Studies show that alcohol influences the composition of our gut microbiota, which in turn influences our behavior. But does the gut microbiota influence our behavior towards alcohol? Spanish researchers have explored this hypothesis by comparing the weekly alcohol consumption and gut microbiota composition of 507 students. They first noted that the “heavier drinkers” had harder stools typical of constipation. This came as a surprise since alcohol was thought to cause diarrhea. They then found that the main difference in gut flora composition between the students who drank the most alcohol and those who did not drink was that the former had significantly higher levels of Actinobacteria (sidenote: Actinobacteria Actinobacteria are one of the gut microbiota’s four major bacterial groups (phyla), together with Bacteroidetes, Firmicutes, and Proteobacteria. Notable among Actinobacteria are Bifidobacteria, the most common Actinobacteria in the gut flora. Binda C, Lopetuso LR, Rizzatti G, et al. Actinobacteria: a relevant minority for the maintenance of gut homeostasis. Digestive and Liver Disease. 2018 May 1;50(5):421-8. ) .

Rats receiving the microbiota of alcoholic conspecifics develop a taste for alcohol

The scientists continued their research on rats by making them dependent on alcohol and transplanting their fecal microbiota into “sober” rats. Two weeks after the procedure, when given a choice between water containing alcohol and pure water, the formerly sober rats were more likely to prefer the water containing alcohol than “control” rats. According to the researchers, the time-lapse suggests that the new gut microbiota composition is the cause, rather than a consequence, of increased alcohol consumption. In the recipient rats, the gut microbiota of the alcoholic rats is a predisposing factor in an increased desire to consume alcohol, which in turn favors the abundance of certain “alcohol-loving” bacteria. Through the “gut-brain axis“, the gut microbiota may also affect the so-called “reward” neuronal circuits, which are involved in the development of addictions.

The scientists thus believe that the gut microbiota modifies our behavior towards alcohol. A recent study, this time on humans, seems to confirm this, but with a more positive outcome: alcoholics saw their cravings for alcohol strongly reduced after a fecal microbiota transplant from non-alcoholics.

Probiotics, a solution to alcoholism? 

A gut microbiota analysis in the alcoholic donor and recipient rats suggests that the bacterial genus Porphyromonas, which was less abundant in these animals than in controls, may be associated with the increased urge to consume alcohol. The researchers did not find any bacterial genus with increased content, but noted that in other studies, Actinobacteria were more abundant in alcoholic mice, just like they are in humans. However, they believe that treating the human gut microbiota with, for example, probiotics and/or prebiotics, may help manage alcohol use disorder. The relevant genera and species have yet to be determined.

Discover content to keep your microbiota healthy during the festive season. We wish you a merry Christmas and a happy microbiota!

Good resolutions to take care of your intestinal flora

No need to feel guilty, the holidays are good for our gut microbiota!

It’s a well-known dietary trick: avoid weight gain by replacing sugar in our diet with non-nutritive sweeteners (NNS). Although usually considered risk-free, previous studies in mice have found that these ingredients could disrupt the intestinal microbiota and glycemic response. The same team this time explored the effects of NNS in humans using a randomized controlled trial of 120 healthy adults divided into six groups. Four groups were administered sachets containing, respectively, sucralose, saccharine, aspartame, or stevia, all at doses lower than the acceptable daily intake (sidenote: The acceptable daily intake, or ADI, is the estimated quantity of a substance in food or drinking water that can be ingested daily over a lifetime with no appreciable health risk. ) for these substances. Because the sweeteners contained glucose (vehicle ingredient), a fifth group was given sachets of glucose (glucose control) and a sixth received no supplement at all (no supplement).

Sweeteners modify the microbiota and its functions...

Sequencing (shotgun) found that the four sweeteners caused specific changes (i.e., specific to each NNS) in the composition and/or metabolic function of the intestinal microbiota and oral microbiota. The most marked effect on intestinal microbiota was observed in the sucralose group. However, only sucralose and saccharine had a significant effect on glucose tolerance, with an increase in glycemia in both groups.

...with possible repercussions for the glycemic response

The changes seen in the intestinal microbiota, its functions, and the circulating metabolites mediated by the various NNS were correlated with the participants’ glycemic response. To determine whether these changes were the cause of the glycemic disruption, the researchers transplanted into axenic mice (sidenote: Germ-free mice mice that have no microbes at all, raised in sterile conditions. ) the intestinal microbiota of selected individuals from the four test groups: those whose glycemic response was most affected (top responders) and least affected (bottom responders) by the NNS. The glycemic responses observed in the mice reflected the observations in the respective human donors, thus corroborating the causal hypothesis.

A person-specific, microbiota-dependent response to NNS

Finally, the researchers showed that the intestinal microbiota of the top vs. bottom responders evolved differently during exposure to the various NNS, possibly due to differences in baseline status. This led the researchers to compare the microbiota to a center of reactivity or adaptation that conditions physiological response to sweeteners, with effects only in certain individuals with a specific microbiota.

Guilt-free pleasure, the sweet taste of sugar without either the calories or the health problems (obesity, diabetes etc.) likely to rear their ugly heads if we eat too much: such is the promise of sweeteners, these sugar substitutes that we add to drinks, “diet” fizzy drinks and even “diet” cookies, which are increasingly popular among consumers. Could they be too good to be true? That is what an Israeli study of 120 adults asked to use one of four sweeteners for two weeks (sucralose, saccharine, aspartame or stevia) suggests.

A varying impact on blood sugar, depending on the individual

Ironically, some of the groups taking the sugar substitutes (sucralose and saccharine) soon recorded an abnormal rise in their blood levels of...sugar (glycemia). However, within a single group, there was a wide range in glycemic response between individuals. Given this variability, the researchers turned their attention to the gut microbiota gut microbiota, which is specific to each person and already known to play a direct role in digestion. They found that the four sweeteners, affected the composition of the intestinal (and oral) microbiota and/or its functions, each in its own way. These changes were correlated to the effects on blood sugar levels, suggesting a causal link.

The gut microbiota, a “hangout” for sweeteners

Wanting to be sure of their findings, the researchers transferred the gut microbiota of the participants into axenic (sidenote: Germ-free mice mice that have no microbes at all, raised in sterile conditions. ) mice. In confirmation of their hypothesis, this sole step was enough to reproduce in the recipient mice the same glycemic responses observed in their respective donors. In other words, the mice had a higher blood sugar level if they had received microbiota from participants whose blood sugar level was also affected. This led the researchers to compare the microbiota to a center of reactivity, producing a greater or lesser reaction to sweeteners depending on its make-up.

Although some individuals seem better protected by their microbiota against sweeteners than others, these results cast serious doubt onto the supposed inertia of these substances. Pending further studies to clarify the health recommendations, your next can of soda, whether sugar-full or sugar-free, may leave a bitter taste in your mouth.

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To mark World Antimicrobial Awareness Week (18-24 November), the Microbiota Institute is handing the floor to two antibiotic resistance’s experts: Dr. Windi Muziasari (sidenote: Dr. Windi Muziasari has gained years of experience and the know-how to monitor antibiotic resistance in the environment using a high-throughput gene profiling during her PhD and PostDoc at the University of Helsinki, Finland. She wanted other researchers to gain easy access to this technology and that was why she moved from academia to entrepreneurship by founding Resistomap in 2018. Headquartered in Helsinki, Resistomap's mission is to mitigate the spread of antibiotic resistance by providing robust tools for monitoring. Resistomap combines molecular genetics methods and data science to provide a service to detect and quantify antibiotic resistance genes from environmental samples such as wastewater and soils. Since fully operating in January 2019, Resistomap has served over 250 projects and analysed over 7000 environmental samples across 40 countries. ) , PhD, CEO of Resistomap, and Pr. Christian G. Giske (sidenote: Christian G. Giske is the head physician of bacteriology, mycobacteriology and mycology at Karolinska University Hospital, Solna, Sweden. He is also the head of the Division of Clinical Microbiology and the Division of Clinical Immunology at the Department of Laboratory Medicine at Karolinska Institute, where he also leads a research group. The most important research activities in Giske’s research group pertain to deep-characterization of molecular mechanisms of resistance, virulence, and molecular epidemiology of extensively drug-resistant enteric bacilli. Giske’s research is strongly translational, involving extensive collaboration with infectious diseases (including mycobacteriology), hematology, and intensive care. Giske also has extensive international collaboration, serving in the advisory board of ECDC’s European resistance surveillance, and as the chair of the European Committee on Antimicrobial Susceptibility Testing. ) from Karolinska Institute in Sweden.

Why is antibiotic resistance a major public health problem?

Antibiotic resistance is indeed a global health threat that causes more than 1,2M deaths annually¹. Antibiotic resistance is the condition when antibiotics are no longer efficient to treat bacterial infections. This can lead us back to the era before antibiotics were first discovered by Alexander Flemming in 1928. Bacterial infection diseases such as tuberculosis, pneumonia, and simply urinary tract infection could kill us again and in a worst-case scenario, performing any surgery and delivering a baby could have high mortality rates. Antibiotics are heavily used in both human and animal medicines which accelerate the increase of antibiotic resistance levels in bacteria.

Antibiotic resistance is in fact a web of several problems. It varies a lot between geographical settings whether the problem is confined to hospital-acquired infections or also widespread in the community. The results of antibiotic resistance are well documented – it leads to increased mortality, longer hospital stays, increased costs for healthcare, and more side effects related to the treatment. In many cases some hospital-acquired infections can be extremely difficult-to-treat. Antibiotic resistance will also lead to fear of complications to complicated surgery and/or immunosuppressive treatment – infections with highly drug resistant strains that will severely compromise results of other treatments. Hospital-acquired infections will usually not affect so many individuals, but still represent a public health problem due to the fear that resistant infections cannot be managed. On an individual patient level, the consequences can be dire, but also for patients in the same unit in the hospital to which resistant strains can be transmitted. Community acquired infections will affect more individuals and will also lead to increased hospitalization and thus affect the capacity in health care. There is not one single solution to the antibiotic resistance problem – rather a complex combination of several mitigation approaches is needed.

You’re monitoring antibiotic-resistant genes at hospitals by collecting wastewater samples. Can you explain why, and why are you not collecting samples directly from patients to quantify these genes?

W. Muziasari: There are two important limitations to how antibiotic resistance is currently monitored in hospitals. First, current monitoring focuses mainly on a limited number of pathogenic bacteria. Second, it is often based on passive surveillance of bacteria isolated from patients. This leads to delayed detection of outbreaks, non-comparable data, and the inability to capture other pathogenic bacteria and antibiotic resistance profiles which are often carried by commensal bacteria. 

Wastewater-based monitoring will be a potentially valuable addition to current options for antibiotic resistance monitoring in hospitals. Though not a substitute for existing monitoring methods, wastewater monitoring can provide data that is otherwise hard to obtain and become the easiest means for obtaining comprehensive information on the prevalence of resistance in hospitals. As waste from all patients are released into wastewater, wastewater monitoring can cover a wider range of antibiotic resistance profiles compared to the partial data from a few selected pathogenic bacteria. In addition, analyzing wastewater samples does not require informed consent, thus limiting ethical concerns. The practical and logistical barriers for sampling wastewater are also limited. Wastewater-based monitoring can therefore be used to better understand the development and spread of antibiotic resistant bacteria in hospitals and serve as an early warning system for future outbreaks.

How does your research & technology help physicians to prevent antibiotic resistance?

W. Muziasari: Through wastewater-based monitoring physicians will have in-depth information on the levels of antibiotic resistance from their hospitals over time.

What is the connection between antibiotic resistance and microbiota?

C. G.Giske: Many resistant strains are first acquired as colonizers in the human microbiome – either intestinal or respiratory. Once the strains are acquired in the microbiome, they can establish there as long-term carriage and will sometimes cause infections in the host, or potentially spread to other individuals who may be more susceptible to bacterial infections. Thus, carriage of resistant strains remains a significant risk for resistant infections in either the host or in other people in the proximity of the original host. While in the microbiome, strains can also easily exchange genetic material and thus transmit resistance to other bacterial strains – sometimes strains that are more adapted to the gut of that individual and can therefore remain in the microbiome for very long. Monitoring carriage of resistant strains in the microbiome remains an important part of infection control, as it can inform decisions on patients who need to be hospitalized in single rooms by dedicated staff for instance – to avoid transmission events.

Could microbiota help researchers to tackle antibiotic resistance?

C. G.Giske: The microbiome is complex and contains a variety of microorganisms – among them also viruses. Some of the viruses, the so called bacteriophages, can infect selectively bacterial strains and kill them. Such bacteriophages can be isolated from the microbiome and could be used therapeutically to treat infections in patients. Numerous studies highlight the in vitro and in vivo potential of their therapeutic uses and while a number of clinical trials have taken place over the last decade, the biggest challenge remain to produce additional data presenting a robust regulatory case for their clinical use². Moreover, monitoring resistance in the microbiome can be highly informative for understanding the pool of resistance genes available in a population and can be very useful to design strategies for counteracting antibiotic resistance.

We now know that a diet rich in sugar and fat contributes to increased gut inflammation, and that the gut’s immune system plays a key role in metabolic homeostasis. We also know that the gut microbiota is an important modulator of gut immunity and that it influences metabolic functions as well. Lastly, we know that cells such as type 3 innate lymphoid cells (ILC3) and T helper 17 cells (Th17) may be involved, depending on the context, in protecting against metabolic syndrome. However, the series of molecular mechanisms linking the high-fat diet (HFD) to its metabolic effects remains poorly understood.

To shed some light on the matter, researchers fed mice on an HFD diet or a normal diet for four weeks. Unlike the second group, the HFD group developed a typical metabolic syndrome, involving weight gain, insulin resistance, and glucose intolerance. Analyses of the gut mucosa and feces of the HFD mice revealed that the HFD diet induced a rapid loss of segmented filamentous bacteria (SFB) in the gut microbiota, which in turn led to the loss of Th17, and ultimately the onset of metabolic syndrome.

Probiotics restore protection against metabolic syndrome

Investigations on the involvement of other immune cells such as ILC3 or CD4 T cells allowed the researchers to affirm that the gut microbiota needs Th17 cells to protect against metabolic syndrome. These additional investigations also showed that the loss of Th17 cell homeostasis via the elimination of SFBs was indeed involved in the adverse effects of the HFD diet. 

Next, the mice were fed SFBs by oral gavage for four weeks, which resulted in: 

• Significant recovery in Th17 cells and their expression in the gut 
• Decrease in gut inflammation
• Weight loss
• Protection against insulin resistance 

A microbial diet that stimulates Th17 cells may therefore improve metabolic syndrome and diabetic obesity by recalibrating gut immunity homeostasis.

Is sugar the main culprit in the Western diet’s harmful effects?

However, knowing that in addition to fat, the Western diet is also rich in sugar, the researchers compared the effects on mice of the HFD diet (25% sugar, including sucrose and maltodextrin, common in candy and soda) with the effects of another diet very low in sugar (3%-6%). They found that sugar indirectly reduced Th17 cells by increasing gut microbiota levels of bacteria such as Faecalibaculum rodentium at the expense of SFBs that promote Th17.

A diet that treats metabolic syndrome? Not so fast...

While sugar has been shown to be enough to cause the concomitant loss of SFBs and Th17 cells, the elimination of dietary sugar only has a therapeutic benefit where the appropriate immune cells are present in the gut. A simple change of diet may not be sufficient in some people. The researchers believe their work shows that metabolic syndrome, obesity, and type 2 diabetes mellitus are regulated by a complex network of interactions between diet, the gut microbiota, and immune cells. The management of these diseases cannot therefore be identical for each patient. Accordingly, in the future, precision therapeutic approaches should take into account differences between individuals in terms of the gut microbiota’s immunomodulatory system.

To mark the WHO's annual World Antimicrobial Awareness Week, The Biocodex Microbiota Institute takes stock.

Accredited training on dysbiosis and the impact of antibiotics 

A folder dedicated to the impact of antibiotics on microbiota 

Infographics to share with your patients

Impact of antibiotics on the microbiota: experts' corner 

All the latest news on the impact of antibiotics on microbiota 

To mark the WHO's annual World Antimicrobial Awareness Week, The Biocodex Microbiota Institute takes stock.

Antibiotic resistance and resilience of the gut microbiota

Prof. Harry Sokol sheds light on

Antibiotic resistance: research advances

Prof. Sørensen sheds light on it

Antibiotic resistance: focus on the lung microbiota

The latest news on antibiotic resistance

How can we solve the problem of antibiotic resistance?

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Osteoporosis, which affects nearly 30% of women over the age of 50, is a major public health problem characterized by bone weakening likely to lead to repeated fractures. The mechanisms involved in this disease are not fully known, but a growing number of studies suggest that inflammation could increase the risks.

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Gut microbiota: still an underexplored avenue

We know that certain microorganisms in the gut and vaginal microbiota can modulate the immune response and impact the inflammatory system. Could they be implicated in osteoporosis? This is what researchers from the University of Zhengzhou in China tried to find out.

They enrolled 132 women between the ages of 45 and 70, all menopausal for over a year, and divided them into 3 groups based on their bone density: “no bone problems,” “slightly decreased bone density” and “osteoporosis”. The scientists collected stool and vaginal secretions from all of these female volunteers to analyze and compare their vaginal and gut microbiota. 

Results: The microbiota of women with osteoporosis have different compositions than those of the other two groups, and this difference is particularly visible at the gut level (1).

Inflammation-promoting bacteria 

The gut flora of women affected by osteoporosis was richer in bacteria whose presence is associated with a lower level of interleukin IL-10, a molecule with anti-inflammatory properties, and also in bacteria associated with the production of “pro-inflammatory” cytokines that contribute to bone destruction.

On the other hand, it was poorer than the others in bacterial species producing butyrate, a short-chain fatty acid (sidenote: Short chain fatty acids (SCFA) Short chain fatty acids (SCFA) are a source of energy (fuel) for an individual’s cells. They interact with the immune system and are involved in communication between the intestine and the brain. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25. ) (SCFA) with anti-inflammatory properties, and in bifidobacteria, which improve the intestinal absorption of calcium, essential for good bone density.

With regard to vaginal microbiota, women suffering from osteoporosis had, compared to the others, fewer lactobacteria, known to attenuate the inflammatory response and its harmful effects, and more streptococci which, to the contrary, promote it.

Toward targeted therapies to better prevent osteoporosis

For the researchers, these compositional changes are fundamental. They could one day be used to develop targeted therapies or serve as biomarkers to better prevent osteoporosis.

Recognized by the World Health Organization, fibromyalgia is characterized by generalized chronic pain, fatigue and sleep disorders. This pathology, which mainly affects women, is often difficult to manage due to a lack of diagnosis or appropriate treatment. A recent cross-sectional study might nevertheless give some hope: it looked at the role of the gut microbiota of fibromyalgia patients, and more specifically at certain bacteria producing secondary bile acids (SBAs).

A dysbiotic gut microbiota

The researchers thus closely examined the gut microbiota (stool samples) and circulating SBAs (blood samples) of 42 Canadian women suffering from fibromyalgia and 42 controls. They observed alterations in the relative abundance of several bacterial species involved in SBA metabolism in these patients: reduced presence of Bacteroides uniformis and B. thetaiotaomicron, known to synthesize an SBA called α-muricholic acid; depletion also of Prevotella copri, a bacterium that affects SBA synthesis and the expression of FXR, a hepatic nociceptor; increased abundance of Escherichia bolteae and Clostridium scindens capable of affecting the metabolism of other SBAs.

SBA alterations

This gut dysbiosis was accompanied by significant alterations in the serum SBA concentration, in particular α-muricholic acid, with levels on average 5 times lower in fibromyalgia patients. Furthermore, this depletion was correlated with pain intensity and fatigue. Thus the decrease in serum SBA levels, and in particular that of α-muricholic acid, could disrupt the normal pain inhibition mechanisms. The authors suggest a mode of action: the decrease in circulating levels of α-muricholic acid (inhibitor of the FXR receptor) and the possible increase in excitatory SBAs could lead to the activation of the FXR receptor, leading to hypersensitivity to pain.

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An objectified diagnosis in the pipeline?

A direct consequence of these observations is the possibility of detecting people with fibromyalgia on the sole basis of the concentration of these serum SBAs. This is a major step forward since diagnosis is currently based solely on subjective measurements. The model developed by the authors shows an accuracy of 91.7%, with a specificity of 90.5% and a sensitivity of 92.9%. Enough to fuel the hope of a future diagnostic tool.

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