liver disease, a condition in which the gut flora is profoundly affected.

Key bacteria and their specific molecules

Because different gut bacteria generate signaling molecules, their specificity is restricted. Different bacteria can produce specialized chemicals that interact with the host in different ways. These include immunomodulatory polysaccharides and sphingolipids produced by Bacteroides spp and muropeptides formed by Enterococcus spp.

Proteins that are genetically encoded by one or a few strains of the same species comprise a specific class of unique molecules. Some probiotics are derived from microorganisms that are already commonly used in probiotic supplements. Some can interact with host receptors or cell envelopes when they are secreted.

The caseinolytic protease B (ClpB) proteins are well-known moonlighting proteins found to be partially secreted by various bacteria, including Lactobacilli and Bifidobacteria.

Newly identified molecules, impact on health, and their targets 

Besides the conventional molecules like SCFAs, BAs, or PAMPs, and gut peptides (i.e., GLP-1, PYY), which are all defined as regulators of the host metabolism, gut barrier, and inflammation, a new class of chemicals known as ‘enterosynes’ is gaining traction. Enterosynes are chemicals that target the enteric nervous system to modify the duodenal contraction (ENS). Hormones, bioactive peptides/lipids, nutrients, bacteria, and immunological factors are all examples of chemically varied molecules.

Numerous bioactive chemicals found in the gut microbiota operate on host receptors involved in metabolism and inflammatory control. Some metabolites are helpful to health, while others are possibly harmful, with only association studies or animal tests providing confirmation.

General conclusion and perspectives

The area of gut microbiota and health is progressing toward undeniable causal relationships. Despite this, many studies continue to assert causation when just correlations are shown. Moving from the correlation to causation is still a crucial step in bettering the design of potential therapies. The scientific world is steadily heading toward personalized medicine, owing to multiple efforts and improvements in omics analysis. The microbiome era will be an important aspect of the paradigm change in medicine and dietary methods in the future.

References:

Hur, K. Y., & Lee, M. S. (2015). Gut Microbiota and Metabolic Disorders. Diabetes & metabolism journal, 39(3), 198–203. https://doi.org/10.4093/dmj.2015.39.3.198

Vos, W. M. de, Tilg, H., Hul, M. V., & Cani, P. D. (2022, May 1). Gut microbiome and health: Mechanistic insights. Gut. Retrieved April 29, 2022, from https://gut.bmj.com/content/71/5/1020