Looking to the future – exploring new frontiers in gut microbiome innovation

You’ve completed your 10,000 steps for the day – but have you tracked the state of your microbiome?

Surprising as it might sound, advances in technology mean we are within touching distance of making this a reality.  It is widely understood that an abundance of friendly gut bacteria is good for health and wellbeing, and the growing interest in biotics indicates that digestive health, and its link with good immunity and mental health, is front of mind for many. But how well do we understand the role of the trillions of microbes in our gut and their impact on our health?

To coincide with World Microbiome Day (27^th June 2023), we lift the lid on recent research and explore how it’s providing razor sharp insight into the role of the microbiome and its intricate, synergistic relationship with nutrition and a lifetime of good health.

Research on the gut microbiome is flourishing. It has come a long way from studying microbial colonization of newborn babies’ guts by microscope and petri dish. More recently, adding new technologies, rapid DNA sequencing methods and artificial intelligence (AI) into the mix has unravelled the complexity of the microbiome and propelled our understanding into new territory. And, with promising innovations in machine learning and data science, scientists have unprecedented access to large, complex data sets with tens of thousands of samples from across populations and even regions. They can analyze how different microbial species in our gut interact and communicate, the elements of our food they utilize and, more importantly, how they turn these into molecules that impact our health.

“We are lucky as microbiologists to work in this area now as the field of microbiome research has accelerated so quickly over the last decade. The technology and genomic tools available are extraordinary and it is exciting to see how breakthroughs will benefit future health,” explains Dr Guus Roeselers, head of Microbiology research at Danone Research & Innovation.

Building a blueprint from the earliest days

We know that the right nutrition in the first weeks of life is vital for the development of a healthy microbiome and robust immune system¹ Vandenplas Y, et al. Wiley 2015 Chichester, West Sussex, United Kingdom, ed 1. 2015 ² Martin R, et al. Early life: gut microbiota and immune development in infancy. Benef Microbe.2010;1:367-82 –. It is also well-documented that external factors, such as the mother’s diet during pregnancy, type of delivery and use of antibiotics, can impact babies’ gut bacteria.

The rates of Caesarean section (C-section) delivery are rising globally, accounting for more than one-fifth of all births and set to increase to nearly one-third of all births by 2030³ https://www.who.int/news/item/16-06-2021-caesarean-section-rates-continue-to-rise-amid-growing-inequalities-in-access. In some countries, the rates are even above 50%.  Epidemiological studies have indicated an association between C-section birth and an increased risk of developing childhood infections and non-communicable diseases such as allergies. Scientists believe that the compromised microbiome that results from C-section birth is one of the risk factors that mediates disease risk.

Danone Research & Innovation supports the World Health Organization’s global public health recommendation for exclusive breastfeeding for the first six months of life and continued breastfeeding up to two years and beyond, combined with the safe introduction of appropriate complementary foods. It’s not surprising then that specialized nutrition interventions to improve the baseline microbiome of babies born by C-section are being investigated. “These babies aren’t exposed to good microbes from their mothers via the birth canal and this impairs their microbiome’s ability to digest the oligosaccharides (sugars) in human milk,” explains Associate Professor Dr Christophe Lay, Senior Scientist Gut Microbiome at Danone Research & Innovation. Dr Lay was involved in a study⁴Lay C, et al. A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants. BMC Microbiol. 2021 Jun 25;21(1):191  showing that C-section born babies still have the undigested sugars from human milk in their stools in the first days of life, which is not the case for vaginally born babies. Introducing a synbiotic supplementation restored the ability of the microbiome to utilize these sugars. This contributes to the establishment of a healthy gut environment, closer to the one observed in babies born vaginally. This restoration of the microbiome of babies born by C-section could help reduce the risk of diseases associated with C-section birth. With the global rising prevalence of C-section delivery, this is an important discovery and will help ensure there are specific solutions to optimize infants’ gut microbiome for life-long health, regardless of their delivery.

Increasingly prevalent, allergies are another important area of early life microbiome research. Food allergies affect 10% of children globally, with cows’ milk protein allergy the most common. Nearly 80% of our immune system is located around the gut but the immune system needs to be trained. A blank sheet at birth, it must quickly learn which microbes have to be tolerated and which trigger an inflammatory response. If the immune system gets confused, the system derails – a key factor in allergy development.

Studies exploring the microbiome in cow’s milk allergic infants found that hydrolyzed cows’ milk protein – cutting the protein up into smaller parts – makes it unrecognizable for the compromised immune system.  Extensively hydrolyzed whey protein formula as a result was found to be well tolerated in 97% of children with a proven cow’s milk allergy⁵Giampietro, P.G., et al. Hypoallergenicity of an extensively hydrolysed whey formula. Pediatr Allergy Immunol. 2001. 12 (2): p. 83-6. . Examining the window of opportunity in early life for microbiome development and defining which specific solutions can rebalance the microbiome and train the immune system will go a long way towards addressing a compromised microbiome, reducing disease risks, resolving allergy symptoms, and improving general health.

How data evolution can transform adult health

As complex as a fingerprint, the gut microbiome can be affected by diet, lifestyle, medication, and the environment. Microbiome testing and profiling, using stool samples, has been around for a while to understand the links between gut microbiome composition, diet, and health. But knowing more about what these microbes do and how they interact will give a clearer understanding of how the gut microbiome impacts our health. This opens the door to the development of personalized nutritional recommendations, based on gut microbiome profiles, to optimize gut health.

New technology and sequencing tools, as well as machine and deep learning with their powerful predictive and informative potential, allow scientists to investigate the different interactions, capabilities, and roles within microbial ecosystems. Extracting DNA molecules from samples and using sequencing technology developments permit scientists to go far beyond identification of different species and help identify new biomarkers and metabolic responses. They pave the way for international large-scale population studies where the microbiome can be interrogated at a much deeper level, analyzing the relationship between what it is and what it does and, perhaps more importantly, how different foods influence it and affect people differently.

Researchers from Danone Research & Innovation put this into action by collaborating with top scientists worldwide, using state-of-the-art analysis techniques. For instance, The Human Diet and Microbiome Initiative (THDMI), a partnership with the University of California San Diego and the Microsetta Initiative, conducted one of the largest analyses of the composition of the human microbiome, helping to analyze 35,000 stool samples and collect 2,500 new stool samples from diverse populations across five countries⁶Tap, J., Lejzerowicz, F., Cotillard, A. et al. Global branches and local states of the human gut microbiome define associations with environmental and intrinsic factors. Nat Commun 14, 3310 (2023). . Researchers combined comprehensive public datasets and used advanced techniques to classify the microbiome into communities based on certain configurations of microorganisms. Findings highlight the intricate organization of the human gut microbiome, with scientists identifying that the human gut microbiome can be divided into different gut microbiome branches with varying diversity gradients – from rich to low diversity.

This knowledge can serve as a foundation for personalized nutrition and therapeutics, utilizing an individual’s unique gut microbiome composition to deliver targeted interventions for optimal health. The next stage is to determine how these microbiome branches influence the response of the gut microbiome to changes like age, disease progression, diet and antibiotics use.

AI revealing insights from large-scale data

Danone Research & Innovation’s collaborative large-scale initiative THDMI is discovering more about the complexity and diversity of the world’s gut microbiomes, and how different diets can benefit our gut health and wellbeing than ever before. It is an unprecedented international research study conducted across the US, UK, Mexico, Spain, and Japan. Helping to unveil the secrets of the gut, it provides insight into the various impacts of different diets on the gut microbiome and what can be learned to benefit population health. Discoveries so far include that it is the overall eating pattern that has more of an important influence on gut microbial communities than individual diet components. This will inform personalized dietary strategies for the general population and help address specific health needs, including allergies, gastrointestinal disorders, diabetes, and obesity.

“Artificial intelligence has been used for a while in our research already – not in the same way as chat GPT, but to precisely determine the species identity of thousands of microbial DNA sequences detected in stool samples and to interrogate these huge complex data sets to find new biomarkers or predictors to see how likely someone is to develop an allergy, or how well someone metabolically responds to eating certain food. That knowledge can be used to define healthier nutrition, diets, and lifestyle.  The real advantage of machine learning and AI now is that we can integrate far more data sets that we collect from the lab, clinical studies and the real world and put these together in a more meaningful way,” explains Guus Roeselers.

The next step? Putting microbiome data into everyone’s hands so they can choose the right nutrition at the right time to benefit their microbiome and positively impact their health. In the not-too-distant future, it is conceivable that we will have stool apps and smart toilets that can instantly analyze our microbiome from our stools, which can then be translated into readings to help manage individual gut and immune health. Danone Research & Innovation is also developing digital health solutions to support gut health, based on their ‘OneBiome’ service. By profiling an individual’s microbiome and associated dietary lifestyle data, the aim is to fuel the science on personalized nutrition.

Looking ahead: addressing dysbiosis and optimizing treatment

We know that less diversity of certain species in the microbiome can indicate poor health. And this is where science is now shifting its focus to understand how an imbalanced microbiome, known as dysbiosis, impacts those who are unwell, frail, undergoing treatment or recovering from surgery, and how nutrition can be used in a curative way.

For example, with cancer patients, microbes impact how chemotherapy is metabolized. For some, their microbes may make the drug more toxic. Others may make patients able to tolerate higher doses. If side effects are too hard to bear, the patient may be less compliant or only be able to tolerate a lower dose. So, the microbiome can have a direct effect on the success of some cancer treatments. Modulating the microbiome with biotics solutions and supplementing the diet with more calories or protein can help maximize how the patient responds to their treatment.

“We are taking inspiration from the early life nutrition research in this field as in many cases in adult patients, it helps to hit the reset button. We are finding out how beneficial it can be to give adults active ingredients or biotics solutions more typically consumed in early life, like human milk oligosaccharides and or early life type prebiotics, for a short time. They stimulate the growth of good bacteria, and these can temporarily rejuvenate the microbiome and then pave the way for beneficial adult type microbes to settle and, alleviate dysbiosis,” explains Guus Roeselers.

Using nutrition as a fundamental part of prevention and treatment is a vital area of research and will revolutionize how patients respond to treatment and recover from illness. Findings from a recent precision nutrition studies⁷Gijbels, A., et al. The PERSonalized glucose optimization through nutritional intervention (PERSON) study: rationale, design and preliminary screening results. Front. Nutr. 8, 694568. 2021 , ⁸Inez Trouwborst, et al. Cardiometabolic health improvements upon dietary intervention are driven by tissue-specific insulin resistance phenotype: A precision nutrition trial, Cell Metab. 35 (1): … Continue reading have already shown that tailoring nutritional interventions according to metabolic and insulin resistant phenotypes helps improve obesity and cardiometabolic health conditions, including heart attack, stroke, diabetes, insulin resistance and non-alcoholic fatty liver disease, rather than opting for a one-size-fits-all dietary approach.

Where can this science take us? Potentially, screening patients before treatment to find missing microbes or specific microbiome phenotypes before treatment to determine personalized nutritional interventions to help improve treatment success.

“One of the big challenges that remains is to understand how the microbiome of an individual varies over time. Continuing to co-build complex data sets and using big data analytic approaches to integrate and analyze microbiome data, nutrition data, health data and also lifestyle factors, will help us scientists design specific biotic interventions for specific groups of individuals (with a specific baseline microbiome profile) to manage their health and improve their response to illness. This will give them a better chance of recovery and good health,” adds Christophe Lay.