Chemicals produced by healthy bacteria could be used to assess the health of the gut microbiome and help identify critically-ill children at greatest risk of organ failure, a study published in Critical Care Medicine has found.
The gut microbiome is a trillions-strong community of healthy bacteria that live inside us.
They make important contributions to our health, including fermenting the food we eat, making vitamins and regulating our appetite.
In critical illness, patients often receive lots of antibiotics, and this may inadvertently damage many healthy gut bacteria.
Children have a less developed microbiome so may be at particular risk following strong antibiotic therapy.
If the antibiotics damage healthy gut bacteria, this can result in the loss of important functions of the microbiome and an increase in potentially disease-causing and antibiotic-resistant bugs; in turn, these can cause complications including organ failure.
In this new study, researchers looked at how critical illness affects the functions of the gut microbiome.
Researchers examined genetic profiles of gut bacteria and measured levels of chemicals these bacteria produce in 60 critically ill and 55 healthy children.
They looked at gut bacterial populations by sequencing the DNA in faecal samples.
They then undertook chemical analysis of urine and faecal samples from children participating in the study.
The researchers found that in seriously ill children, the numbers of ‘good’ bacteria were reduced compared to healthy children.
Alongside this, chemicals normally produced by the healthy gut microbiome were dramatically reduced. Levels of some of these chemicals were associated with how sick the children were.
In urine, three bacterial chemicals (called hippurate, formate and 4-cresol sulphate) were dramatically depleted in samples from critically ill patients.
In faeces, the researchers found patients had lost a group of chemicals called short chain fatty acids.
These chemicals, normally produced by healthy gut bacteria, have a number of beneficial activities for the body.
These include maintaining a healthy gut lining, regulating appetite and supporting the immune system.
The lead investigator, Dr. Nazima Pathan, from the Department of Paediatrics at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, said: “Trillions of healthy bacteria live in our guts, keeping it healthy as well as supporting our digestion and metabolism.
Serious illness may strike a severe blow to the ability of these bacteria to survive and continue their beneficial activities.
“Chemicals produced by healthy gut bacteria are effectively a signature of the presence of a healthy, functioning microbiome.
Measuring their levels could offer doctors a way of identifying who needs treatment to restore a healthy microbiome, and for how long.”
The researchers say that biochemical measures could complement the assessment of gut microbiome composition and offer an insight into the microbiome’s functional capacity.
The researchers are working on a rapid assay to help monitor gut health by measuring these chemicals as an indicator of gut health.
It could help identify patients who need probiotics to restore the numbers of healthy bacteria in the gut.
More than 100 trillion symbiotic microorganisms live on and within human beings and play an important role in human health and disease.
The human microbiota, especially the gut microbiota, has even been considered to be an “essential organ” , carrying approximately 150 times more genes than are found in the entire human genome .
Important advances have shown that the gut microbiota is involved in basic human biological processes, including modulating the metabolic phenotype, regulating epithelial development, and influencing innate immunity , , , .
Chronic diseases such as obesity, inflammatory bowel disease (IBD), diabetes mellitus, metabolic syndrome, atherosclerosis, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma have been associated with the human microbiota ,  (Fig. 1).
In recent decades, a tremendous amount of evidence has strongly suggested a crucial role of the human microbiota in human health and disease , , , , , , , , , , , , , , ,  via several mechanisms. First, the microbiota has the potential to increase energy extraction from food , increase nutrient harvest , , and alter appetite signaling , .
The microbiota contains far more versatile metabolic genes than are found in the human genome, and provides humans with unique and specific enzymes and biochemical pathways .
In addition, a large proportion of the metabolic microbiotic processes that are beneficial to the host are involved in either nutrient acquisition or xenobiotic processing, including the metabolism of undigested carbohydrates and the biosynthesis of vitamins . Second, the human microbiota also provides a physical barrier, protecting its host against foreign pathogensthrough competitive exclusion and the production of antimicrobial substances , , .
Finally, the microbiota is essential in the development of the intestinal mucosa and immune system of the host , . For example, germ-free (GF) animals have abnormal numbers of several immune cell types, deficits in local and systemic lymphoid structures, poorly formed spleens and lymph nodes, and perturbed cytokine levels .
Studies on GF animals have suggested that the immune modulation functions of the microbiota are primarily involved in promoting the maturation of immune cells and the normal development of immune functions .
In addition, studies have revealed the central role of microbial symbiosis in the development of many diseases , such as infection , liver diseases , gastrointestinal (GI) malignancy , metabolic disorders , respiratory diseases , mental or psychological diseases , and autoimmune diseases .
In this article, we provide an overview of the role of the human microbiota in health and disease, the advent of microbiome-wide association studies, and potential and important advances in the development of clinical applications to prevent and treat human disease.
The human microbiota in health
The human microbiota affects host physiology to a great extent. T
rillions of microbes colonize the human body, including bacteria, archaea, viruses, and eukaryotic microbes.
The body contains at least 1000 different species of known bacteria and carries 150 times more microbial genes than are found in the entire human genome . Microbiotic composition and function differ according to different locations, ages, sexes, races, and diets of the host .
Commensal bacteria colonize the host shortly after birth. This simple community gradually develops into a highly diverse ecosystem during host growth .
Over time, host-bacterial associations have developed into beneficial relationships. Symbiotic bacteria metabolize indigestible compounds, supply essential nutrients, defend against colonization by opportunistic pathogens, and contribute to the formation of intestinal architecture .
For example, the intestinal microbiota is involved in the digestion of certain foods that cannot be digested by the stomachand small intestine, and plays a key role in maintaining energy homeostasis.
These foods are primarily dietary fibers such as xyloglucans, which are commonly found in vegetables and can be digested by a specific species of Bacteroides .
Other non-digestible fibers, such as fructooligosaccharides and oligosaccharides, can be utilized by beneficial microbes, such as Lactobacillus and Bifidobacterium . Studies have clarified the role of the gut microbiota in lipid and proteinhomeostasis as well as in the microbial synthesis of essential nutrient vitamins .
The normal gut microbiome produces 50–100 mmol·L−1 per day of short-chain fatty acids (SCFAs), such as acetic, propionic, and butyric acids, and serves as an energy source to the host intestinal epithelium .
These SCFAs can be quickly absorbed in the colon and serve many diverse roles in regulating gut motility, inflammation, glucose homeostasis, and energy harvesting , . Furthermore, the gut microbiota has been shown to deliver vitamins to the host, such as folates, vitamin K, biotin, riboflavin (B2), cobalamin (B12), and possibly other B vitamins. A previous study demonstrated that B12 can be produced from delta-aminolevulinate (ALA) as a precursor .
In addition, gut-colonizing bacteria stimulate the normal development of the humoral and cellular mucosal immune systems .
The signals and metabolites of microorganisms can be sensed by the hematopoietic and non-hematopoietic cells of the innate immune system and translated into physiological responses . Studies comparing normal mice with GF mice have found that GF mice show extensive defects in the development of gut-associated lymphoid tissue and antibodyproduction , .
A report has also demonstrated that the gut microbiota generates a tolerogenic response that acts on gut dendritic cells and inhibits the type 17 T-helper cell (Th17) anti-inflammatory pathway . However, not all microbiota lead to health benefits. Some induce inflammation under certain conditions.
The human microbiota in disease
The human microbiota and infectious diseases
Infection is one of the most common diseases caused by dysbiosis of the microbiota. Importantly, infectious disease and its treatment have a profound impact on the human microbiota, which in turn determines the outcome of the infectious disease in the human host (Fig. 2).
Offending pathogens colonize the intestinal mucosa, thus resulting in the induction of a strong inflammatory response, followed by the translocation of the intestinal bacteria , .
Numerous studies have demonstrated the intimate relationship between infection and dysbiosis of the microbiota, and have shown that infection is associated not only with the microbiome, but also with viruses , .
For example, the intestinal microbiota of patients with Clostridium difficile (C. difficile) infection (CDI) is significantly altered , . Disturbance of the microbiota is also associated with the progression of human immunodeficiency virus (HIV) , , hepatitis B virus (HBV) , and other diseases , .
An increasing number of in vivo and human studies have indicated that interactions between the gut microbiota and host genotype or dietary changes may be crucial factors that contribute to obesity and related metabolic disorders , .
Ridaura et al.  demonstrated that the microbiota from lean or obese co-twins induces similar adiposity and metabolic phenotypes in mice.
Moreover, the lean co-twin’s microbiota can prevent adiposity gain in obese-recipient mice, if the mice are fed with an appropriate diet .
Several studies on the gut microbiota indicated that diet modulates the composition and function of microbes in humans  and rodents .
For example, a mouse study revealed that mice that were fed with lardfor 11 weeks exhibited increased Toll-like receptor activation and white adipose tissue inflammation, along with reduced insulin sensitivity, compared with mice that were fed with fish oil .
However, phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition.
Increasing evidence shows that the gut microbiota is an important modulator of the interaction between diet and the development of metabolic diseases . Furthermore, recent studies have shown that the gut microbiota influences the circadian clock and undergoes circadian oscillations .
Disruption of the host circadian clock induces dysbiosis, which is associated with host metabolic disorders . Obesity, which is associated with gut microbiota dysbiosis and altered metabolic pathways, induces impaired gut epithelial barrier function and has significant influences on physiological processes , such as gut and immune homeostasis , energy metabolism , acetate  and bile acid metabolism , and intestinal hormone release .
Type 2 diabetes
T2D is a prevalent metabolic disease worldwide; the link between the gut microbiome composition and the development of T2D is gradually being uncovered , , .
Growing numbers of studies indicate that an altered gut microbiome characterized by lower diversity and resilience is associated with diabetes.
The mechanisms that cause the disease may be related to the translocation of microbiota from the gut to the tissues, thus inducing inflammation .
Pedersen et al.  recently demonstrated that the human gut microbiome may affect the serum metabolome and induce insulin resistance through species such as Prevotella copri and Bacteroides vulgates.
Metformin is one of the most widely used antidiabetic drugs and is thought to confound the results of metagenomics data analysis .
The gut microbiota may directly affect T2D through its effect on the metabolism of amino acids; thus, future antidiabetic treatment strategies may target bacterial strains that cause imbalances in amino acid metabolism , .
Therefore, obesity and its associated metabolic complications may be a result of complex gene-environment interactions. Microbiome interventions aimed at restoring the homeostasis of the gut microbiome have recently emerged, such as the ingestion of specific fibers or therapeutic microbes. These are promising strategies to reduce insulin resistance and related metabolic diseases.
The human microbiota and other diseases
Growing evidence indicates that alterations in the microbiota are implicated in the pathogenesis of a number of other diseases, such as severe asthma, food allergies, autism, and major depressive disorder (MDD) , , , , , , all of which have recently received considerable scientific interest.
Interestingly, these diseases may not involve direct interactions with the microbiota. However, the regulating function of the microbiota, such as the microbiota-gut-brain axis, may participate in the specific pathways of the diseases.
The complex microbiota-host interactions are dynamic, involving a variety of mechanisms that include immune, hormonal, and neural pathways.
Therefore, changes in the microbiota may result in the dysregulation of host homeostasis and in an increased susceptibility to these diseases.
On the basis of these well-established connections between disease and the disruption of homeostatic interactions in the host, microbiota-targeted therapies may alter the community composition, and microbiota restoration might be used for treating these diseases.
The microbiota and allergic diseases
An early-life, antibiotic-driven low diversity in gut microbiota enhances susceptibility to allergic asthma , and thus may also affect asthma development in childhood after long-term follow-up.
Of course, the mode, place of delivery, and infant feeding also affect the GI microbiota composition and subsequently influence the risk of atopic manifestations . Bunyavanich et al.  found that infants with a gut microbiota enriched in Clostridia and Firmicutes at a host age of 3–6 months are associated with the resolution of cow’s milk allergy (CMA) by the age of 8 years.
Because the intestinal microbiota of an infant evolves rapidly in the first year, the early-life gut microbiota composition may be one of the determinants for CMA outcomes in childhood. The gut microbiota interacts with the immune systemintimately, providing signals to promote the maturation of regulatory antigen-presenting cells and regulatory T cells (Tregs), which play a crucial role in the development of immunological tolerance.
The specific members of the microbiota, such as Clostridium species, interact with Treg and regulate immunoglobulin E (IgE) levels . Saarinen et al.  showed that the clinical course and prognosis of CMA are highly dependent on the milk-specific IgE status.
A previous study also found that specific microbiotic signatures, such as that of Clostridium sensu stricto, can distinguish infants with IgE-mediated food allergies from those with non-IgE-mediated ones, and that Clostridium sensu stricto is positively correlated with specific IgE level in serum .
The microbiota and psychiatric diseases
Psychiatric diseases have posed a severe threat to human health throughout history. They are caused by a combination of biological, psychological, and environmental factors , , .
The existence of a gut-brain axis has been acknowledged for decades.
The gut-brain axis plays a key role in maintaining normal brain and GI function. More recently, the gut microbiota has emerged as a critical regulator of this axis.
The concept of this axis has been extended to the “microbiota-gut-brain axis,” and is now seen to involve a number of systems, including the endocrine system, neural system, metabolic system, and immune system, all of which are engaged in constant interaction .
Gut microbiota dysbiosis may increase the translocation of gut bacteria across the intestinal wall and into the mesenteric lymphoid tissue, thereby provoking an immune response that can lead to the release of inflammatory cytokines and the activation of the vagus nerve and spinal afferent neurons , .
Autism spectrum disorder (ASD) has been reported as correlated with an altered gut microbiota, and low relative abundances of the mucolytic bacteria Akkermansia muciniphila and Bifidobacterium spp. have been found in the feces of children with autism .
Our previous study found an altered fecal microbiotic composition in patients with MDD. Most notably, the MDD groups had increased levels of Enterobacteriaceae and Alistipes, but reduced levels of Faecalibacterium .
These studies suggest the role of the gut microbiota in autism and MDD as a part of the gut-brain axis; this suggested role should form a basis for further investigation of the combined effectsof microbial, genetic, and hormonal changes in the development and clinical manifestation of autism and MDD.
More information: Anisha Wijeyesekera et al, Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child, Critical Care Medicine (2019). DOI: 10.1097/CCM.0000000000003841
Journal information: Critical Care Medicine
Provided by University of Cambridge