On May 14th 2020, BaseClear organised the 1st Infant & Pregnancy Microbiome Experts Meeting, which was attended by 55 participants from 30 companies, with a nice blend of 70-30 commercial-academia profiles. The online event was open for public after registrations and was chaired by Dr. Radhika Bongoni, Dr. Derek Butler, Dr. Ali May.

The speakers included industry thought leaders and key players:

Dr. Clara Belzer – Wageningen University, Netherlands; Dr. Katri Korpela – University of Helsinki, Finland; Dr. Marijke Faas – University Medical Center Groningen, Netherlands; Dr. Ali May – BaseClear, Netherlands; Dr. Kaouther Ben Amor – Danone, Netherlands; Dr. Katja Parschat – Jennewein Biotechnologie Germany; Dr. Steve James – Quadram Institute Biosciences, UK; and Dr. Maciej Chichlowski – RB/Meadjohnson Nutrition USA.

The event was segmented into two themes

  • Session 1: 10:50-12:30 EXPLORING THE MICROBIOME
  • Session 2: 15:00-16:30 MODULATING THE MICROBIOME

Both the sessions were followed by 30 minutes of panel discussions with the speakers, including questions from the participants. All the presentations were technical including unpublished data and future research. At the end of the day, all 9 speakers were involved in concluding remarks with broad questions which will be stated under the ‘way forward’ section of this report. There was a surprise online pub quiz with 3 winners, closing the event with raising a virtual toast.

Session 1: EXPLORING THE MICROBIOME

Dr. Clara Belzer, an Associate Professor at Wageningen University, introduced the significance of the microbiome in her talk, “The Nature and Nurture of our Microbiome”. Microbes are important to human health; they help us degrade our food, stimulate our immune systems, and protect us against pathogens. As infants, our early microbiomes can influence our health later in life. The early infant microbiome can affect the prevalence of type I diabetes, obesity, and diseases along the atopic spectrum, such as allergies or asthma. Nutrition, mode of delivery, antibiotics, and environmental factors all influence the early microbiome. Infants born via C-section have gut microbiota that resembles the skin microbiota of their mothers and caretakers, while infants born vaginally have microbiota that resembles the vaginal microbiome of their mothers. Moreover, breast feeding attracts the growth of Bifidobacterium, which aids the infant in the digestion of human milk. Dr. Belzer provided an overview that was necessary for the remainder of the meeting and invited attendees to understand that the microbiome is a tool that can help us diagnose, treat, and prevent disease.

The next presentation by Dr. Katri Korpela, researcher at University of Helsinki, was a deeper dive into the effects of birth mode and the use of antibiotics on the mother-infant microbiome interface. At the interface, the mother passes her gut microbes to the infant’s gut and feeds them with breast milk. The infant receives signals from gut microbes that affect the development of the immune system, metabolism, and possibly the neuronal system. Infants have adapted to receive specific microbial signals at specific times. Dr. Korpela posed an interesting question, what happens then the signals are not present? Her unpublished research using 16S amplicon data shows that C-sections and antibiotics both disrupt the transmission of microbes from the mother to the infant and this disturbance can be seen until 6 months of age. Probiotics given to the infant may help correct the disruption, but the strains may not mimic the strains of the mother. However, she shows that C-section induced dysbiosis of the infant gut can be corrected by a faecal microbiota transplant from the mother. Although the method looks promising, further research should confirm these findings. Research that deals with the absence of a microbiome cannot be ethically or realistically conducted in humans and using other animal models is necessary.

Dr. Marijke Faas, Principal Investigator at UMCG,  is interested in whether the gut microbiome affects immune changes and uses mouse models to search for answers. It is known that maternal immune cells are able to interact with faetal tissue in humans and more, we know that there is a shift in the mother’s immune system when a faetus is present. Dr. Faas hypothesized that these changes are linked to the gut microbiome. Her lab studied this effect in conventional and germfree mice. Germfree mice are bred to prevent growth of any micro-organisms and allow researchers to make comparisons regarding the presence or absence of the microbiome. In the study, Dr. Faas found differences in immune changes between the mice; conventional mice show activation of monocytes and increases in T cells (Th2 and Treg). The abundance of species found in the conventional mice differed before and at the end of the pregnancy, and some of the species were correlated to immune changes. This research suggests a role for the gut microbiome in immune changes, and highlights the importance of using mouse models.

The last speaker of the first session was Dr. Ali May, Product manager at BaseClear, who promoted the use of shallow shotgun sequencing in infant microbiome studies. Compared to amplicon sequencing, shotgun sequencing gives multi-domain coverage, species-level information, and can be used to conduct functional analyses. Shallow shotgun sequencing involves sequencing samples at a lower depth of reads than shotgun sequencing, but was shown to provide the same information content in adult samples from the Human Microbiome Project. To find whether this is also true in the infant microbiome, Dr. May subsampled results from two studies. From the first, species abundances were compared between 12 million reads per sample and subsampled 1 million reads per sample. Both showed nearly identical species abundance and rare species abundance, which have a maximum 1% relative abundance of the total species. From the second study, he showed that microbial functional profiles are almost the same between samples with 13 million reads and subsampled 1 million reads. Dr. May predicts a transition to shallow shotgun sequencing, as it gives more information than amplicon sequencing and is less expensive and as informative as shotgun sequencing.

Session 2: MODULATING THE MICROBIOME

Earlier in the meeting, the influences of mode of delivery on microbiome were discussed. Infants born via C-section have different microbiota than infants delivered vaginally, and these differences may predispose infants born via C-section to health conditions later in life.

To begin the second session, Dr. Kaouther Ben Amor, Senior Team Leader Probiotics, Danone, revisited this topic by discussing a nutritional intervention for C-section born infants. Among other components, human milk contains prebiotics and bacteria. To mimic this, Danone has created a pre- and probiotic mixture containing Bifidobacterium breve. They conducted a clinical trial with 30 vaginally born infants and 153 C-section born infants, which were randomized into control, prebiotic only, and pre- and probiotic mixture groups. The pre- and probiotic group had an abundance of Bifidobacterium most similar to vaginally delivered infants. Future research should continue to explore restoration of microbiome composition in C-section infants to prevent increased risk for future health conditions.

Dr. Kartja Parschat, Deputy Head of R&D, Jennewein Biotechnologie, continued the discussion of breast milk with her talk, “Human Milk Oligosaccharides as a Novel Functional Food Ingredient”. Human milk oligosaccharides (HMOs) are complex sugar molecules that are not digestible by the infant. HMOs have evolved to reduce the risk of bacterial and viral infection, support brain development by supporting the building blocks of brain tissue, help shape the gut microbiome, and mature the intestinal barrier. The abundance and type of HMOs in breast milk depends on the mother. Her genotype, phenotype, and the environment are all influential. It has been shown that breast feeding for more than 2 months helps to maintain the abundance of Bifidobacterium, and some strains are able to degrade HMOs to short chain fatty acids and other metabolites able to be accessed by the infant. Dr. Parschat also explained that HMOs play a role in the immune system by mimicking receptors to which pathogens bind. Infants who are breast fed have shown to be protected against a norovirus infection and HMOs may be responsible. Questions about the infant’s first exposure to HMOs still remain, as HMOs may be transferred via faetal tissue prior to birth.

Dr. Steve James, Researcher, Quadram Institute Bioscience brought a novel topic to the table with his presentation about the young infant gut mycobiome, or the fungal microbiome. Fungi are typically overlooked in this field because they are present in low abundances (0.1% of the adult gut microbiome). Even with low abundance, we know that they are important and can be linked to inflammable bowel disease, allergic diseases, and obesity. It is also known that antibiotic treatments can lead to fungal overgrowth. Similarly to bacteria, factors that influence the infant mycobiome include the maternal mycobiome, the mode of delivery, the bacterial microbiome, antibiotics, diet, and gestational age at delivery. To learn more about which fungi are present, Dr. James collected stool at 6, 12, and 18 months from pre-term born infants. Fungal DNA and amplicon sequencing was used to find fungal communities. He found that infants in this age range have a low fungal diversity, with Candida as the dominant genera found and C. parapsilosis as the most common species. Although infant gut diversity was generally low, it increased from 6 to 12 to 18 months. Dr. James thinks this can be due to the introduction of foods.

Dr. Maciej Chichlowski, Scientist at RB/Mead Johnson Nutrition, brought the meeting to a close with a question that remains unanswered in this community. His research focuses on exploring what constitutes a “healthy” gut microbiome. A higher diversity is believed to be more desirable, but Dr. Chichlowski explains that breast fed infants have shown a lower alpha diversity than formula fed infants. A lower alpha diversity is also seen in children with food sensitizations, necrotizing enterocolitis, eczema, asthma, inflammatory bowel disease, irritable bowel syndrome, obesity, and diabetes. The question of what makes a microbiome “healthy” versus “unhealthy” still remains, and is clouded by the differences in mother-infant dyads.

PANEL DISCUSSION HIGHLIGHTS

The event addresses several challenging topics mostly with open question with a quest to gain better understanding on:

  • microbiome development during pregnancy
  • mode of delivery
  • complication during delivery
  • vaginal versus urgent C-section versus planned C-section
  • colonisation of microbiome in the infant
  • phased development of microbiome in the first 1000 days
  • ‘window of opportunity’
  • Modes to modulate microbiome
  • Decoding the meaning of diversity profiles of microbes
  • Among others

While ‘window of opportunity’ plays a key role in training the immunity, as well later stage health status of an child, we learnt that there is a strong correlation between bacterial profiles during pregnancy and immune responses in the mother. Immune response of the pregnancy in turn determines the mode of delivery as well as complication in delivery. Thus the open question remains, is the ‘window of opportunity’ actually starting during pregnancy and that mothers play a key role? Some of the thoughts that are discussed and presented as a way to modulate the microbiome are:

  • HMOs & GOS, not just for infants but also for pregnant and adults,  for its role in antimicrobial properties, prebiotic functions, immune modulation, neurological development (gut-brain axis) etc.
  • The focus goes beyond bacterial population, as mycobiome despite being lower in abundances and studied to lesser extent play a key role in preventing pathogenic activities, acting against diarrhoea. Yeast unlike bacteria are better in adopting to colonisation in preterm infants.
  • Gap in colonisation in preterm infant and/or infants via c-section, can be supplemented with symbiotics
  • The need to study overall microbial population as opposed to single microbial group such as bacteria or yeast or fungi.
  • Would FMT be an alternative to preterm or C-section infants to fill the gap of mother-infant microbiome transfer?
  • How well is the consumer educated about different infant milk formulas or about the dietary supplements for a pregnant soon-to-be mother?
  • Without industry standardisation on the methods of analysis, as well conduction of clinical trials, how can we conclude between studies? Specially to comment on gut-brain-skin axis where compounds like HMOs seem to have role in immunity, cognitive development and in allergies in infants? Also in the context of  advanced analysis such as machine learning or artificial intelligence to predict or simulate the outcomes, e.g.,  effectiveness of a dietary intervention?
  • How should we translate the information on diversity profiles?
  • Is it time to talk about multi-omics approach?

BOOK OF ABSTRACT

Download the book of abstracts here: Brochure Infant Pregnancy Microbiome Experts Meeting 14 May 2020

UPCOMING EXPERTS MEETINGS

BaseClear routinely organises experts meeting and this meeting will have a follow edition. We look forward to see what progress will have been made. For the complete overview of BaseClear’s Experts Meetings, visit https://www.baseclear.com/experts-meetings/ and follow us on LinkedIn (https://www.linkedin.com/company/baseclear) to keep up to date.

Acknowledgement:

Ms. Jolanta Szkodon, University of Amsterdam and Vrije University for contribution via notes.

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