Friday, December 25, 2020

The Infant Gut Microbiome and Probiotics that Work

 reposted from

The Infant Gut Microbiome and Probiotics that Work

The gut microbiome is more malleable in the first two years after birth, allowing probiotics to make their mark. Can we exploit this to improve infants’ health?

Jennifer T. Smilowitz and Diana Hazard Taft
Jun 1, 2020


In the fall of 2018, a team of researchers from the Weizmann Institute of Science in Israel published findings that a cocktail of 11 strains of Lactobacillus and Bifidobacterium had minimal immediate impact and no lasting effect on the makeup of the gut microbiome of mice or people.  In fact, the probiotic bacteria were not found in any of the fourteen adult participants after supplementation ended.

These recent findings received quite a lot of press and added to growing sentiment among the public that probiotics—live microorganisms that are purported to confer benefits on the human host—don’t work. Decades of research have shown that most probiotics aren't able to colonize or exert lasting benefits in the human gut. Some critics even suggested that probiotics may not be a promising avenue for treating disease or otherwise improving health and wellness. But we thought: “Don’t throw the baby out with the bathwater—our work shows that the right probiotic can work in the infant gut.” Findings we published in 2017 showed that feeding breastfed babies a probiotic that included a specific strain of Bifidobacterium longum subspecies infantis (B. infantis EVC001) resulted in a 10,000,000-fold average increase in levels of fecal B. infantis. This level persisted for one month after the supplement was consumed, and levels remained elevated for up to one year after treatment.

To understand why the infant gut microbiome changed so drastically over the past century, we sought to understand how the infant gut microbiome forms.

Colonization of the infant gut by B. infantis had protective effects, such as lower levels of potential gut pathogens and fecal endotoxin, an outer membrane component of Gram-negative organisms known to trigger inflammation. We also found that infants given the B. infantis probiotic had reduced intestinal inflammation compared with breastfed infants who did not receive the probiotic. The gut microbiomes of B. infantis supplemented babies harbored fewer antibiotic resistance genes—a sign of fewer pathogens—and showed less degradation of mucin, a glycoprotein secreted by the intestinal epithelium that protects epithelial cells from direct contact with gut microbes. These data support earlier findings from Mark Underwood and colleagues at the University of California, Davis. In 2013, Underwood’s team showed that feeding preterm infants a different strain, B. infantis ATCC15697, resulted in greater increases in fecal Bifidobacterium and reduced levels of potential pathogens compared with infants given a probiotic containing B. lactis.

While the scientific community and the public grappled with repeated findings that probiotic supplements taken by adults are not consistent in effectively colonizing the gut or conferring benefit, we now had convincing evidence that babies’ gut microbiomes responded incredibly well to specific strains of B. infantis. The question was why. 

Microbiome origins  

Hints about the infant microbiome can be found in century-old articles on commensal bacteria in infant feces. W. R. Logan, a clinical pathologist at the Research Laboratory of the Royal College of Physicians in Edinburgh, was the first to report, 100 years ago, that bacteria in fecal smears from breastfed infants were a near monoculture of Bacillus bifidus, which is today known as the genus Bifidobacterium. Fecal smears from formula-fed infants of that time, by contrast, had a diversity of bacteria, with relatively few Bifidobacterium—more similar to the microbial diversity found in today’s breastfed infants. 

These striking changes in the gut microbiome composition seen over the past century were consistent with our recent finding that the fecal pH in breastfed infants dramatically increased from pH 5.0 to 6.5 within the past 100 years, a change associated with an apparent generational loss of Bifidobacterium and concomitant increase in potential pathogens. The reduction in Bifidobacterium in the gut microbiome of breastfed infants is likely an unintended consequence of medical practices that can save lives but do not support the growth of Bifidobacterium. Such medical practices include treatment with antibiotics to which Bifidobacterium are sensitive; infant formula that doesn’t provide the specific food the bacterium requires; and greater numbers of cesarean section deliveries, which bypass the route by which the bacterium is transferred from mother to baby. These medical practices have been implicated in the increased risk for allergic and autoimmune diseases prevalent in resource-rich nations. The reduction in Bifidobacterium and increase in proinflammatory microbes in early infancy is proposed to occur during the critical window of immune system development, and thereby may increase the risk for immune disease later in life.

To understand why the infant gut microbiome changed so drastically over the past century, we sought to understand how this community forms. Infant gut microbiome colonization begins at delivery with exposure to maternal microbes—mostly vaginal and fecal microbes for vaginally delivered babies or predominately microbes from the skin, mouth, and surrounding environment in infants born by cesarean delivery. After birth, infants are bombarded by a vast array of microbes found in the environment, including in breast milk, but the species that go on to become durable members of the microbial community are often those transmitted by the infants’ mothers through physical contact

Children continue to acquire gut microbiome species from their mothers and others in the community during early life. This stands in contrast to an adult’s gut microbiome, which is stable and resists change largely because the available space and food is already used by established microbes—the ecological niches are simply occupied in adult guts. Thus, it makes sense that a probiotic has a better chance of persisting in the infant gut, where it faces less competition, and therefore is more likely to have food it can consume and a location where it can grow. A probiotic serves as just one more source of exposure to new bacteria for the infant. 

Recognizing this, we began to wonder: In our studies, what ecological niche did B. infantis fill that supported its persistence in infants long after probiotic administration stopped?

The Changing Infant Microbiome

Historically, the breastfed infant gut microbiome was a near monoculture of Bifidobacterium (J Pathol Bacteriol, 18:527–51, 1913). The formula-fed infant gut microbiome was much more diverse. The breastfed infant gut microbiome and the formula-fed infant gut microbiome are now more similar to the historical formula-fed infant gut microbiome, although modern breastfed infants do have more Bifidobacterium than modern formula-fed infants.

See full infographic: WEB | PDF

Setting the stage

A major factor in determining which bacteria thrive in the gut is the availability of their carbohydrate food sources. Thus, for a probiotic to work in an infant, microorganisms should be selected so that the food source they use most efficiently matches what’s available—a food that is present and not already being consumed by other bacteria. We set out to determine what carbohydrates B. infantis consumes in the infant gut. 

Naturally, we turned to breast milk, which for millions of years has been the single food that can exclusively nourish and protect babies for the first six months of life. Human milk delivers nutrients as well as non-nutritive, bioactive molecules, including carbohydrates known as human milk oligosaccharides (HMOs). Back in the mid-1900s, Paul György, a world-renowned biochemist, nutritionist, and pediatrician from the Hospital of the University of Pennsylvania, and colleagues unknowingly referred to HMOs when they proposed the existence of a “bifidus factor,” something unique in breast milk that fed Bifidobacterium. While humans cannot digest HMOs, it turns out that Bifidobacterium, especially B. infantis, can. In 2007, our group at UC Davis used mass spectrometry–based tools coupled with microbiology to show that B. infantis gobbles up HMOs as its sole energy source, while other species of Bifidobacterium consume only some HMOs in addition to plant-, animal-, and host-derived carbohydrates.

HMOs are a diverse class of complex carbohydrate molecules synthesized by the mammary gland. With approximately 200 different molecular species, they represent the third most abundant solid component in human milk following lactose and fat. Because HMOs are complex and vary in structure, they are expensive to manufacture. Current infant formulas may contain one or two simple HMO structures, but at a fraction of the concentration found in breast milk. Infant formulas lack the abundance and complexity of HMOs to selectively feed beneficial gut microbes and to bind and neutralize pathogens from the gut. 

The bacterial species in the infant gut capable of consuming HMOs can be considered the milk-oriented microbiome (MOM). Although B. infantis appears to be the most efficient consumer of HMOs, other species of Bifidobacterium, in particular, B. breve and B. bifidum, can and do consume some HMOs but also consume plant-, animal-, and host-derived carbohydrates. The Bifidobacterium species that colonize the gut change throughout life in response to available carbohydrates in the host diet. For instance, B. infantisB. breve, and B. bifidum are MOM bifidobacteria typically found in the stool of exclusively breastfed infants, while B. longum and B. adolescentis, which preferentially consume plant- and animal-derived carbohydrates, are typically found in the stool of adults. Yet there is variation and overlap in the species present at different life stages.

A major factor in determining which bacteria thrive in the gut is the availability of its carbohydrate food source.

Of the MOM bifidobacteria found in the infant gut microbiome, different species may have different implications for the microbiome. For example, when we gave exclusively breastfed infants a supplement with the probiotic B. infantis EVC001, their gut became dominated by the genus Bifidobacterium—upwards of 80 percent relative abundance of the gut microbiome—and potential pathogens made up less than 10 percent of the community. On the other hand, the gut microbiomes of exclusively breastfed infants who were not supplemented with B. infantis EVC001 had much lower levels of Bifidobacterium, with only about 30 percent relative abundance, and potential pathogens constituted about 40 percent of the microbes in their gut, findings that are consistent with previous work from our group and others. This near-monoculture of Bifidobacterium appeared to be driven by B. infantis, which represented about 90 percent of the total Bifidobacterium in infants fed the probiotic. In contrast, B. longum was the predominant gut Bifidobacterium in the control group, followed by B. breve and B. bifidum. These data highlight the vital importance of strain specificity in probiotics, and the combination of the presence of B. infantis and breastfeeding to support a protective gut environment in infants. 

To understand how supplementary B. infantis can so successfully outcompete other microbes in the infant gut, we took a deep dive into its feeding strategy. Turns out it is a picky eater, exclusively dining on HMOs, and when HMOs are abundant, B. infantis gobbles them up ravenously. Unlike other MOM bifidobacteria, B. infantis possesses all the genes necessary for the complete, internal degradation of HMOs and preferentially uses HMOs over any other carbohydrate source. Other MOM bifidobacteria such as B. bifidum and B. breve strains display growth capabilities with only a subset of HMOs. B. infantis thus has a competitive advantage when breast milk makes up the entire diet. 

A 2008 study from colleagues at UC Davis and their collaborators showed how B. infantis makes quick use of HMOs: with binding proteins to grab HMOs from the gut lumen and transporters to usher them into the cytoplasm, breaking them down into monosaccharides that are then fermented into lactate and the short-chain fatty acid acetate that are secreted from the cell. These end products maintain a lower pH in the intestinal milieu, supporting the transport of these compounds into the intestinal epithelium for use by the host and creating an undesirable environment for potential pathogens. The production of acetate also blocks the infiltration of toxic molecules produced by pathogenic bacteria by enhancing intestinal barrier function and inhibiting pro-inflammatory and apoptotic responses. Recent findings from one in vitro study have shown that the amount of acetate and lactate produced by different bifidobacterial species is dependent on how well they consume the carbohydrates available to them. Hence, feed a carbohydrate-consuming microbe its preferred carbohydrate, and it has greater potential to produce more of its protective end-products.

Another reason why B. infantis outcompetes other bifidobacterial strains in the gut of breastfed infants is that all of its HMO digestion happens inside the bacterial cell. B. bifidum, on the other hand, digests HMOs externally. This extracellular digestion liberates simple carbohydrates and may cross-feed other species of Bifidobacterium, but also cross-feeds and thus opens an ecological niche for other, perhaps less beneficial microbes. Cross-feeding among microbes diversifies the gut microbiome, which is considered to be generally beneficial in adults.

But is there an advantage to having a near monoculture of Bifidobacterium in infants? By asking this question, our focus turned to immune development.

The Milk-Oriented Microbiome

Human milk oligosaccharides (HMOs) are complex carbohydrates that microbial species of the milk-oriented microbiome (MOM) can use as  a food source. Bifidobacterium infantis encodes many proteins that specifically bind and transport all types of HMOs into its cell and digest them internally. Other Bifidobacterium species digest only some HMOs and some do so externally. Digestion of HMOs by MOM Bifidobacterium results in the production of lactate and the short chain fatty acid acetate, that are secreted into the gut lumen. These molecules lower the pH in the intestinal milieu, which improves their transport into the epithelium for use by the host and creates an undesirable environment for potential pathogens such as E. coli


B. infantis preferentially consumes all HMO species over any other carbohydrate source.

  1. Binding proteins glom on to HMOs and usher the carbohydrates to transporters that move them into the bacterial cell.
  2. Intracellular glycosyl hydrolases cleave each glycosidic linkage
    of all HMO structures, yielding monosaccharides.
  3. These monosaccharides are metabolized into acetate and lactate that are secreted from the cell.

B. bifidum eats only a subset of HMOs.

  1. Glycosyl hydrolases attached to the outer cell membrane break down
    HMOs into mono- and disaccharides in the extracellular space.
  2. These molecules are imported via transporters, and some are gobbled up by other intestinal microbes, a process called cross-feeding. 
  3. The mono- and disaccharides are further metabolized into acetate and lactate, though because B. bifidum is a less efficient consumer of HMOs, it likely produces less of these products than B. infantis.
See full infographic: WEB | PDF

Benefits of a Bifidobacterium

The decline of Bifidobacterium in infant gut microbiomes and the associated dysregulation of the microbial community, with more numerous potential pathogens, has been suggested as one possible contributor to the increased incidence of autoimmune diseases that plague residents of resource-rich nations. Conversely, observational studies have shown beneficial immune effects of having a fecal microbiome dominated by Bifidobacterium. In two studies in Bangladeshi infants and young children, fecal B. infantis and Bifidobacterium abundances at two months of age were strongly correlated with improved vaccine responses at six months and two years old compared with infants not colonized by B. infantis or with low relative abundances of Bifidobacterium.

Additionally, bifidobacteria are less likely than other microbes, especially potential pathogens, to carry and share antimicrobial resistance genes, which can lead to a higher risk of antibiotic-resistant infections. In an observational study of Bangladeshi and Swedish infants, a dominance of intestinal Bifidobacterium was associated with a significant reduction in both the number and the abundance of antibiotic resistance genes. Moreover, compared with matched-control breastfed infants, supplementation with B. infantis EVC001 led to a reduction of antibiotic resistance genes by 90 percent, a drop largely driven by a reduction in levels of EscherichiaClostridium, and Staphylococcus—potentially pathogenic bacteria that play a major role in the evolution and dissemination of antibiotic resistance genes.

In an effort to restore the Bifidobacterium-dominated infant gut microbiome that was typical of breastfed babies 100 years ago, we decided to conduct a randomized, controlled trial using the B. infantis EVC001 probiotic. Given that not all B. infantis strains consume all HMOs efficiently, we selected B. infantis EVC001 because we knew this strain had the full cassette of genes needed to fully digest all HMOs. Healthy, full-term, breastfed infants were randomized to consume B. infantis EVC001 for 21 consecutive days starting on day 7 postnatal or to not receive the probiotic. 

A PROBIOTIC THAT STICKS: Scanning electron micrographs of infant fecal samples show a large increase in the number of Bifidobacterium microbes in those treated with a probiotic called EVC001 (right) compared with controls (left).
PEDIATR RES, 86:749–57, 2019

Compared with breastfed control infants who did not receive the probiotic, supplementation resulted in a 10,000,000-fold average increase in levels of fecal B. infantis and increased fecal Bifidobacterium by 79 percent during the supplementation period, and this was still true at one month post supplementation. This means Bifidobacterium colonization persisted without the continuation of probiotic supplementation. Additionally, colonization of B. infantis persisted until one year of age if infants were continuing to consume any breast milk and were not exposed to antibiotics. Importantly, the supplemented infants exhibited an 80 percent reduction in potential gut pathogens belonging to the families Enterobacteriaceae and Clostridiaceae and reduced fecal endotoxin. Additionally, we saw a 2-fold increase in fecal lactate and acetate and a 10-fold decrease in fecal pH. The supplemented infants’ gut microbiomes and biochemistry resembled norms observed a century ago. 

We also identified some clues about the consequences of the gut microbiome’s “modernization.” Breastfed infants with low fecal Bifidobacterium had excreted 10-fold more HMOs in their stool throughout the two-month study period than infants supplemented with B. infantis EVC001, indicating that HMOs—the third most abundant component in breast milk—were going to waste. We also found that infants with low fecal Bifidobacterium had several-fold higher levels of fecal
proinflammatory cytokines compared with infants whose gut microbiomes were dominated by Bifidobacterium post supplementation with B. infantis EVC001.

Taken together, these data demonstrate that this particular strain of B. infantis, provided as a probiotic to breastfed infants, dramatically colonized the infant gut microbiome during and after supplementation, and beneficially remodeled the microbial, biochemical, and immunological environment in the infant gut. Many infants around the world never acquire B. infantis, but the combination of breastfeeding and probiotic supplementation with this bacterium seems to lead to a nourishing and protective gut environment. 

Many infants around the world never acquire B. infantis, but the combination of breastfeeding and probiotic supplementation with this bacterium seems to lead to a nourishing and protective gut environment.

Our findings also support the hypothesis that the ineffectiveness of some probiotics in adults is due in part to the fact that they are introducing a new species to an established community with few ecological niches still open. Probiotics may not work in infants when there is a mismatch between the carbohydrate needs of the probiotic and the availability of highly specific carbohydrates such as HMOs in breast milk. Because B. infantis efficiently consumes almost all HMOs found in breast milk, it is likely to find an open ecological niche and then outcompete other microbes, especially proinflammatory pathogens.

Many scientists are working to understand what the infant gut microbiome really means for health across the lifespan. Meanwhile, we are turning our attention to other questions: How do colonization patterns of Bifidobacterium differ in infant populations around the world from infancy to weaning? And what solid foods support a healthy gut and immune system? Working with funding from the National Institutes of Health, we are now conducting a study designed to understand how the carbohydrate structures of complementary foods influence microbial function that will support a healthy gut microbiome and immune system development in late infancy and early toddlerhood. The ultimate goal is to identify specific carbohydrate structures in the diet that selectively feed beneficial gut microbes in children during the critical window of immune development for lifelong health. 

Jennifer Smilowitz is the associate director of the Human Studies Research Program at the Foods for Health Institute and a research scientist in the Department of Food Science and Technology at the University of California, Davis. Diana Hazard Taft is a postdoctoral research fellow in David Mills’s lab in the Department of Food Science and Technology and a member of the Foods for Health Institute at UC Davis. 

Thursday, December 10, 2020

Dementia Care Mapping: Care home managers and staff need more support to improve care

 reposted from


Dementia Care Mapping: Care home managers and staff need more support to improve care

Many care homes are struggling to implement a tool designed to help them better meet the needs of people with dementia. New research suggests that care home managers need to be supported, trained and engaged when such tools are introduced into care homes.

The tool, called Dementia Care Mapping (DCM), aims to improve practices in care homes for people living with dementia. The programme asks staff to put themselves in the place of residents, through watching and assessing residents’ experiences. The observations are fed back to the staff team who work together to develop action plans to improve care.

A previous study found that DCM did not lead to improvements in homes. This study explored why. It found that implementation is patchy and vulnerable to issues such as staff and manager turnover, their confidence or skills to lead changes in practice, and inadequate staffing and funds.

The researchers suggest that how well managers understand, value and engage with DCM has a key influence, as does their leadership style.

What’s the issue?

Many people with dementia, particularly those with more complex needs, live in care homes. Care homes often use DCM to improve the quality of care offered to residents with dementia.

To implement DCM, two members of care home staff (the ‘mappers’) are trained to use the tool. They brief other staff about the tool and then sit in the lounge or other public areas to see what daily life is like for residents. They note what residents are doing, how they are feeling and the actions that make residents happy or cause them distress. After coding and analysing their observations, the mappers write a report and feed this back to the team. Improvements are suggested by the staff team, put in place, and the cycle is repeated a few months later.

Earlier studies outside of the UK found that DCM had mixed results across care homes. Where DCM was led by the researchers, there were some benefits for residents and staff. However, where DCM was led by care home staff, no benefits were found and there were problems implementing the tool.

The current study was part of a UK trial which asked trained staff in 31 care homes to complete three cycles of DCM. The first was supported by an external expert provided by the research team. Compared to 19 homes not using DCM, this trial found no benefits in terms of reduced resident agitation, neuropsychiatric symptoms such as depression, use of anti-psychotic drugs, use of healthcare resources or improvements in quality of life. Implementation of DCM was variable.

What’s new?

This study explored the barriers and facilitators in introducing a complex tool like DCM, including the influence of care home managers. It looked at the actions and attitudes of managers themselves, but also the circumstances that enabled managers to support DCM.

Researchers interviewed 48 care home staff (managers and staff trained to use DCM) who were implementing DCM at a range of different-sized care homes in different locations across England. They found that managers played many crucial roles in supporting implementation.

Analysis of the programme identified five themes:

  • Managers' support for the intervention was essential. One DCM expert provided by the research team to support implementation of DCM said about a care home that only carried out one cycle: “She [the manager] never attended anything. She never supported, as far as I could see, the mapper.”
  • Managers’ understanding of DCM and its potential benefits was variable. Responses ranged from: “It’s a brilliant tool, and just gives you the time to look and focus on what is going on in your home” to: “I didn’t realise how long things would take and how much effort it would take.”
  • The choice of staff trained to lead DCM influenced the outcome. One DCM expert said: “Some managers were really clear [on their choice of mappers]. ‘Yep, those two are good communicators, good agents of change, they’ll be good to lead this.’ For other managers it was completely random.”
  • Management stability was a challenge with a change of manager in two in five care homes during the 16-month study period. These changes often undermined implementation: “The study was interrupted, the staff that were doing the mapping… left the company, so when I already arrive here [as a new manager], they were not here and I never had any contact with the mapping,” said a manager of a care home that did not complete any DCM cycles.
  • Managers' engagement and leadership depended on how well they valued DCM. In homes with higher levels of implementation, managers had the influence to involve the whole team. One expert said, ‘They had plenty of un-rostered time… so they could prioritise it.”

Why is this important?

The study suggests ways to tackle the difficulties in improving care in care homes.

Implementing tools such as DCM in care homes can be challenging and it relies on the support of managers. Management style is rarely studied in the social care sector, yet this study found that managers in homes that had most success with DCM played many crucial supportive roles.

For example, some protected staff time to implement DCM, assisted less confident staff, and engaged staff across the home in DCM and the associated changes in practice.

Managers’ leadership skills and understanding of DCM affected their ability to provide the necessary support. A change in manager often undermined implementation and the researchers suggest it may not be feasible for care homes to introduce such interventions when there is managerial instability.

The findings suggest that managers and staff may require greater support to implement interventions such as DCM. Greater, ongoing support from external experts may also help.

What’s next?

The findings should have direct impact on the delivery of DCM in care homes: they showed that managers need better support, such as a clear understanding of what DCM involves, and extra funds to pay for dedicated staff time. DCM was more likely to be successfully implemented with support from researchers or external experts. They said this was needed on an ongoing basis, not just during the first cycle.

These findings have implications for research on other interventions in care homes.  Managers need to be actively engaged from the outset of a research study. The high turnover of managers means intervention research should include strategies to engage and support new managers, and to ensure ongoing engagement from existing senior staff.

You may be interested to read

The full study: Kelley R, and others. The influence of care home managers on the implementation of a complex intervention: findings from the process evaluation of a randomised controlled trial of dementia care mappingBMC Geriatrics. 2020;20:303

The wider trial findings: Surr C, and others. Effectiveness of Dementia Care Mapping™ to reduce agitation in care home residents with dementia: an open-cohort cluster randomised controlled trialAging & Mental Health. doi: 10.1080/13607863.2020.1745144

An infographic showing the results of the wider DCM trial

A summary of DCM implementation: Griffiths A, and others. Barriers and facilitators to implementing dementia care mapping in care homes: results from the DCM™ EPIC trial process evaluationBMC Geriatrics. 2019;19

The role of external experts: Surr CA, and others. Exploring the role of external experts in supporting staff to implement psychosocial interventions in care home settings: results from the process evaluation of a randomized controlled trialBMC Health Services Research. 2019;19:790

How well DCM was implemented in the trial: Surr C, and others. The Implementation of Dementia Care Mapping in a Randomized Controlled Trial in Long-Term Care: Results of a Process EvaluationAmerican Journal of Alzheimer’s Disease & Other Dementias. 2019;34:390-398


This research was supported by the NIHR Health Technology Assessment Programme.

Wednesday, December 9, 2020

Distinct Microbiome and Metabolites Linked with Depression

 reposted from

Distinct Microbiome and Metabolites Linked with Depression

Distinct Microbiome and Metabolites Linked with Depression

The gastrointestinal tracts of people with major depressive disorder harbor a signature composition of viruses, bacteria, and their metabolic products, according to the most comprehensive genomic and metabolomic analysis in depression to date.


The human gut microbiome is a world in miniature, populated by a chatty community of bacteria, viruses, fungi, and protozoa nestled within various gastrointestinal niches. Over the past decade, researchers have linked disturbances within this complicated microbial society to a variety of diseases. Major depressive disorder (MDD) is one such condition, but the studies have been small and the findings imprecise. A study published December 2 in Science Advances changes all that with its vivid description of a distinct microbiome associated with major depressive disorder, as well as the profile of molecules these organisms produce. The researchers were able to use this microbial “fingerprint” to distinguish between individuals with MDD and healthy controls, solely on the composition of a few microbes and compounds in their fecal matter.

“What this paper does is bring the complexity of the ecology of the microbiome into focus,” says neuroscientist John Cryan at APC Microbiome Ireland and University College Cork who was not part of the study team. “It’s a welcome addition to the field.”

“The strength of the paper is this dual approach to both the metagenomics to identify the key taxa as well as the metabolites, because in the end we need to link whatever the biosignature of the taxa are to the host,” McMaster University’s Jane Foster, who was not part of the study, tells The Scientist. She adds that it’s one of the first studies to conduct metagenomics and metabolomics in the same sample for depression.

Microbiome researchers studying MDD have been using an inexact technique called 16S ribosomal RNA sequencing, which can identify bacteria only down to the genus level within a batch of microorganisms, and it excludes viruses. But psychiatrist Shaohua Hu at Zhejiang University School of Medicine in China and his group wanted a more precise picture of the organisms present, so they gathered fecal samples from 236 people, half of whom had been diagnosed with MDD and were unmedicated, and half who were healthy. They sequenced the total genomic DNA of all the bacteria and viruses in the samples, and then used statistical programs to analyze the differences and similarities between people with MDD and healthy controls.

The depressed symptoms can influence our diet behavior, so it can influence our gut characteristics and composition, and also on the other side, our bacteria can produce some special metabolites and have a special pathway that can influence our brain function.

—Shaohua Hu, Zhejiang University School of Medicine

They found that 18 bacterial species were more abundant in people with MDD (mainly belonging to the genus Bacteroides) and 29 were less common (primarily the genera Blautia and Eubacterium) compared to healthy controls. Hu and his team also found three bacteriophages (viruses that infect bacteria) whose levels were different in MDD versus healthy controls, the first time the virome has been studied in MDD.

Sequencing entire microbial genomes allowed the team to distinguish between organisms that are genetically similar, but functionally very unique, writes University of Melbourne, Australia, researcher Carra Simpson in an email. “Compared to the commonly employed marker gene sequencing approaches, [the authors] have greater resolution to distinguish these species and within a comparatively large sample size.” This helps to “elucidate the functional implications of bacterial alterations on the host.”

To determine the effect of these changes, Hu and the group analyzed the so-called “functional readout”—the molecules the microorganisms produce—of the entire gut microbiome using gas chromatography-mass spectrometry (GC-MS). It turns out that MDD patients harbored significantly more of 16 metabolites and less of 34 compounds than did healthy controls; most of these molecules were involved in amino acid metabolism. The three most important pathways were related to gamma-aminobutyric acid (GABA) metabolism, phenylalanine metabolism, and tryptophan metabolism.

Hu’s team then created a biomarker panel consisting of two species of bacteria, two types of bacteriophage viruses, and two different metabolites. In a separate group of 75 subjects (half with MDD, half healthy controls), the biomarker panel was able to accurately pick out those with depression around 90 percent of the time.

Possible microbial effects on depression—and vice versa

The researchers point out that GABA is a neurotransmitter in the brain, but it’s also made by gut microbes; fecal levels of GABA and certain of its metabolites were decreased in the MDD patients, and the team also found that GABA-related microbial genes were altered in MDD patients, suggesting that microbes modulate GABA levels. Hu and his team hypothesize that this may dysregulate the function of GABA in the brain, and could lead to depressive symptoms.

In addition, the scientists hypothesize that perhaps the increase in Bacteroides bacteria, which induce cytokine production, could increase inflammation, a condition that has been linked to MDD. Also, decreased Blautia, which has been shown to have anti-inflammatory effects, could contribute to MDD. Other studies have also found that when researchers transplant the entire microbiota of a person with MDD into a germ-free rat, the rat starts to behave depressed.

These are speculative assertions, and Hu says this one cross-sectional study can’t determine causality, and rather, “I think it’s a bi-directional axis. The depressed symptoms can influence our diet behavior, so it can influence our gut characteristics and composition, and also on the other side, our bacteria can produce some special metabolites and have a special pathway that can influence our brain function.”

“This sets the scene for a lot more work to validate whether any of these pathways are actually causally related to depression,” says Cryan, who receives research funding from Dupont Nutrition, Cremo SA, and Nutricia Danone. “There’s a whole emerging field in nutritional psychiatry right now. Can we target the microbiome through diet, could we alleviate some of the effects of depression?”

J. Yang et al., “Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders,” Science Advances, 6:eaba8555, 2020.