In recent years, the link between gut dysbiosis and diseases such as metabolic syndrome, obesity and diabetes mellitus has become clear. Among potential solutions for these diseases, fecal microbiota transplant (FMT)¹ is thought to have therapeutic potential. More recently, fecal virome transplant (FVT)–i.e. transplantation of the microbiota’s viral community–has been shown to be effective in eliminating the symptoms of recurrent Clostridioides difficile infection since the gut viral community, dominated by bacteriophages, is thought to play a key role in the structure of the microbiota.

FVT to normalize weight and metabolism

In order to assess the extent to which FVT can convert an initially obese phenotype into a lean one, certain physiological parameters (weight, blood sugar level) and the expression of key metabolic genes were measured in lean mice (LF)² and mice fed on a fatty diet for 14 weeks (HF)². The results of the analysis showed that FVT from an LF donor decreased weight gain and normalized blood sugar levels and energy homeostasis in HF mice. In particular, seven genes involved, among other things, in leptin signaling pathways, glucose metabolism and lipolysis, were impacted, suggesting a beneficial effect of FVT on weight and metabolism also.

Beneficial effect via intestinal modulation

Pre-treatment with ampicillin (Amp)² in HF mice rendered FVT ineffective, suggesting that the beneficial effect of FVT involves a modulation of the intestinal microbiota. Indeed, the different treatments (FVT or FVT + Amp) on the HF mice had different scores on the Shannon index of viral and bacterial diversity. Unsurprisingly, Amp and/or the HF diet decreased bacterial diversity, which FVT restored to a level similar to that of the LF mice. As for viral diversity, it appears to be little impacted by the HF diet but increased strongly with the use of Amp, whether or not followed by FVT. The use of Amp apparently results in the induction of prophages³ that profoundly modify the bacterial and viral communities, which are only partially restored by FVT.

Microbiota and metabolome affected

FVT appears to have strongly influenced the bacterial and viral composition of the recipient mice’s intestinal microbiota. Indeed, the microbial profile of the HF + FVT group was significantly different from those of the HF and LF groups. This was due to the high viral diversity within the LF group and the difference between HF and LF diets. The same was true for the microbial profile of certain circulating metabolites associated with obesity, where significant differences between the HF + FVT group and the HF and LF groups were observed. Therefore, the transplanted viruses are thought to modulate the composition of the microbiota, leading to a phenotype that more closely resembles that of lean mice. This proof of concept encourages future studies on humans regarding the effectiveness of FVT as a treatment for diseases associated with a dysbiosis.

1) FMT is currently only used to treat recurrent Clostridioides difficile (formerly Clostridium difficile) infections.

2) Five treatment groups: a low fat (LF) control group of lean mice receiving a normal diet; a high fat (HF) group of mice receiving a high-fat diet for 14 weeks; HF + ampicillin (HF + Amp); HF + Amp + FVT; HF + FVT. Amp treatment: 24 hours prior to FVT treatment; FVT treatment: during weeks 6 and 7.

3) A prophage is a bacteriophage inserted into the genome of the infected bacterium

References to lactobacilli may make you think of yogurt (rich in these bacteria) or the intestinal microbiota, but did you know that these rod-shaped microorganisms which produce lactic acid (hence the name) are also present in our nasal passages?

Lactobacilli are more abundant in the nose in the absence of sinusitis

A comparison of the microbiota in the upper respiratory tract of around 100 healthy individuals with that of over 200 patients with chronic rhinosinusitis has shown lactobacilli to be more abundant in the nasal cavities (nose and nasopharynx) of the former group than in those of the latter. By observing lactobacilli (sidenote: Lactobacilli Rod-shaped bacteria whose main characteristic is the production of lactic acid, from where they get the name “lactic acid bacteria”.  Lactobacilli are present in the oral, vaginal and gut microbiota of humans, but also in plants and animals. They are found in fermented foods, such as dairy products (e.g. certain cheeses and yoghurts), pickles, sauerkraut, etc. Lactobacilli are also found in probiotics, with certain species recognized for their beneficial properties.   W. H. Holzapfel et B. J. Wood, The Genera of Lactic Acid Bacteria, 2, Springer-Verlag, 1st ed. 1995 (2012), 411 p. « The genus Lactobacillus par W. P. Hammes, R. F. Vogel Tannock GW. A special fondness for lactobacilli. Appl Environ Microbiol. 2004 Jun;70(6):3189-94. Smith TJ, Rigassio-Radler D, Denmark R, et al. Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis ssp. lactis BB-12® on health-related quality of life in college students affected by upper respiratory infections. Br J Nutr. 2013 Jun;109(11):1999-2007. ) more closely in “healthy noses”, the researchers noted certain features that make them especially suited to the upper airways. These included their ability to live in an oxygen-rich environment (i.e. the nose)–instead of one containing no oxygen, such as the bottom of a yogurt–thanks to the acquisition of tools enabling them to survive therein.

When colonization is only a few hairs away

In particular, certain types of Lactobacillus casei (a species of lactobacillus) identified in healthy noses displayed multiple hairs allowing them to adhere strongly to the nasal walls. Like Spider-Man scaling a building, these specific lactobacilli can climb our nasal cavities even against wind (sneezing) and rain (runny noses). Once in place, L. casei inhibits infectious agents by preventing them from settling in the ground it has already occupied and hindering their growth via the lactic acid it produces.

A probiotic spray soon?

These initial results led the researchers to test a spray containing these “hairy lactobacilli” in 20 healthy volunteers. The results revealed that the bacteria seem able to settle, at least temporarily, in the nasal cavities. Therefore, the beneficial role of lactobacilli is far from being limited to the intestinal and vaginal microbiota. Their effect on the respiratory tract, hitherto largely unknown, gives hope for new approaches in the treatment of chronic respiratory diseases.

Alzheimer’s disease is the most frequent neurodegenerative disease. We still do not know the exact mechanisms at play, but little doubt remains that the gut microbiota is involved in its development. Since the gut microbiota is in turn impacted by what we eat, the idea to prevent this disease with our diet is catching on fast. Mediterranean diet (sidenote: Mediterranean diet Rich in fruit, vegetables, cereals, oilseeds (nuts) and fish, and low in red meat, saturated fats and dairy products. Lăcătușu CM, Grigorescu ED, Floria M, et al. The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription. Int J Environ Res Public Health. 2019 Mar 15;16(6):942. ) and ketogenic diet–known for its impact on the gut microbiota and the brain–seem to be especially indicated. But we first need to understand how they act on the disease progression...

Combined diet

American researchers have thus tried to identify microbiome and brain markers of early stages of the disease, in order to assess the impact of diet on its development. To this end, they enrolled 17 subjects–11 patients with moderate cognitive disorder (early stage of the disease), and 6 healthy volunteers–who were alternately given two types of diet: one combining the principles of Mediterranean and ketogenic diet, and the other low-fat and high-carb. They also compared their gut microbiota, before and after these diets.

Bacterial “signatures” associated to cognitive decline

Even though microbial diversity was relatively similar between healthy volunteers and patients before and after adopting one of the two diets, the researchers identified, in the patient group, several markers (including the activity of various gut bacteria) which could be used to recognize a moderate cognitive decline. They also observed that both diets changed the gut microbiota of participants, but with very different effects according to the type of diet and the cognitive state of subjects. The scientists concluded that these results open the way to further studies to define new cognitive decline markers related to the gut microbiota and understand how these interactions with diet could improve the status of high-risk patients.

Chronic kidney disease (CKD) is associated with specific changes in the gut microbiota and circulating metabolites. However, the functions of the microbiota and its complex relationship with the host’s metabolism during the progression of CKD are still only loosely understood. Hence this study involving 72 patients with CKD at different severity stages (26 mild, 26 moderate and 20 advanced cases) and 20 control subjects with normal renal function. Fecal samples were subjected to shotgun sequencing (sidenote:  Shotgun sequencing method is more accurate than 16S rARN. ) , while blood metabolite profiling was performed, targeting bile acids (BA), short- and medium-chain fatty acids and uremic toxins.

A bacterial and metabolic signature

13 bacterial species and 6 circulating metabolites experienced significant changes (increases or decreases) from early to advanced stages of CKD, or at a specific stage or stages only. For example, Bacteroides eggerthii distinguished control subjects from patients in the early stages of CKD, while Prevotella sp. 885 correlated with urea excretion and reflected progression of the disease. Some gut bacteria can therefore act as useful biomarkers for the early diagnosis and monitoring of CKD. As regards metabolites, propionic acid decreased significantly in late stages of CKD, with its absence strongly signaling advanced patients.

Etiological leads

Bacterial genes associated with the biosynthesis of secondary BA were found to be more prevalent in the early stage of CKD, indicating that the conversion of primary BA into secondary BA by intestinal bacteria occurs at the onset of kidney function decline. The advanced stages of the disease were correlated with enrichment of pathways linked:

– on the one hand, to the metabolism of lipids (sidenote: Steroids, ether lipids, polyunsaturated fatty acids )  (probably involved in metabolic syndrome, which is often associated with dyslipidemia, known to be an etiological factor in CKD)

– and, on the other hand, to the biosynthesis of lipopolysaccharides (LPS, inflammatory endotoxins) Therefore, changes in the metabolism of the microbiota and inflammation in the host are thought to influence renal health.

Bacteria-metabolite links

The team identified gut bacteria linked to changes in circulating metabolites, suggesting the potential involvement of the intestinal microbiota in the development of CKD. For example, the notable decrease in B. eggerthii in CKD patients was correlated with the synthesis of secondary BA at an early stage of the disease. Similarly, the increased synthesis of LPS in late stages was partly attributed to an increase in Escherichia coli and other Enterobacteriaceae. These bacteria-metabolite links may indicate either that the bacterial species produces this metabolite or that the metabolite enhances/inhibits the growth of the bacterial species. In sum, this clearer understanding of the relationship between intestinal bacteria species and host metabolism at different stages of CKD provides potential etiological and diagnostic leads for the disease.

^{1 _{A high throughput DNA sequencing technique, known as “random sequencing”, which allows large quantities of DNA to be sequenced in very short periods. This method can be used to sequence entire genomes, for example.}}

Hypercholesterolemia, i.e. elevated circulating cholesterol levels, is strongly associated to the development and progression of cardiovascular diseases, that are responsible for one out of every four deaths in developed countries¹. Drugs such as statins are therapeutic strategies that lower blood cholesterol levels. Unfortunately, these molecules do not act on dietary cholesterol and can have many side effects. What if a new avenue for the treatment of hypercholesterolemia was found deep in our gut

Uncovering the mechanism at play in humans

Researchers recently identified within the gut microbiota the mechanism responsible for cholesterol metabolism by some bacteria, thus decreasing fecal and blood levels. The idea that some gut bacteria can break down cholesterol is not new since this bacterial activity was already well known for a hundred years. But the exact functioning could never be identified in humans because most of bacteria are hard to cultivate in petri dishes in laboratory settings, thus making their study extremely complicated.

A key player: IsmA gene

Using multiple analytical methods, the researchers identified within these bacteria the IsmA gene (Intestinal Steroid Metabolism A) which could be involved in intestinal cholesterol metabolism. People carrying this gene in their gut microbiota had reduced (55% to 75%) cholesterol contents in their stool compared to non-carriers. Blood cholesterol levels were also lower in carriers.

Towards new therapeutic strategies?

This new promising research could lead to new strategies targeting the gut microbiota: by introducing these cholesterol-metabolizing bacteria in the gut microbiota or by increasing their number using prebiotics, it could be possible to fight high blood cholesterol levels.

^{1 Goldstein, J.L., and Brown, M.S. (2015). A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172.}

Current treatments for major depressive disorders, such as fluoxetine, a selective serotonin reuptake inhibitor, are only partly effective. Although the gut microbiota, which is sensitive to chronic stress, represents a therapeutic target for the treatment of depression, no study had evaluated whether it can affect the efficacy of antidepressants, until recently. This gap has now been filled thanks to the work of a French research team. Their goal was to evaluate whether an intestinal dysbiosis induced by chronic stress can induce metabolic changes that impact emotional behavior and responses to serotonergic drugs.

Transferring depression via fecal transplants

To find out whether depression is transmissible, the researchers transplanted the (imbalanced) gut microbiota of a mouse suffering from moderate chronic stress into healthy recipient mice previously treated with antibiotics. In doing so, they transferred most of the elements responsible for the mouse’s dysbiosis. Among the recipients, depressive-like behavior was observed, with a reduction in neurogenesis in the hippocampus and in serotonin levels (in the latter case, limitation of its synthesis and reuptake, and stimulation of its degradation). This process seems to involve tryptophan (a dietary amino acid that is a precursor to serotonin, the metabolism of which may be altered by dysbiosis), since lower levels of this compound were noted in the recipients’ serum. Lastly, the disturbances described were exacerbated by the transplant, with the recipient mice more affected than the donors, a discrepancy which may be explained by the decrease of a bacterial cluster in connection with lower tryptophan levels.

Resistance to antidepressants

Another notable effect of the fecal transplant was the altered antidepressant and neurogenic effects of fluoxetine in the recipient mice (but not in the donors). The antidepressant did not increase levels of serotonin in the hippocampus, failing to restore normal levels of neurotransmitter synthesis, reuptake, or degradation. However, treatment with an immediate serotonin precursor (5-HTP1, a hydroxylated tryptophan derivative) did restore serotonin levels in the hippocampus, improve neurogenesis and relieve depression.

A mechanism, a therapy, and a biomarker

Intestinal dysbioses may therefore explain the development of certain forms of depression and the lack of efficacy of fluoxetine (via alterations of the serotonergic pathway in the metabolism of tryptophan). According to the authors, modulating the microorganisms involved in the catabolism of tryptophan represents a potential therapeutic strategy. At the same time, the levels of tryptophan in the plasma may guide therapeutic choices by acting as a biomarker. Nevertheless, these results still require validation in humans.

People with hypertension know that they have an increased risk of stroke, heart attack, and heart failure; and they must watch their diet and especially their salt intake. Because salt and hypertension are not a good mix. Based on studies carried out with mice, the mechanism connecting the two could be found in out gut. Moreover, since our entire diet has an impact on our microbiota, why not salt?

Salt-sensitive microbiota

British researchers thus wondered whether a salt-rich diet could modulate our gut microbiota. The experiment conducted on 145 untreated hypertensive subjects seems to prove them right: a decrease in salt intake, even modest, impacted the types of bacteria living in their intestines. Their altered gut microbiota produced more short-chain fatty acids (SCFA*) (sidenote: Short chain fatty acids (SGFA) Short chain fatty acids are a source of energy (fuel) for an individual’s cells. They interact with the immune system and are implicated in communication between the gut 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. ) , which are substances that enter the bloodstream and activate vascular receptors. This is greatly beneficial to hypertensive subjects: the increase in SCFA circulating in their bloodstream seemed to be directly correlated with a decrease in their blood pressure and pulse wave velocity, which is used to measure arterial stiffness. This beneficial effect could be related to anti-inflammatory properties that are attributed to these fatty acids of bacterial origin.

Only in hypertensive women

Another finding of the study is that the underlying mechanisms appear to be different between men and women. On closer examination, the change in blood SCFAs resulting from a low-salt diet was proven only in women, and it is still unclear why. In any case, every cook should make sure not to use too much salt in their recipes, especially if someone with high blood pressure (man or woman) is eating at their table: salt consumption remains too high all around the world, and it is recommended to reduce salt intake for everyone, and especially for those with hypertension.

Irritable bowel syndrome (IBS), the most common FGD

FGDs encompass a set of symptoms such as IBS, constipation, diarrhea, functional bloating, and non-specific FGDs.

IBS alone affects 10% of the population and is distinguished from other FGDs by abdominal pain associated with constipation, diarrhea, or alternations between them. It often presents with abdominal bloating and a higher level of stress than the general population.

FGDs don’t spare children

In very small children, FGDs represent the most common gastrointestinal reason for a doctor’s visit. This includes baby colic with regurgitation and constipation problems, IBS, and other less well characterized functional problems. Stomach pain, bloating, diarrhea, and constipation are commonly associated with FGDs and can have major consequences on a child’s daily life. Stress and anxiety can also favor or prolong certain symptoms, particularly pain.

Disrupted communication between the intestines and the brain

The causes of IBS are still poorly understood. The risk of developing IBS increases five-fold after a bacterial infection causing acute diarrhea. It has been suggested that it could be related to dysfunction in the communication between the brain and the intestine, in conjunction with an imbalance in the intestinal flora. In the majority of cases, there is a loss of diversity (sidenote: Dysbiosis Generally defined as an alteration in the composition and function of the microbiota caused by a combination of environmental and individual-specific factors. Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219-232.   ) among the bacterial species that make up the microbiota, with fewer positive bacteria and more harmful bacteria. This dysfunction causes intestinal motor problems: transit is slowed, the intestinal barrier is modified, and slight inflammation develops. It also causes hypersensitivity in the mucosa that makes normal phenomena, like the movement of intestinal gas, painful.

Promising data for probiotics

For adults, in addition to a controlled diet, treatment options include antispasmodics, laxatives, and antidiarrheals. In children, relaxation and hypnosis techniques, which can relieve pain, are preferred. Sometimes antispasmodics are also prescribed. To modify the microbiota, there are promising data currently available about probiotics, particularly bifidobacteria (sidenote: Bifidobacterium A genus of Y-shaped bacteria, most species of which are beneficial to humans. They are found in the gut of humans, and in some yogurts.

They:
- Protect the gut barrier 
- Participate in the development of the immune system and help fight inflammation 
- Promote digestion and improve symptoms of gastrointestinal disorders Sung V, D'Amico F, Cabana MD, et al. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics. 2018 Jan;141(1):e20171811.  O'Callaghan A, van Sinderen D. Bifidobacteria and Their Role as Members of the Human Gut Microbiota. Front Microbiol. 2016 Jun 15;7:925. Ruiz L, Delgado S, Ruas-Madiedo P, et al. Bifidobacteria and Their Molecular Communication with the Immune System. Front Microbiol. 2017 Dec 4;8:2345. ) and lactobacilli (sidenote: Lactobacilli Rod-shaped bacteria whose main characteristic is the production of lactic acid, from where they get the name “lactic acid bacteria”.  Lactobacilli are present in the oral, vaginal and gut microbiota of humans, but also in plants and animals. They are found in fermented foods, such as dairy products (e.g. certain cheeses and yoghurts), pickles, sauerkraut, etc. Lactobacilli are also found in probiotics, with certain species recognized for their beneficial properties.   W. H. Holzapfel et B. J. Wood, The Genera of Lactic Acid Bacteria, 2, Springer-Verlag, 1st ed. 1995 (2012), 411 p. « The genus Lactobacillus par W. P. Hammes, R. F. Vogel Tannock GW. A special fondness for lactobacilli. Appl Environ Microbiol. 2004 Jun;70(6):3189-94. Smith TJ, Rigassio-Radler D, Denmark R, et al. Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis ssp. lactis BB-12® on health-related quality of life in college students affected by upper respiratory infections. Br J Nutr. 2013 Jun;109(11):1999-2007. ) , and about fecal transplants. However, large-scale clinical trials still have to be conducted to confirm each of these options.

At a time when more people around the world die from over-eating than under-eating, obesity is defined as excessive fat accumulation in the organism¹. It is defined by a body mass index (BMI) equal to or greater than 30. Between 1975 and 2014, the prevalence of obesity among adults increased by 7.6% in men and 8.5% in women¹. However, such data covers up significant disparities. For example, the prevalence of obesity in Japanese adults is under 4% while the United States has ten times that number. While almost all countries are facing this pandemic (some regions of the world show particularly marked increases²), only Japan, North Korea and some Sub-Saharan countries still have low obesity rates¹.

Increase in the number of obese adults over the years. Prevalence of obesity among adults by country in 1975 (a) and 2014 (b). The number of obese adults rose significantly between 1975 and 2014. Global Health Observatory (GHO) database.

A risk factor for many diseases...

The consequences of excess weight are not all apparent at first glance. But the science backs it up—people who are obese have a higher risk of developing other diseases (metabolic disorders like type 2 diabetes, cardiovascular diseases³, depression, some types of cancer, etc.). In addition, men who are overweight have an increased risk of developing urinary disorders and erectile dysfunction, along with a drastically reduced quality of life⁴. Overall, obese people can expect to live 7 fewer years compared to those of normal weight⁴.

...whose causes are not that easy to grasp

Absorbing too many calories, particularly fats and sugars, relative to actual energy expenditure is the main and now well-known cause of obesity and excess weight^1,5. Yet sometimes adopting healthy behaviors (good nutrition, physical activity, etc.) is not enough to reabsorb the excess weight¹. What are the hidden causes?