We are pursuing the dream of eternal life. We fast to stay healthy. And each year, we spend billions of kroner on treatment to make sure we stay alive. But some people turn 100 years old all by themselves. Why is that?
Researchers from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen have set out to find the answer.
Studying 176 healthy Japanese centenarians, the researchers learned that the combination of intestinal bacteria and bacterial viruses of these people is quite unique.
We are always eager to find out why some people live extremely long lives. Previous research has shown that the intestinal bacteria of old Japanese citizens produce brand new molecules that make them resistant to pathogenic – that is, disease-promoting – microorganisms. And if their intestines are better protected against infection, well, then that is probably one of the things that cause them to live longer than others.”
Postdoc Joachim Johansen, first author of the new study
Among other things, the new study shows that specific viruses in the intestines can have a beneficial effect on the intestinal flora and thus on our health.
“Our intestines contain billions of viruses living of and inside bacteria, and they could not care less about human cells; instead, they infect the bacterial cells. And seeing as there are hundreds of different types of bacteria in our intestines, there are also lots of bacterial viruses,” says Associate Professor Simon Rasmussen, last author of the new study.
Joachim Johansen adds that aside from the important, new, protective bacterial viruses, the researchers also found that the intestinal flora of the Japanese centenarians is extremely interesting.
“We found great biological diversity in both bacteria and bacterial viruses in the centenarians. High microbial diversity is usually associated with a healthy gut microbiome. And we expect people with a healthy gut microbiome to be better protected against aging-related diseases,” says Joachim Johansen.
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Once we know what the intestinal flora of centenarians looks like, we can get closer to understanding how we can increase the life expectancy of other people. Using an algorithm designed by the researchers, they managed to map the intestinal bacteria and bacterial viruses of the centenarians.
“We want to understand the dynamics of the intestinal flora. How do the different kinds of bacteria and viruses interact? How can we engineer a microbiome that can help us live healthy, long lives? Are some bacteria better than others? Using the algorithm, we are able to describe the balance between viruses and bacteria,” says Simon Rasmussen.
And if the researchers are able to understand the connection between viruses and bacteria in the Japanese centenarians, they may be able to tell what the optimal balance of viruses and bacteria looks like.
Optimizing intestinal bacteria
More specifically, the new knowledge on intestinal bacteria may help us understand how we should optimize the bacteria found in the human body to protect it against disease.
“We have learned that if a virus pays a bacterium a visit, it may actually strengthen the bacterium. The viruses we found in the healthy Japanese centenarians contained extra genes that could boost the bacteria. We learned that they were able to boost the transformation of specific molecules in the intestines, which might serve to stabilize the intestinal flora and counteract inflammation,” says Joachim Johansen, and Simon Rasmussen adds:
“If you discover bacteria and viruses that have a positive effect on the human intestinal flora, the obvious next step is to find out whether only some or all of us have them. If we are able to get these bacteria and their viruses to move in with the people who do not have them, more people could benefit from them.”
Even though this requires more research, the new insight is significant, because we are able to modify the intestinal flora.
“Intestinal bacteria are a natural part of the human body and of our natural environment. And the crazy thing is that we can actually change the composition of intestinal bacteria. We cannot change the genes – at least not for a long time to come. If we know why viruses and intestinal bacteria are a good match, it will be a lot easier for us to change something that actually affects our health,” says Simon Rasmussen.
Johansen, J., et al. (2023). Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan. Nature Microbiology. doi.org/10.1038/s41564-023-01370-6.
Thought LeadersDr. Sandor KasasResearch LeadEcole Polytechnique Fédérale de Lausanne
News Medical speaks with Dr. Sandor Kasas, a lead researcher at Ecole Polytechnique Fédérale de Lausanne in Switzerland. Here we discuss his recent development of a novel and highly efficient method for rapid antibiotic susceptibility testing using optical microscopy.
The new technique, known as Optical Nanomotion Detection (ONMD), is an extremely rapid, label-free, and single-cell sensitive method to test for antibiotic sensitivity. ONMD requires only a traditional optical microscope equipped with a camera or mobile phone. The simplicity and efficiency of the technique could prove to be a game changer in the field of antibiotic resistance.
Please can you introduce yourself, tell us about your career background, and what inspired your career in biology and medicine?
I graduated in medicine but never practiced in hospitals or medical centers. After my studies, I started working as an assistant in histology at the University of Fribourg in Switzerland. My first research projects included image processing, scanning tunneling, and atomic force microscopy.
Later, and for most of the rest of my scientific carrier, I focused primarily on the biological applications of AFM. For the past ten years, my research interest is about nanomotion, i.e., the study of oscillations at a nanometric scale of living organisms.
Image Credit: dominikazara/Shutterstock.com
You started working on biological applications of the atomic force microscope (AFM) in 1992. From your perspective, how has the antibiotic resistance landscape changed over the last two decades? What role has the advancement in technology played in furthering our understanding?
In the early ’90s, the AFM was mainly used for imaging. Later, AFM microscopists noticed that the instrument could also be used to explore the mechanical properties of living organisms. More recently, many “exotic” applications of the AFM have emerged, such as its use to weigh single cells or study their oscillations at the nanometric scale. In the 1990s, antibiotic resistance was not as serious a problem as today, but several teams were already using AFM to assess the effects of antibiotics on bacterial morphology.
The first investigations were limited to structural changes, but later, as the fields of application of AFM expanded, the instrument made it possible to monitor the mechanical properties of the bacterial cell wall upon exposure to antibiotics. In the 2010s, with G. Longo and G. Dietler, we demonstrated that AFM could also track nanoscale oscillations of living organisms. The very first application we had in mind was using the instrument to perform rapid antibiotic susceptibility testing.
We have therefore developed devices based on dedicated AFM technology to perform fast AST (i.e., in 2-4h). AFM-based nanomotion detection instruments are already implemented in medical centers in Switzerland, Spain, and Austria. However, this type of device has some drawbacks, including the need to fix the organism of interest on a cantilever. To overcome this limitation, we have developed with R. Willaert a nanomotion detector based on an optical microscope.
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Your most recent research has led to the development of a novel and highly efficient technique for rapid antibiotic susceptibility testing using optical microscopy. Please could you tell us why the development of rapid, affordable, and efficient testing methods is so important in the world of antimicrobial resistance?
Rapid antibiotic susceptibility testing could reduce the use of broad-spectrum antibiotics. Traditional ASTs based on replication rate require 24 hours (but up to 1 month in the case of tuberculosis) to identify the most effective antibiotic. Doctors prescribe broad-spectrum antibiotics between the patient’s admission to a medical center and the results of the AST.
These drugs quickly improve patients’ conditions but, unfortunately, promote resistance. A rapid AST that could identify the most suitable antibiotic within 2-4 hours would eliminate broad-spectrum antibiotics and increase treatment efficiency and reduce the development of resistant bacterial strains. Since bacterial resistance is a global problem, rapid ASTs should also be implemented in developing countries. Therefore, affordable and simple-to-use tests are needed.
Image Credit: Fahroni/Shutterstock.com
Were there any limitations and obstacles you faced in the research process? If so, how did you overcome them?
Antibiotic sensitivity detection with ONMD is very similar to the AFM-based technique. As long as the bacterium is alive, it oscillates; if the antibiotic is effective, it kills the micro-organism, and its oscillations stop. The first limitation we faced when developing the ONMD was our microscopes’ depth of field of view. To prevent the bacteria from leaving the focal plane of the optical microscope during the measurement, we had to constrain the microbes into microfluidic channels a few micrometers high.
Microfabrication of such devices is relatively straightforward in an academic environment, but we were looking for simpler solutions. One option for constructing such a device is to use 10-micron double-sided rubber tape. It allows you to “build” a microfluidic chamber in 5 minutes with two glass coverslips and a puncher.
Another challenge was nanoscale motion detection. For this purpose, we used freely available cross-correlation algorithms that achieve sub-pixel resolution. (i.e., a few nanometers). We first developed the ONMD for larger organisms, such as yeast cells, and expanded the method to bacteria. This further development took us around two years.
You worked alongside Dr. Ronnie Willaert, a professor of structural biology at Vrije Universiteit Brussel, on developing this new rapid AST technique. How did your areas of expertise and research backgrounds complement each other in developing ONMD?
R. Willaert is an expert in yeast microbiology and microfluidics, while our team in Lausanne is primarily involved in AFM-based nanomotion detection and applying AFM to clinically relevant problems. The two teams were supported by a joint grant from the Swiss National Science Foundation and the Research Foundation Flanders (FWO) which enabled the development of the method.
The field of antimicrobial resistance requires a high level of international collaboration, with everyone working together to achieve a common goal. With antimicrobial resistance rising to dangerously high levels in all parts of the world, how important is collaboration in this field?
Our project required expertise in various fields, such as microbiology, microscopy, microfluidics, programming, and data processing. In the development of rapid AST instruments and many others, only a multidisciplinary approach and close collaboration between teams with complementary expertise is today the only path to success.
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You and Dr. Willaert have said, ‘The simplicity and efficiency of the method make it a game-changer in the field of AST.’ Can you please expand on what makes ONMD a game changer in the AST field and what implications this research could have in clinical and research settings?
As mentioned earlier, bacterial resistance is a global health problem. Rapid AST should also be easily implemented in developing countries to limit the spread of resistant strains. The cheaper and simpler the technique, the more likely it is to be used on a large scale. We are convinced that the ONMD approach can meet these requirements. ONMD could also be used for drug discovery or basic research.
While we recognize the importance of rapid AST, what next steps must be taken before this technique can be used globally in research and clinical landscapes?
For fundamental research, there are no other important developments to be made. Any reasonably equipped research center can implement the technique and use it. Regarding implementing the technique in developing countries or extreme environments, stand-alone devices have to be used, which have yet to be manufactured.
There is a rapidly expanding need for efficient AST globally; however, the need for affordable, accessible, and simple techniques are of grave importance in developing countries disproportionately affected by antibiotic resistance due to existing global health disparities. Could this rapid AST technique be utilized in low-middle-income countries to slow the growing spread of multi-resistant bacteria? What would this mean for global health?
We are confident that ONMD-based AST testing can soon be implemented in research centers in both developed and developing countries. However, accreditation by the health authorities is necessary to use it as a standard diagnostic tool; this process can take several years, depending on the government health policy.
What’s next for you and your research? Are you involved in any exciting upcoming projects?
We want to develop a self-contained device for extreme environments. It would consist of a small microscope equipped with a camera and a data processing unit. The microfluidic part of the device could contain different antibiotics ready to be tested.
The ONMD technique could also monitor contamination levels in enclosed environments such as submarines, spacecraft, and space stations. One of our recent projects is funded by the European Space Agency (ESA) to develop a rapid antifungal susceptibility test that could work in microgravity. Additionally, ONMD could be used for even more exciting projects, such as chemistry-independent life detection in the search for extraterrestrial life.
Where can readers find more information?
Villalba MI, Rossetti E, Bonvallat A, Yvanoff C, Radonicic V, Willaert RG*, Kasas S.*.Simple optical nanomotion method for single-bacterium viability and antibiotic response testing. PNAS 2023, May 2;120(18):e2221284120. doi: 10.1073/pnas.2221284120. Epub 2023 Apr 24. PMID: 37094120. * Contributed equally. https://doi.org/10.1073/pnas.2221284120
Radonicic, V.; Yvanoff, C.; Villalba, M.I.; Devreese, B.; Kasas, S.; Willaert, R.G. Single-Cell Optical Nanomotion of Candida albicans in Microwells for Rapid Antifungal Susceptibility Testing. Fermentation 2023, 9:365. https://doi.org/10.3390/fermentation9040365
Parmar P, Villalba MI, Horii Huber AS, Kalauzi A, Bartolić D, Radotić K, Willaert RG, MacFabe DF and Kasas S. Mitochondrial nanomotion measured by optical microscopy. Front. Microbiol. 2023, 14:1133773. https://doi.org/10.3389/fmicb.2023.1133773
Starodubtseva MN, Irina A. Chelnokova IA, Shkliarava NM, Villalba MI, Tapalski DV, Kasas S, Willaert RG. Modulation of the nanoscale motion rate of Candida albicans by X-rays. Front. Microbiol. 2023, 14:1133027. https://doi.org/10.3389/fmicb.2023.1133027
Radonicic V, Yvanoff C, Villalba MI, Kasas S, Willaert RG. The Dynamics of Single-Cell Nanomotion Behaviour of Saccharomyces cerevisiae in a Microfluidic Chip for Rapid Antifungal Susceptibility Testing. Fermentation. 2022; 8(5):195. https://doi.org/10.3390/fermentation8050195
About Dr. Sandor Kasas
Nanomotion is a fascinating and novel approach to observing living organisms.
Our team focuses almost exclusively on recording the nanomotion of bacterial mitochondria and mammalian cells with optical and AFM-based devices.
Recently, we demonstrated that the technique could be used not only for fast antimicrobial sensitivity testing but also to explore the metabolism of unicellular organisms. We hope our efforts will permit us to expand the application domains of ONMD.
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LMU researchers have discovered a weakness in the bacterium Helicobacter pylori, which could be exploited to develop new drugs.
The pathogen Helicobacter pylori, which is responsible for widespread illnesses such as gastric ulcers and stomach cancer, has a weak point, which could be exploited to create new drugs. This was discovered by a research group led by LMU biologists Professor Rainer Haas and Dr. Wolfgang Fischer from the Max von Pettenkofer Institute of Hygiene and Medical Microbiology. Their results have now been published in the journal CellChemical Biology.
More than four billion people worldwide are infected with the stomach bacterium, leading to over 800,000 cases of stomach cancer every year. Because the bacterium is becoming increasingly resistant to current drugs, the World Health Organization (WHO) has classified it as a pathogen with high priority for the research and development of new antibiotics. New approaches and therapeutics are urgently required to replace or complement established treatment methods.
The new study has taken an important step in this direction. “We were able to demonstrate that the bacteria are very sensitive to certain substances that inhibit cellular respiration,” says Haas.
Fighting helicobacter and protecting the gut microbiome
The researchers were able to identify several compounds from various substance groups that incapacitate the respiratory chain of H. pylori even in small concentrations. For other useful bacteria, including representatives of the normal gut microbiome, these substances are unproblematic. These bacteria tolerate larger amounts of the substances.
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The authors of the study used a broad spectrum of biochemical and microbiological methods as well as molecular modeling techniques to discover why H. pylori reacts so sensitively to these substance groups. They identified the cause in a slightly modified structure of the so-called quinone binding pocket in respiratory complex I.
This Achilles heel offers great potential for the development of specifically tailored new active agents that could be used as pathogen blockers against H. pylori. “Our results reveal a surprising weakness in the metabolism of these bacteria, which are well adapted otherwise to their unusual environment,” says Fischer.
The research team at LMU was also able to identify possible mutations that would make the bacteria less sensitive to the inhibitors. However, these mutations also weaken the metabolism of the pathogens. This means that less resistance is formed to the complex I inhibitors.
“Overall, our results are very promising,” adds Haas. “We managed to identify a whole group of inhibitors that do not exhibit any cross-resistance with current therapeutics. They are less susceptible to the development of resistance and have a small impact on the gut microbiome.”
In addition to scientists at LMU, the German Center for Infection Research and researchers from Ghent University, the Max Planck Institute of Biophysics in Frankfurt, the Technical University of Munich, Helmholtz Munich and Helmholtz Braunschweig, Goethe University Frankfurt, and BASF Ludwigshafen all made significant contributions to the study.
In a recent study published in the journal Nature Microbiology, researchers investigated whether intestinal microbial alterations contribute to anorexia nervosa (AN) pathogenesis.
AN, a disorder associated with altered eating, has caused considerable mortality, especially among women. However, therapies based on scientific evidence are scarce. AN pathogenesis likely involves several environmental and genetic factors. Studies have reported intestinal microbial dysbiosis among AN-affected individuals. However, data were obtained from small sample sizes, and genus-level microbial alterations were analyzed by amplicon sequencing.
In the present study, researchers assessed the association between the intestinal microbiome and AN.
The team performed metabolomics and shotgun metagenomic analyses on serum and fecal samples, respectively, that were obtained from women with AN (n=77) and age- and sex-matched healthy controls (n=70). Further, the fecal microbiome was transplanted from anorexia nervosa cases to murine animals fed calories-limited diets over three weeks to simulate AN eating behavior for in vivo analysis. In addition, the team explored causal associations in silico by bidirectional mediation analysis. The intestinal microbiome was analyzed at functional, taxonomic, and genetic levels.
The team used the eating disorder inventory-3 (EDI-3) questionnaire to assess eating behaviors and insulin resistance was assessed using the homoeostatic model assessment for insulin resistance (HOMA-IR) tool. The team examined covariations between bacterial abundance at species and genus levels and clinical variables for AN cases and controls. Linear regression modeling was performed, adjusting for confounders such as age, smoking status, medications, and body mass index (BMI).
Further, the team evaluated the growth dynamics of gut bacteria by calculating peak-to-trough ratios (PTR) using the metagenomic dataset. The functional modules of gut bacteria were identified using gut-brain modules (GBMs) and gut metabolic modules (GMMs). Differences in bacterial genomics were explored based on the Canberra distance of bacterial structural variant profiles.
Graphical abstract of the study workflow and findings.
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Results
Several bacterial organisms (including Clostridium) were altered among individuals with anorexia nervosa and were associated with mental well-being and eating behavior estimates. Bacterial functional-type modules related to neurotransmitter degradation were enriched among those with anorexia nervosa. Further, several structural variants (SVs) in bacterial organisms were associated with the metabolic characteristics of anorexia nervosa.
The findings indicated a probable role of the intestinal microbiome in AN-associated changes concerning satiety and the metabolism of secondary bile acids. The metabolomic analysis indicated an elevation in metabolites linked to lowered food consumption (including taurine-hyodeoxycholic acid, taurine-α-muricholic acid, and indole-3-propionic acid molecules). Causal inference analysis indicated that serological bacterial metabolites probably mediate the effect of gut microbial alterations on anorexia nervosa. At the phylum level, AN microbiome samples showed lowered Actinobacteriota and Bacteroidota counts. Among families of bacteria, Christensenellaceae species, particularly CAG-138, showed the most significant enrichment in AN.
At the genus level, elevated Lactobacillus counts were observed in the AN microbiota. The Ruminococcacea-enterotype was more prevalent in cases of AN. Species-level analysis indicated greater β-diversity among AN-affected women. In AN, Roseburia inulinivorans and Roseburia intestinalis were depleted, whereas those of Erysipelatoclostridium ramosum, Blautia species CAG, and Enterocloster bolteae innocuum (Clostridium) were increased. Clostridium counts correlated positively with eating disorder scores. The abundance of Bifidobacterium and Parasutterella, in absolute terms, showed positive correlations with perfectionism and body dissatisfaction, respectively.
Absolute Brachyspira count showed a positive association with ‘drive for thinness’ markers in anorexia nervosa. Median values for PTR markedly differed between individuals with AN and controls. Women with AN were leaner, had lower fasting serological insulin, glucose, and C-reactive protein (CRP) levels, and were more sensitive to insulin than controls. Bacterial organisms with significant growth retardation, among AN case individuals included Alistipes finegoldii,Akkermansia muciniphila, Eubacterium siraeum, Coprococcus catus, SS3/4, and Odoribacter splanchnicus.
In addition, the intestinal virome was altered among AN-affected individuals, including lowered bacterial-viral interactions, due to attenuated interactions of viruses with short-chain fatty acid (SCFA)-producing bacteria, including Roseburia inulinivorans, Roseburia hominis, and Faecalibacterium prausnitzii. The team observed greater viral richness and Shannon diversity in the fecal samples of AN cases compared to controls. Notably, 25/30 viruses increased in AN were Lactococcus bacteriophages. The abundance of GBMs for serotonin synthesis and degradation of tryptophan, glutamate, and dopamine, were enriched in AN.
The team detected 2,423 and 5,056 variable SVs and deletion SVs, respectively, across 56 species of bacteria, including Bacteroides uniformis, Faecalibacterium prausnitzii, Parabacteroides distasonis, Methanobrevibacter smithii. Individuals with AN lacking the genomic region of B. uniformis had greater scores for self-denial and bulimia. The genetic deletion in B. uniformis could result in the deficiency of thiamine, a vitamin associated with intestinal and mental health. The serotonin synthesis module causally affected BMI through glycoursodeoxycholic acid, which is upregulated by serotonin.
Serum leucine mediated the influence of B. vulgatus counts on glucose homeostasis. Mice receiving AN individuals’ fecal transplants initially lost more weight with a slower gain of weight with time than those receiving fecal transplants of control individuals. The finding was related to greater levels of hypothalamic appetite-suppressing genes and thermogenesis-associated genes in the adipose tissues of mice receiving fecal transplants from individuals with AN.
Based on the study findings, gut microbial disruptions may contribute to the pathogenesis of AN.
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In an article published in the journal Current Opinion in Microbiology, scientists have provided a detailed overview of the factors affecting maternal gut microbiota during pregnancy and its impact on maternal and infant health.
Pregnancy is associated with a wide range of hormonal, immunological, and metabolic changes needed for fetal development. The most notable changes include increased cardiac output, higher levels of T regulatory cells, and alteration in gut microbiome composition.
Alteration in gut microbiota composition and diversity is associated with changes in women’s metabolic, immunological, and neurological processes, irrespective of pregnancy status. In addition, changes in gut microbiota composition are known to affect insulin sensitivity. In children with type 1 diabetes, functional and metabolic changes in gut microbiota have been documented.
Alteration in gut microbiota during pregnancy
Only limited evidence is available to thoroughly understand the changes in gut microbiota during pregnancy and its impact on maternal and fetal health. However, according to the available literature, low-grade inflammation at the intestinal mucosa as well as hormonal changes, might be responsible for gut microbiota alteration during pregnancy.
Regarding hormonal changes, pregnancy-related induction in progesterone levels is known to directly associate with increased Bifidobacterium levels in women. Bifidobacterium is a beneficial bacterium that naturally resides in the intestine. Therefore, the gut-to-gut transmission of this bacterium from the mother to the infant is crucial during the neonatal period. In infants, this bacterium helps degrade human milk oligosaccharides coming from maternal milk, in addition to developing infant gut microbiota and immune system.
Factors influencing maternal gut microbiota during pregnancy
Adult human gut microbiota can be influenced by many factors, including body mass index (BMI), medications, diseases, environment, and lifestyle (diet, physical activity, smoking, and drinking habits). Pre-pregnancy exposure to these factors can lead to structural and functional alteration in maternal gut microbiota during pregnancy.
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Animal studies have shown that maternal diet influences maternal and infant gut microbiota composition before and during pregnancy. Both pre-pregnancy body weight and pregnancy-related weight gain have been found to alter the composition and diversity of maternal gut microbiota.
Infant gut microbiota are influenced by the way they are delivered. For example, infants delivered vaginally have been shown to gain beneficial changes in gut microbiota compared to those delivered by c-section.
Functional studies in animals have shown that smoking-related nicotine exposure during pregnancy affects maternal gut microbiota, which in turn alters fetal exposure levels to circulating short-chain fatty acids and leptin during in-utero development.
Certain diseases before pregnancy, such as inflammatory bowel disease, have been found to influence maternal microbiota during pregnancy. The microbiota of the pregnant mother’s gut has also been shown to be affected pre-pregnancy and during pregnancy by certain medications, including antibiotics, proton-pump inhibitors, metformin, laxatives, and probiotics.
Maternal health impact of altered gut microbiota
Studies have found maternal gut microbiota alteration during pregnancy is associated with pregnancy complications, including gestational diabetes and preeclampsia.
Gestational diabetes
A spontaneous induction in blood glucose levels during pregnancy is medically termed gestational diabetes. Studies have shown that a reduced abundance of beneficial bacteria and an increased abundance of pathogenic bacteria are responsible for the onset of gestational diabetes.
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In the microbiome of gestational diabetes patients, an increased abundance of membrane transport, energy metabolism, lipopolysaccharides, and phosphotransferase system pathways has been observed. Recent evidence indicates that gut microbiota-derived dopamine deficiency in the blood, impaired production of short-chain fatty acids, and excessive metabolic inflammation are collectively responsible for the development of gestational diabetes.
Preeclampsia
Preeclampsia is characterized by new-onset hypertension, proteinuria, and organ dysfunction during pregnancy. Studies involving pregnant women with preeclampsia have found gut microbiota dysbiosis (imbalance in gut microbiota composition) and increased plasma levels of lipopolysaccharide and trimethylamine N-oxide.
Recent evidence indicates that preeclampsia onset is associated with reduced bacterial diversity in gut microbiota. Specifically, the changes in gut microbiota include a depletion in beneficial bacteria and an enrichment in opportunistic bacteria.
Some mechanistic studies have pointed out that gut microbiota dysbiosis induces immune imbalance and intestinal barrier disruption in pregnant women, leading to the translocation of bacteria to the intrauterine cavity, placental inflammation, and poor placentation. All these factors collectively contribute to the development of preeclampsia.
Infant health impact of altered gut microbiota
Alteration in maternal gut microbiota has been found to affect the fetus’s neurodevelopment via signaling microbially modulated metabolites to neurons in the developing brain. These changes can have long-term effects on an infant’s behaviors.
Maternal microbiota-derived metabolites such as short-chain fatty acids are known to shape the metabolic system of infants. Some evidence has also indicated that maternal gut microbiota influences an infant’s susceptibility to allergic diseases.
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In an article published in the journal Current Opinion in Microbiology, scientists have provided a detailed overview of the factors affecting maternal gut microbiota during pregnancy and its impact on maternal and infant health.
Pregnancy is associated with a wide range of hormonal, immunological, and metabolic changes needed for fetal development. The most notable changes include increased cardiac output, higher levels of T regulatory cells, and alteration in gut microbiome composition.
Alteration in gut microbiota composition and diversity is associated with changes in women’s metabolic, immunological, and neurological processes, irrespective of pregnancy status. In addition, changes in gut microbiota composition are known to affect insulin sensitivity. In children with type 1 diabetes, functional and metabolic changes in gut microbiota have been documented.
Alteration in gut microbiota during pregnancy
Only limited evidence is available to thoroughly understand the changes in gut microbiota during pregnancy and its impact on maternal and fetal health. However, according to the available literature, low-grade inflammation at the intestinal mucosa as well as hormonal changes, might be responsible for gut microbiota alteration during pregnancy.
Regarding hormonal changes, pregnancy-related induction in progesterone levels is known to directly associate with increased Bifidobacterium levels in women. Bifidobacterium is a beneficial bacterium that naturally resides in the intestine. Therefore, the gut-to-gut transmission of this bacterium from the mother to the infant is crucial during the neonatal period. In infants, this bacterium helps degrade human milk oligosaccharides coming from maternal milk, in addition to developing infant gut microbiota and immune system.
Factors influencing maternal gut microbiota during pregnancy
Adult human gut microbiota can be influenced by many factors, including body mass index (BMI), medications, diseases, environment, and lifestyle (diet, physical activity, smoking, and drinking habits). Pre-pregnancy exposure to these factors can lead to structural and functional alteration in maternal gut microbiota during pregnancy.
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Animal studies have shown that maternal diet influences maternal and infant gut microbiota composition before and during pregnancy. Both pre-pregnancy body weight and pregnancy-related weight gain have been found to alter the composition and diversity of maternal gut microbiota.
Mode of delivery has been found to influence infant gut microbiota. For example, infants delivered vaginally have been shown to gain beneficial changes in gut microbiota compared to those delivered by c-section.
Functional studies in animals have shown that smoking-related nicotine exposure during pregnancy affects maternal gut microbiota, which in turn alters fetal exposure levels to circulating short-chain fatty acids and leptin during in-utero development.
Certain diseases before pregnancy, such as inflammatory bowel disease, have been found to influence maternal microbiota during pregnancy. Similarly, pre-pregnancy and during-pregnancy consumption of certain medications, including antibiotics, proton-pump inhibitors, metformin, laxatives, and probiotics, has been found to influence maternal gut microbiota during pregnancy.
Maternal health impact of altered gut microbiota
Studies have found maternal gut microbiota alteration during pregnancy is associated with pregnancy complications, including gestational diabetes and preeclampsia.
Gestational diabetes
A spontaneous induction in blood glucose levels during pregnancy is medically termed gestational diabetes. Studies have shown that a reduced abundance of beneficial bacteria and an increased abundance of pathogenic bacteria are responsible for the onset of gestational diabetes.
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In the microbiome of gestational diabetes patients, an increased abundance of membrane transport, energy metabolism, lipopolysaccharides, and phosphotransferase system pathways has been observed. Recent evidence indicates that gut microbiota-derived dopamine deficiency in the blood, impaired production of short-chain fatty acids, and excessive metabolic inflammation are collectively responsible for the development of gestational diabetes.
Preeclampsia
Preeclampsia is characterized by new-onset hypertension, proteinuria, and organ dysfunction during pregnancy. Studies involving pregnant women with preeclampsia have found gut microbiota dysbiosis (imbalance in gut microbiota composition) and increased plasma levels of lipopolysaccharide and trimethylamine N-oxide.
Recent evidence indicates that preeclampsia onset is associated with reduced bacterial diversity in gut microbiota. Specifically, the changes in gut microbiota include a depletion in beneficial bacteria and an enrichment in opportunistic bacteria.
Some mechanistic studies have pointed out that gut microbiota dysbiosis induces immune imbalance and intestinal barrier disruption in pregnant women, leading to the translocation of bacteria to the intrauterine cavity, placental inflammation, and poor placentation. All these factors collectively contribute to the development of preeclampsia.
Infant health impact of altered gut microbiota
Alteration in maternal gut microbiota has been found to affect the fetus’s neurodevelopment via signaling microbially modulated metabolites to neurons in the developing brain. These changes can have long-term effects on an infant’s behaviors.
Maternal microbiota-derived metabolites such as short-chain fatty acids are known to shape the metabolic system of infants. Some evidence has also indicated that maternal gut microbiota influences an infant’s susceptibility to allergic diseases.
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Since the beginning of the COVID-19 pandemic, researchers have been working on mucosal vaccines that can be administered through the nose. Now, scientists in Berlin have developed a live attenuated vaccine for the nose. In “Nature Microbiology”, they describe the special immune protection it induces.
Coronaviruses spread primarily through the air. When infected people speak, cough, sneeze or laugh, they expel droplets of saliva containing the virus. Other people then breathe in these airborne pathogens and become infected themselves. A research team in Berlin decided to try to fight the virus that causes COVID-19 where it first takes hold: the mucous membranes of the nose, mouth, throat, and lungs. To do so, the scientists developed a live attenuated SARS-CoV-2 vaccine that is administered through the nose. In the latest issue of the journal “Nature Microbiology“, the interdisciplinary team describes how this live attenuated vaccine confers better immunity than vaccines injected into muscle.
Already in the fall of last year, two nasal vaccination formulations were approved for use in India and China. These contain modified adenoviruses – which typically cause respiratory or gastrointestinal illnesses – that are self-attenuating, meaning they either replicate poorly or stop replicating altogether, and therefore never trigger disease. Other live nasal vaccines are currently undergoing development and testing around the world.
Protection at the site of infection
The benefits of a nasal vaccine go far beyond just providing an alternative for people afraid of needles. When a vaccine is injected, it infers immunity primarily in the blood and throughout the entire body. However, this means that the immune system only detects and combats coronaviruses relatively late on in an infection, as they enter the body via the mucous membranes of the upper respiratory tract. “It is here, therefore, that we need local immunity if we want to intercept a respiratory virus early on,” explains the study’s co-last author Dr. Jakob Trimpert, a veterinarian and research group leader at the Institute of Virology at Freie Universität Berlin.
“Nasal vaccines are far more effective in this regard than injected vaccines, which fail or struggle to reach the mucous membranes,” emphasizes Dr. Emanuel Wyler, another co-last author. He has been researching COVID-19 since the start of the pandemic as part of the RNA Biology and Posttranscriptional Regulation Lab, which is led by Professor Markus Landthaler at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB).
In an ideal scenario, a live intranasal vaccine stimulates the formation of the antibody immunoglobulin A (IgA) directly on site, thus preventing infection from occurring in the first place. IgA is the most common immunoglobin in the mucous membranes of the airways. It is able to neutralize pathogens by binding to them and preventing them from infecting respiratory tract cells. At the same time, the vaccine stimulates systemic immune responses that help provide effective overall protection from infection.
Memory T cells that reside in lung tissue play a similarly useful role to antibodies in the mucosa. These white blood cells remain in affected tissue long after an infection has passed and remember pathogens they have encountered before. Thanks to their location in the lungs, they can respond quickly to viruses that enter through the airways.” The co-first author draws attention to one of the observations the team made during their study: “We were able to show that prior intranasal vaccination results in the increased reactivation of these local memory cells in the event of a subsequent SARS-CoV-2 infection. Needless to say, we were particularly pleased with this result.”
Dr. Geraldine Nouailles, immunologist and research group leader at the Department of Pneumology, Respiratory Medicine, and Intensive Care Medicine at Charité
Local immunity impedes viral infection
The scientists tested the efficacy of the newly developed intranasal COVID-19 vaccine on hamster models that had been established by Trimpert and his team at Freie Universität Berlin at the beginning of the pandemic. These rodents are currently the most important non-transgenic model organisms for research into the novel coronavirus, as they can be infected with the same virus variants as humans and develop similar symptoms. They found that after two doses of the vaccine, the virus could no longer replicate in the model organism. “We witnessed strong activation of the immunological memory, and the mucous membranes were very well protected by the high concentration of antibodies,” Trimpert explains. The vaccine could therefore also significantly reduce the transmissibility of the virus.
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In addition, the scientists compared the efficacy of the live attenuated vaccine with that of vaccines injected into the muscle. To do so, they vaccinated the hamsters either twice with the live vaccine, once with the mRNA and once with the live vaccine, or twice with an mRNA or adenovirus-based vaccine. Then, after the hamsters were infected with SARS-CoV-2, they used tissue samples from the nasal mucosa and lungs to see how strongly the virus was still able to attack the mucosal cells. They also determined the extent of the inflammatory response using single-cell sequencing. “The live attenuated vaccine performed better than the other vaccines in all parameters,” Wyler summarizes. This is probably due to the fact that the nasally administered vaccine builds up immunity directly at the viral entry site. In addition, the live vaccine contains all components of the virus – not just the spike protein, as is the case with the mRNA vaccines. While spike is indeed the virus’s most important antigen, the immune system can also recognize the virus from about 20 other proteins.
Better than conventional vaccines
The best protection against the SARS-CoV-2 was provided by double nasal vaccination, followed by the combination of a muscular injection of the mRNA vaccine and the subsequent nasal administration of the live attenuated vaccine. “This means the live vaccine could be particularly interesting as a booster,” says the study’s co-first author Julia Adler, a veterinarian and doctoral student at the Institute of Virology at Freie Universität Berlin.
The principle of live attenuated vaccines is old and is already used in measles and rubella vaccinations, for example. But in the past, scientists generated the attenuation by chance – sometimes waiting years for mutations to evolve that produced an attenuated virus. The Berlin researchers, on the other hand, were able to specifically alter the genetic code of the coronaviruses. “We wanted to prevent the attenuated viruses from mutating back into a more aggressive variant,” explains Dr. Dusan Kunec, a scientist at the Institute of Virology at Freie Universität Berlin and another co-last author of the study. “This makes our live vaccine entirely safe and means it can be tailored to new virus variants,” stresses Kunec, who was instrumental in developing the vaccine.
The next step is safety testing: The researchers are collaborating with RocketVax AG, a Swiss start-up based in Basel. The biotech company is developing the live attenuated SARS-CoV-2 vaccine and preparing a phase 1 clinical trial in humans. “We are thrilled to be at the forefront of developing and manufacturing the live attenuated SARS-CoV-2 vaccine as a nasal spray at RocketVax. Our goal is to rapidly scale-up production and advance clinical development towards market access to provide protection against post-COVID symptoms for all. We see great potential in the market for seasonal nasal vaccines”, says Dr. Vladimir Cmiljanovic, CEO of RocketVax.
The future will show which nasal vaccine will ultimately provide better protection. The manufacturers of the nasal adenovirus vaccines developed in India and China have not yet applied for approval in Europe. But one thing is clear to the scientists: since they are administered as nasal sprays or drops, nasal vaccines are a good option for use in places with limited access to trained medical staff. They are also inexpensive to produce and easy to store and transport. Last but not least, live attenuated vaccines such as this one have been proven to provide cross-protection against related viral strains, and thus presumably also against future SARS-CoV-2 variants.
Nouailles, G., et al. (2023). Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nature Microbiology. doi.org/10.1038/s41564-023-01352-8
Increases in multidrug-resistance in the bacteria Streptococcus pneumoniae have made it the fourth-leading cause of death associated with antibiotic resistance.
In a study in PLOS Biology, researchers report a new target to fight against pneumonia due to infections by this opportunistic lung pathogen -; interference with the bacteria’s fermentation metabolism. This may offer a novel therapeutic option in the urgent need to discover new strategies to combat drug-resistant S. pneumoniae.
In a proof of principle, University of Alabama at Birmingham researchers showed that giving an existing drug -; one already approved by the United States Food and Drug Administration to treat methanol poisoning – in combination with the antibiotic erythromycin significantly reduced disease in mice infected with a virulent, multidrug-resistant S. pneumoniae. The combination therapy reduced bacterial burden in the lungs by 95 percent, and bacterial burdens in the spleen and heart by 100- and 700-fold, respectively. The FDA-approved drug alone, or erythromycin alone, had no effect.
Fomepizole, the FDA-approved drug, disrupts activity of the enzyme alcohol dehydrogenase in the bacteria. The mice were infected intratracheally with the multidrug-resistant clinical isolate S. pneumoniae serotype 35B strain 162–5678, which has high resistance to erythromycin. Notably, the S. pneumoniae 35B serotype has been reported as an emerging multidrug-resistant serotype in clinical settings. Eighteen hours after infection, the mice were given a single injection of erythromycin, with or without fomepizole.
Fomepizole, or other drugs that inhibit bacterial metabolism, have potential to dramatically increase the efficacy of erythromycin and other antibiotics, respectively, in vivo.”
Carlos Orihuela, Ph.D., professor and interim chair of the UAB Department of Microbiology
A broad foundation of basic research preceded this proof-of-principle experiment.
S. pneumoniae relies on fermentation and glycolysis to produce energy. During fermentation, pyruvate is converted to lactate, acetate and ethanol, and NADH is oxidized to regenerate NAD+, which is needed for glycolysis. Accordingly, maintenance of an available NAD+ pool, necessary for redox balance, is vital for sustained energy production, bacterial growth and survival.
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Orihuela and UAB colleagues made S. pneumoniae mutants in five enzymes involved in fermentation and NAD+ production, and they found, in general, that the mutants had impaired metabolism. Two of the mutants, one for lactate dehydrogenase and one for alcohol dehydrogenase, had stark decreases in intracellular pool of ATP, the energy molecule of living cells. The other three mutants had significant, but more modest, decreases.
NAD+/NADH redox imbalances in the mutants generally interfered with production of S. pneumoniae virulence factors and colonization in the mouse nasopharynx. Some of the mutations influenced susceptibility to antibiotics, as tested with three antibiotics, including erythromycin, that interfere with protein synthesis, two antibiotics that disrupt cell wall synthesis and one antibiotic that targets DNA transcription.
Researchers found that treating a wildtype S. pneumoniae, which did not have mutations in alcohol dehydrogenase or the other enzymes, with fomepizole alone caused redox imbalances. In vitro tests showed that treatment of S. pneumoniae with fomepizole enhanced the susceptibility to antibiotics, including fourfold decreases in the minimal inhibitory concentrations of the antibiotics erythromycin and gentamicin.
“We also evaluated whether fomepizole treatment impacted the antibiotic susceptibility of other anaerobic gram-positive bacteria, including other streptococcal pathogens, including Streptococcus pyogenes, Streptococcus agalactiae and Enterococcus faecium, to erythromycin or gentamicin,” Orihuela said. “We observed from twofold to eightfold decreased minimal inhibitory concentration with fomepizole in most cases, including E. faecium.”
“Our results indicate that the blocking of NAD+ regeneration pathways during infection is a way to increase antibiotic susceptibility in drug-resistant gram-positive anaerobic pathogens,” Orihuela said. “This has clinical potential with regard to microbial eradication and treatment of disseminated infection.”
Globally, more than 3 million individuals are hospitalized due to pneumococcal disease annually, and hundreds of thousands die as a result.
Memory B cells play a critical role to provide long-term immunity after a vaccination or infection. In a study published in the journal Immunity, researchers describe a distinct and novel subset of memory B cells that predict long-lived antibody responses to influenza vaccination in humans.
These effector memory B cells appear to be poised for a rapid serum antibody response upon secondary challenge one year later, Anoma Nellore, M.D., Fran Lund, Ph.D., and colleagues at the University of Alabama at Birmingham and Emory University report. Evidence from transcriptional and epigenetic profiling shows that the cells in this subset differ from all previously described memory B cell subsets.
The UAB researchers identified the novel subset by the presence of FcRL5 receptor protein on the cell surface. In immunology, a profusion of different cell-surface markers is used to identify and separate immune-cell types. In the novel memory B cell subset, FcRL5 acts as a surrogate marker for positive expression of the T-bet transcription factor inside the cells. Various transcription factors act as master regulators to orchestrate the expression of many different gene sets as various cell types grow and differentiate.
Nellore, Lund and colleagues found that the FcRL5+ T-bet+ memory B cells can be detected seven days after immunization, and the presence of these cells correlates with vaccine antibody responses months later. Thus, these cells may represent an early, easily monitored cellular compartment that can predict the development of a long-lived antibody response to vaccines.
This could be a boon to the development of a more effective yearly influenza vaccine. “New annual influenza vaccines must be tested, and then manufactured, months in advance of the winter flu season,” Lund said. “This means we must make an educated guess as to which flu strain will be circulating the next winter.”
Why are vaccine candidates made so far in advance? Pharmaceutical companies, Lund says, need to wait many weeks after vaccinating volunteers to learn whether the new vaccine elicits a durable immune response that will last for months. “One potential outcome of the current study is we may have identified a new way to predict influenza vaccine durability that would give us an answer in days, rather than weeks or months,” Lund said. “If so, this type of early ‘biomarker’ could be used to test flu vaccines closer to flu season -; and moving that timeline might give us a better shot at predicting the right flu strain for the new annual vaccine.”
Seasonal flu kills 290,000 to 650,000 people each year, according to World Health Organization estimates. The global flu vaccine market was more than $5 billion in 2020.
To understand the Immunity study, it is useful to remember what happens when a vaccinated person subsequently encounters a flu virus.
Following exposure to previously encountered antigens, such as the hemagglutinin on inactivated influenza in flu vaccines, the immune system launches a recall response dominated by pre-existing memory B cells that can either produce new daughter cells or cells that can rapidly proliferate and differentiate into short-lived plasmablasts that produce antibodies to decrease morbidity and mortality. These latter B cells are called “effector” memory B cells.
“The best vaccines induce the formation of long-lived plasma cells and memory B cells,” said Lund, the Charles H. McCauley Professor in the UAB Department of Microbiology and director of the Immunology Institute. “Plasma cells live in your bone marrow and make protective antibodies that can be found in your blood, while memory B cells live for many years in your lymph nodes and in tissues like your lungs.
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“Although plasma cells can survive for decades after vaccines like the measles vaccine, other plasma cells wane much more quickly after vaccination, as is seen with COVID-19,” Lund said. “If that happens, memory B cells become very important because these long-lived cells can rapidly respond to infection and can quickly begin making antibody.”
In the study, the UAB researchers looked at B cells isolated from blood of human volunteers who received flu vaccines over a span of three years, as well as B cells from tonsil tissue obtained after tonsillectomies.
They compared naïve B cells, FcRL5+ T-bet+ hemagglutinin-specific memory B cells, FcRL5neg T-betneg hemagglutinin-specific memory B cells and antibody secreting B cells, using standard phenotype profiling and single-cell RNA sequencing. They found that the FcRL5+ T-bet+ hemagglutinin-specific memory B cells were transcriptionally similar to effector-like memory cells, while the FcRL5neg T-betneg hemagglutinin-specific memory B cells exhibited stem-like central memory properties.
Antibody-secreting B cells need to produce a lot of energy to churn out antibody production, and they also must turn on processes that protect the cells from some of the detrimental side effects of that intense metabolism, including controlling the dangerous reactive oxygen species and boosting the unfolded protein response.
The FcRL5+ T-bet+ hemagglutinin-specific memory B cells did not express the plasma cell commitment factor, but did express transcriptional, epigenetic and metabolic functional programs that poised these cells for antibody production. These included upregulated genes for energy-intensive metabolic processes and cellular stress responses.
Accordingly, FcRL5+ T-bet+ hemagglutinin-specific memory B cells at Day 7 post-vaccination expressed intracellular immunoglobulin, a sign of early transition to antibody-secreting cells. Furthermore, human tonsil-derived FcRL5+ T-bet+ memory B differentiated more rapidly into antibody-secreting cells in vitro than did FcRL5neg T-betneg hemagglutinin-specific memory B cells.
Lund and Nellore, an associate professor in the UAB Department of Medicine Division of Infectious Diseases, are co-corresponding authors of the study, “A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.”
Co-authors with Lund and Nellore are Esther Zumaquero, R. Glenn King, Betty Mousseau, Fen Zhou and Alexander F. Rosenberg, UAB Department of Microbiology; Christopher D. Scharer, Tian Mi, Jeremy M. Boss, Christopher M. Tipton and Ignacio Sanz, Emory University School of Medicine, Atlanta, Georgia; Christopher F. Fucile, UAB Informatics Institute; John E. Bradley and Troy D. Randall, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Stuti Mutneja and Paul A. Goepfert, UAB Department of Medicine Division of Infectious Diseases.
Funding for the work came from National Institutes of Health grants AI125180, AI109962 and AI142737 and from the UAB Center for Clinical and Translational Science.
Nellore, A., et al. (2023). A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans. Immunity. doi.org/10.1016/j.immuni.2023.03.001.
The human intestine is an environment inhabited by many bacteria and other microorganisms collectively known as the gut microbiome, gut microbiota or intestinal flora. In most people, it contributes to wellness. A healthy gut indicates a stronger immune system, improved metabolism, and a healthy brain and heart, among other functions.
Escherichia coli is one of the bacteria found in practically everyone’s gut microbiota, where it performs important functions, such as producing certain vitamins.
But there’s a vast amount of genetic diversity in the species. Some of its members are pathogenic and can cause diseases such as urinary tract infections. E. coli is the main agent of this type of infection among both healthy people and hospitalized patients or users of healthcare services.”
Tânia Gomes do Amaral, Head of the Experimental Enterobacterial Pathogenicity Laboratory (LEPE), Federal University of São Paulo’s Medical School (EPM-UNIFESP), Brazil
Amaral is first author of an article published in the journal Pathogens on the virulence of these bacteria and their resistance to antibiotics in hospitalized patients.
“Our study focused on hospitalized patients because patients who stay in hospital for a long period are more likely to undergo various procedures, such as urine catheter insertion or venous access. Although these procedures are performed to assure life support, they may facilitate the entry of bacteria into the organism and cause an infection,” Amaral explained.
She earned a PhD in microbiology from EPM-UNIFESP in 1988, conducting part of her research at New York University Medical School and the Center for Vaccine Development at the University of Maryland, Baltimore (UMB) in the United States.
The article reports the findings of a broader study led by Amaral, with 12 co-authors who are researchers and graduate students, on the virulence and drug resistance of E. coli strains associated with urinary tract infections. The study was supported by FAPESP via three projects (18/17353-7, 19/21685-8 and 17/14821-7).
The main aim of this part of the study, described in the master’s dissertation of José Francisco Santos Neto, was to evaluate the diversity and drug resistance of pathogenic E. coli strains isolated from the gut microbiota of inpatients, and to analyze the frequency of endogenous infection (caused by bacteria from the patient’s own microbiota).
The UNIFESP group first investigated the genetic diversity and drug resistance of E. coli strains isolated from the gut microbiota of hospitalized patients, sequencing these strains as well as others isolated from their urine and comparing the results in order to evaluate dissemination of the bacteria in the hospital environment.
“We also compared the genomes of these strains with those of E. coli strains isolated in different parts of the world in order to see if any globally disseminated pathogenic bacteria were present in the study sample,” said Ana Carolina de Mello Santos, a postdoctoral researcher working on the LEPE team.
Urinary tract infections proved to be endogenous for the vast majority of the patients in the study (more than 70%). The results also showed that the patients’ gut microbiota contained at least two genetically different populations of E. coli and that about 30% were colonized by non-lactose-fermenting E. coli strains, which are less common, with some of the patients studied having only such strains in their gut microbiota.
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“This finding is most interesting because previous research conducted in other countries to analyze the composition of human gut microbiota didn’t investigate non-lactose-fermenting E. coli,” Santos said.
The authors also note the presence of bacteria with all the genetic markers required for classification as pathogenic and the detection of pathogenic bacteria in the gut microbiota of all patients that had not yet developed an infection. “Hospitalized patients are more susceptible to infection because by definition they are already unwell. Colonization by pathogens is the first step in the spread of hospital-acquired infections now so frequent worldwide,” Santos said.
With regard to antibiotics and other antimicrobials, the authors stress that drug resistance is also a growing global problem, and enterobacterial resistance to third-generation cephalosporins as well as colistin is critical. In all patients whose gut microbiota was colonized by drug-resistant bacteria, the same bacteria also caused endogenous urinary tract infections. In other words, the multidrug-resistant bacteria colonized the gut and traveled to the urinary tract, where they caused an infection.
“In light of these findings, early assessment of gut microbiota in hospitalized patients, at least in cases of E. coli infection, can facilitate and guide their treatment, while also identifying patients who risk progressing to extra-intestinal diseases such as urinary tract infections, which were part of the focus for our study,” Amaral said. “We don’t yet know whether the findings also apply to other bacteria found in gut microbiota, such as the genera Klebsiella, Enterobacter, Pseudomonas and others that can cause infections when they travel to extra-intestinal sites.”
These bacterial genera tend to be even more drug-resistant than E. coli, representing a major public health problem in the hospital environment. As the researchers noted, the World Health Organization (WHO) considers E. coli strains resistant to cephalosporin and colistin to be a critical global health threat. “The presence in human gut microbiota of drug-resistant bacteria associated with severe infectious disease is a matter of great concern, not least because they could spread to people outside the hospital environment,” Amaral said.
Another point raised by the study is the importance of finding out when colonization of the patient’s gut by drug-resistant virulent bacteria occurred. The authors of the article were unable to determine whether the bacteria resistant to cephalosporins and colistin colonized the patients before or after they were hospitalized.
By analyzing the genomes of the strains, however, the researchers were able to identify global risk clones that can cause severe disease and are associated with antimicrobial resistance. “One such clone found in the gut microbiota of two patients was identical to others isolated from urinary tract infections in Londrina, Paraná [a state in South Brazil], and in the United States, as well as European and Asian countries. This shows that some strains found in the study are clones generally associated with infections in all regions of the world,” Amaral said.
This type of information is important when patients are hospitalized. Knowledge of bacterial virulence and drug resistance can be used to prevent infection in parts of the organism outside the intestine and stop the bacteria from spreading to other patients in the same hospital.
Santos-Neto, J.F., et al. (2023) Virulence Profile, Antibiotic Resistance, and Phylogenetic Relationships among Escherichia coli Strains Isolated from the Feces and Urine of Hospitalized Patients. Pathogens.doi.org/10.3390/pathogens11121528.
Microbiome: From Research and Innovation to Market
