Whatʼs in the web for family physicians - gut microbiome and its influence on health

Sio-pan Chan 陳少斌，Wilbert WB Wong 王維斌，Alfred KY Tang 鄧權恩

HK Pract 2021;43:11-12

The gut microbiome is undoubtedly one of the hottest topics in medicine in the past decade or so. Potentially this could be a new paradigm shift in the management of many diseases. The term “microbiome” is practically used synonymously with “microbiota”. Actually, “microbiota” refers to all the bacteria, fungi, viruses and microbes that can be identified by means of earlier 16s rRNA genes sequencing technique. “Microbiome”, on the other hand, includes all the “microbiota” plus any genomes and genetic metabolites that can be detected by the more advanced techniques such as shotgun sequencing, next generation sequencing techniques and mass spectrometry. Therofore, “microbiome” is probably a more comprehensive and precise term in describing the gut ecology system.

We acquire our gut microbiome since birth and it takes about 2 to 3 years to develop into a unique adult pattern specific to each individual. There are many factors that can affect the characteristics of one’s gut microbiome. The more important ones include mode of delivery (vaginal vs Caesarean Section), genetics, race, geographic location, diet, aging, drugs and particularly antibiotics intake. As most of our gut bacteria are anaerobes and cannot be cultured for study, we are only beginning to understand the complexity of our gut microbiome with the advent of metagenomic analysis.

On average, an adult has about 2kg of gut bacteria, our gut microbiome has at least 100 times more cells than our whole body. It contains over a few hundred times more genes than human. On average, typical gut microbiome contains over 3.3 million microbial genes compared with 23,000 genes in human genome. There are enough toxins and harmful bacteria in our gut to kill us multiple times. Yet our body's defence against this constant threat relies on a single cell thick lining of epithelial cells. Behind this epithelium, we have the largest collection of lymphoid cells making our gut the biggest immune organ in the body. Also found in our gut lining, there are over 100 million neurons. This is the largest collection of neurons outside our brain, this Enteric Nervous System (ENS) is considered by some as our second brain. Given such close relationships, it is easy to envisage that even a slight tipping of this homeostatic balance could have profound effects on our health.

Interestingly, as early as in the 16th Century the famous Chinese physician (李時珍) had already used faecal extract (人中黃) to treat severe diarrhoea. It was not until 1978, the first successful faecal transplant (FMT) to treat Clostridium Difficile infection (CDI) was documented. More recent studies revealed that the gut microbiome have a much wider influence in many aspects of our health and potentially can modify our treatment approach to many medical conditions. Experiments by transplanting human faecal materials into laboratory germ free mice demonstrated microbiome have a significant effect on obesity. The mice that had received FMT from obese human became obese mice, while those received transplants from lean person became lean mice. Furthermore, faecal transplant from young mouse to an old mouse with cognitive impairment can improve cognitive function of the older mouse. Other potential applications of faecal microbiome may include asthma, autoimmune conditions, inflammatory bowel diseases, depression, autism related syndromes, etc. We shall try to explore this Pandora's Box by looking at the available literature in the internet.

It should be noted that not all stools are equal, it is extremely difficult to find a healthy stool donor or become one. Also there are no definitive superior route of administration, dose or duration of treatment for any condition. It is much too early to tell whether this is going to be a real paradigm shift or just another medical hype. Up to the present moment, FDA only approves FMT in treatment of resistant CDI, all other applications are to be done on clinical trial basis.

Treatment of severe or recurrent clostridium difficile infection

Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent clostridium difficile infection (CDI)

The present indication for FMT is for severe or recurrent CDI. RCT trials revealed an over 90% efficacy compared with < 30% success rate of conventional treatment with vancomycin. (In 2015 FDA has issued warning concerning safety of FMT because of a few cases of post FMT infections). FMT remains to be the most effective treatment severe or recurrent CDI.

Short Chain Fatty Acids (SCFAs)-Mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases

Production of short chain fatty acids (SCFAs), SCFAs (acetate, propionate, and butyrate) are essential for maintaining the integrity of the bowel mucosal lining. The mucosal lining is the largest component of the entire immune system. Any deficiencies in this lining can result in leaky gut syndrome, IBS, inflammatory bowel diseases etc.

The brain-gut-microbiome axis

Studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least three parallel and interacting channels involving nervous, endocrine, and immune signalling mechanisms. Alternatively the brain can affect the community structure and function of the gut microbiome through the autonomic nervous system, localised gut mobility, permeability and many other pathways.

The vagus nerve at the interface of the microbiota-gut- brain axis

The Vagus nerve is the principal component of the parasympathetic system. It is bi-directionally connecting the CNS and ENS (enteric nervous system) and act as a moderator between the brain and the gut microbiome.

A novel faecal Lachnoclostridium marker for the non-invasive diagnosis of colorectal adenoma and cancer

Colorectal cancer - the gut microbiome has an important role in the carcinogenesis of CRC. New studies had identified specific markers for colorectal polyps and colorectal cancers. It opened up a new way of screening for colorectal polys and cancers without going through colonoscopy.

Fecal Microbiota Transplantation relieves gastrointestinal and autism symptoms by improving the gut microbiota in an open-label study

The authors of this recent trial in China proved that FMT was well tolerated and effective in improving gastrointestinal symptoms and autism-like behaviours in children with Autism Spectrum Disorder (ASD). FMT seemed to induce the production of a microbiota that was significantly different from the pre-FMT microbiota and much more similar to those of the healthy donor and typically developing children.

Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review

Associations between gut microbiome and depression have been observed in recent years. The Gut-Brain-Axis is a bidirectional signalling pathway between the gastrointestinal (GI) tract and the brain. The gut microbes and their metabolites are thought to be the modulators of this connection. They have far reaching effects on the immune system, central and autonomic nervous systems, and GI functioning. These interactions have also been linked to various psychiatric illnesses such as depression, anxiety, substance abuse, autism spectrum and eating disorders. It is hypothesised that techniques aimed at strengthening and repopulating the gut microbiome, such as FMT may be useful in the prevention and treatment of psychiatric illnesses. Further FMT studies in psychiatric illnesses could be worth pursuing, crucial in determining the potential of FMT in psychiatric illnesses.

Systematic review with meta-analysis: encapsulated faecal microbiota transplantation – evidence for clinical efficacy

Faecal microbiome transplantation can be performed in different ways such as through endoscopy, enemas or capsules. The transfer through capsules is preferred by the patients and has the advantages that it can be administered long-term and can be delivered to the patients in their home. Treatment with capsules is safe when guidelines for screening donors and testing faecal material are followed. The treatment is highly effective in the treatment of recurrent C. difficile infection, often caused by repeated antibiotic treatments. Faecal microbiome transplantation delivered through capsules is as effective as treatment delivered through other routes in the treatment of C. difficile infection. There are promising results in the treatment of other diseases such as liver disease, inflammatory bowel disease and the treatment of multi-drug resistant bacteria.

Influence of diet on the gut microbiome and implications for human health

Diet plays a significant role in shaping the microbiome. This review evaluated systematically the current data regarding the effects of several common dietary components on intestinal microbiome. The conclusion from this paper suggests plant proteins increase SCFA and reduce inflammatory while animal proteins are pro-inflammatory by reducing SCFA. A low fat diet leads to increased faecal abundance of Bifidobacterium with concomitant reductions in fasting glucose and total cholesterol, compared to baseline. Diet rich in high saturated fat increases the relative proportion of Faecalibacterium prausnitzii. Nondigestible carbohydrates such as fibre travel to the large intestine where they undergo fermentation by resident microorganisms. High intake of these carbohydrates in 49 obese subjects resulted in an increase in microbiota gene richness. Hence, dietary fibres are the most essential components in promoting microbiota health.

Therapeutic mechanisms of traditional Chinese medicine to improve metabolic diseases via the gut microbiota

Metabolic diseases such as obesity, type 2 diabetes mellitus, and hyperlipidaemia are associated with the dysfunction of gut microbiota. Traditional Chinese medicines (TCMs) have considerable effects in the treatment of metabolic disorders by regulating the gut microbiota. However, the underlying mechanisms are still unclear. Studies have found that hypoglycaemic drugs like metformin or acarbose can treat metabolic diseases by altering gut microbiota. Studies have also shown that TCMs significantly affect glucose and lipid metabolism by modulating the gut microbiota, particularly mucin-degrading bacteria, bacteria with anti-inflammatory properties, lipopolysaccharide-and short-chain-fatty-acid-producing bacteria, and bacteria with bile-salt hydrolase activity. In this review, scientists explored potential mechanisms by which TCMs improved metabolic disorders via regulating gut microbiota composition and functional structure.

Gut microbiota: a new angle for traditional herbal medicine research

Traditional Herbal Medicine (THM) has been used for thousands of years. However, the effective ingredients in the herbal formulations and their underlying mechanisms of actions are still unknown. In this review, scientists had investigated the studies available that focused on the efficacy, active ingredients and bioavailability of THM, and the role of gut microbiota in THM-mediated treatment of diseases.

During growth and reproduction, gut microbiota produces several enzymes which can degrade Traditional Herbal Medicine components. The active components are transformed into new active metabolites by the action of specific microbial enzymes, which then exert different biological effects.

For example, Saponins have antipyretic, sedative and anti-cancer effects, and are commonly present in ginseng, Panax notoginseng and Bupleurum. Ginsenosides are the main active constituents of P. ginseng, and are metabolised to compound K (20-O-(b-d-glucopyranosyl)-20(S)-protopanaxadiol) by gut microbiota before absorption into the circulation. Compound K has hepato-protective, anti-cancer, anti-wrinkling, and anti-aging properties, and is more potent than the parental ginsenosides. More examples are included in the article and will give readers a better insight into the mechanism of the Traditional Herbal Medicines. 