Friend, not foe: Harnessing the gut microbiome for health benefits

Janet Sasso, Information Scientist/CAS
Rumiana Tenchov, Information Scientist, CAS
Angela Zhou, Information Scientist, CAS

Gut microbiome: From age-old hypothesis to multi-million-dollar industry

Which organ in the body weighs 2kg and is bigger than the average human brain? The gut microbiome may not be the first answer that springs to mind, but it has been named the 'forgotten organ' owing to its extensive influence on our physiology and pathology.

Back in the 20th century, Russian microbiologist and Nobel-Prize winner Élie Metchnikoff first spotted the potential to manipulate the intestinal microbiome with host-friendly bacteria found in yogurt, with a view to enhance health and delay aging. This age-old hypothesis has grown into a multi-million dollar industry since significant activity led Forbes to name the 2010s The Decade of the Microbiome. The global Human Microbiome Market was estimated to be worth $269 million in 2023 and is forecasted to reach $1.37 million by 2029, growing at a CAGR of 31.1% in that time.

The gut microbiome's influence in our health

The four dominant phyla resident in the human gut are Firmicutes (which contains Lactobacilli), Bacteroidetes, Actinobacteria (which contains Bifidobacteria), and Proteobacteria. Human microbiota collaborate closely with the digestive tract to exert five predominant functions, namely to support digestive tract maturation, provide a barrier function against pathogens and toxins, and promote immune system development.

  1. Promote digestion.
  2. Support digestive tract maturation.
  3. Provide a barrier function against pathogens and toxins.
  4. Play a protective role in promoting immunity system development.
  5. Support the synthesis of essential vitamins including Vitamin B.

The extensive genetic material encoded within the gut microbiome can synthesize enzymes with versatile metabolic capabilities and maintain important host functions, e.g., short-chain fatty acids, bile acids, tryptophan and indole derivatives, and neurotransmitters.

Any disturbances to the gut microbiome may trigger pathological processes such as digestive system diseases (e.g., inflammatory bowel disease), neurodegenerative and metabolic disorders, and cancer. More specifically, the gut and central nervous system are now known to communicate via the gut-brain axis (GBA); most gastrointestinal diseases result from altered transmission within the GBA that is influenced by both genetic and environmental factors. The GBA presents an attractive target for the development of novel therapeutics for an ever-growing list of disorders related to mental and digestive health.

Trends in gut microbiome research

CAS identified more than 250,000 scientific articles (mainly journal articles and patents) relating to gut/intestinal microbiome/microbiota, with nearly 15,000 being linked to various aspects of mental and gut health. Microbiome-related literature has sharply increased over the last decade, with steady exponential growth in journal articles from 1997 to 2022 (Figure 1). The number of patents grew rapidly until 2004, possibly correlating with the initial accumulation of knowledge and transfer into patentable applications. After that time, activity plateaued (Figure 1).

An examination of key publication concepts (approx. 4500 total) relevant to gut microbiome research in mental and gut health revealed “immunity” (>4000 documents) and “gut microbiome” (>3500 documents) as top concepts in the area. The “gut-brain relationship” concept exhibited the greatest growth rate between 2021 and 2022 (Figure 1).

trends chart
Figure 1. Journal and patent publication trends in gut microbiome research related to mental and gut health; Inset: Microbiome vs. Proteome document yearly trends.

Correlations were noted between gut microbiota and mental, metabolic, and digestive system disorders, cardiovascular and neurodegenerative diseases, various cancers, and immune and autoimmune diseases (Figure 2).

trends chart
Figure 2. Distribution of the publications in the CAS Content Collection related to gut microbiome-associated diseases.

Dysbiosis, an imbalance in the microbiome structure that ultimately triggers pathological changes, was a particular trend noted in the publications analyzed, with other trending topics including depression, Alzheimer’s disease, Parkinson’s disease, and neurodegeneration (Figure 3).

trends chart
Figure 3. Trends in the number of publications concerning gut microbiome-related conditions during 2016−2021. Percentages are calculated with yearly publication numbers for each condition, normalized by the total number of publications for the same disease in the same period. 

Key players in the microbiome industry

A 2022 report estimates that >130 microbiome companies are evaluating >200 pipeline therapies in various stages of development. The top academic organizations responsible for journal publications were universities and research institutes, with the University College Cork, the Chinese Academy of Science, the University of California, and McMaster University leading the field.

Regarding patent activity, lead universities and medical centers included the University of California, and Johns Hopkins University, while Ares Medical and Merck are leading patent assignees (Figure 4).

Private investment is growing rapidly in microbiome research, which endorses the clinical potential of prebiotics, probiotics, and the gut microbiome overall. The average annual investment within this industry has risen from approximately $2 billion in 2014-2017 to just over $20 billion in 2021. The investment data clearly shows a recent and increasing commercial interest surrounding biotics and their potential in the therapeutic space.

Notable active investors include the French venture capital group Seventure Partners , U.S. life science innovators Flagship Pioneering, UK biotechnology firm Microbiotica, and Swedish probiotics firm Biogaia.

Figure 4. Top patent assignees from companies (A) and universities and hospitals (B) for patents related to gut microbiome research in mental and gut health.

Clinical trial landscape for the treatment of mental health and digestive disorders

There are several notable completed and ongoing clinical trials investigating biotics in both digestive and mental health disorders (Table 1).

Table 1. Completed/ongoing trials investigating the use of biotics in digestive and mental health disorders.

Area of interest Treatment Sponsor Study overview
Functional constipation Retrograde colonic enema with fecal supernatant Shengjing Hospital, China Randomized clinical trial (RCT) investigating the efficacy and safety of retrograde colonic enema with fecal microbiota transplantation (FMT) in the treatment of pediatric functional constipation (NCT05035784)
Irritable bowel syndrome (IBS) Healthy feces microbiota Helse Fonna, Norway FMT intervention led to significantly fewer IBS symptoms and fatigue, and a greater quality of life both at two and three years (NCT03822299)
  MRx1234 (Blautia hydrogenotrophica)  4D pharma plc Data from Phase II RCT supports the use of MRx1234 (given for eight weeks) in both IBS with constipation and IBS with diarrhea (NCT03721107)
  VSL#3; eight strains encompassing Streptococcus, Lactobacillus, Bifidobacteria Kaplan-Harzfeld Medical Center, Israel  PROAGE study: The use of daily probiotics for 45 days in hospitalized elderly patients was associated with a significant reduction in diarrhea and constipation and a significant increase in serum albumin, prealbumin, and protein in patients ≥80 years old (NCT00794924)
  Multi-strain probiotic capsules containing four Bifidobacterium, five Lactobacillus, and one Streptococcus species  Children's Memorial Health Institute, Poland RCT that showed that eight weeks of probiotic treatment was associated with significant improvements in IBS severity and symptoms in patients with diarrhea-prominent IBS (NCT04662957)
Mental health disorders Probiotic drink containing Lactobacillus casei strain Shirota Indian Council of Medical Research/ Yakult Honsha Co., LTD Proof-of-concept RCT showed that probiotics consumed for four weeks led to subtly altered brain activity and functional connectivity in healthy subjects performing an emotional task without major effects on the fecal microbiota composition (NCT03615651)
  Lacticaseibacillus paracasei (Lpc-37®)  Chr Hansen, Denmark A pilot RCT investigating the efficacy of two probiotics given for 12 weeks in adults with depressive symptoms (defined as a score of 20–40 on the Beck's Depression Inventory [BDI-II]; NCT05564767) 
  Bifidobacterium adolescentis or combination of Lactocaseibacillus rhamnosus LGG and Bifidobacterium BB-12 Chr Hansen, Denmark A pilot RCT investigating the efficacy of two probiotics given for 12 weeks in adults with depressive symptoms (defined as a score of 20–40 on the Beck's Depression Inventory [BDI-II]; NCT05564767)
Insomnia FMT capsules Third Military Medical University, China An RCT to investigate whether FMT capsules administered for four weeks can improve sleep in patients with insomnia, and their effect on gut microbiota and its metabolites, inflammatory factors, neurotransmitters, and sex hormones in peripheral blood (NCT05427331)

The gut and beyond: The expanding potential of the microbiome

The past decade has seen a transformation in the way we regard our native bacteria and their impact on our health. There is extensive research activity investigating the use of microbiome therapies for the prevention and treatment of digestive and mental health disorders, with rising interest from pharmaceutical companies. We've seen substantial collaboration between biotechnology companies, academic institutions, and pharma. As such, we should anticipate further partnerships as research interests evolve. Beyond the gut-brain axis, secondary markets are emerging in areas such as dermatology, respiratory, oncology, and general lifestyle, suggesting that the manipulation of microbiota will soon become an intrinsic means of optimizing our health.

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