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?

Decreased bone mass, damage to bone microarchitecture, excessive skeletal fragility, increased risk of fracture... Osteoporosis, strongly linked to ageing, is on the rise in China, where it represents a major public health issue. The confirmation of a link between osteoporosis and an imbalance of the gut microbiota–as numerous studies suggest–would constitute a major advance in our understanding of the mechanisms involved in the development of the disease and significant progress in the development of preventive and/or curative treatments.

Dissimilar gut microbiota

A group of Chinese researchers compared the intestinal microbiota of 48 patients with primary osteoporosis to that of 48 healthy individuals. Unlike secondary osteoporosis, which is caused by disease, primary osteoporosis has no clearly identifiable cause, with age and menopause being its main risk factors. More diverse overall, the gut microbiota of patients with primary osteoporosis was mainly characterized by a greater abundance of bacteria of the Dialister genus, already suspected of being involved in the loss of bone mass, and associated with an increased level of IL-6, a pro inflammatory substance that promotes bone deterioration. It was also richer in bacteria of the Faecalibacterium genus involved in bone formation, which, conversely, the authors believe likely to be the result of an adjustment by the body to counteract the loss of bone mass.

Soon to be a diagnostic tool?

The researchers subsequently tried to assess whether these differences in the composition of the gut microbiota might serve as a diagnostic marker for osteoporosis. The results showed that an analysis of the gut bacteria of Chinese subjects was able to identify osteoporosis with a high degree of accuracy (over 98%). These significant findings open up new approaches to the prevention and treatment of the disease.

Ultraviolet B (UVB) intensity depends on a number of natural factors, including latitude, altitude, weather conditions, time of day and season, with human behavior and lifestyle playing an indirect role also. A recent study on women living in Vancouver, Canada, who were artificially exposed to UVB suggests that UVB increases diversity and richness of the gut microbiota, contributing to good health.

Gut microbiota influenced by the sun

Researchers replicated the study on Brazilian populations whose lifestyle and living conditions were very different from those of the Canadian women. They compared the gut microbiota of the Canadian city dwellers to that of various hunter-gatherer populations, including the Yanomami, an ethnic group living near the Equator, in a region of the Amazon which receives a high amount of sunlight. For the Yanomami, UVB rays are not blocked by pollution, clothing or sunscreen. Like that of the Canadian women, the gut microbiota of the Yanomami seemed to be modulated by exposure to UVB. It showed common characteristics (greater diversity, an increase in bacteria belonging to the Firmicutes phylum, a reduction in bacteria belonging to the Bacteroidetes phylum) that differentiates them from city dwellers. It was also particularly rich in proteobacteria, a peculiarity not fully understood by the researchers, who suggest that high exposure to UVB, due to the Yanomami’s lifestyle and the unique environmental conditions in which they live, may be responsible.

UVB, a factor to be explored

The authors believe that UVB, whether natural or artificial, merits consideration as a factor capable of influencing the composition of the human intestinal microbiota. They conclude that a more in-depth study that takes latitude, and therefore sun exposure, into account could shed new light on the relationship between the host, host’s health, gut microbiota and environment.

The fine particles and pollutants in the air we breathe not only poison our lungs, but apparently disrupt the intestinal microbiota also. The mechanisms involved remain unknown but according to a recent study involving one hundred young Californians exposed to certain air pollutants, science is beginning to hone in on the culprits.

Ozone has been singled out

After measuring the air quality around the volunteers’ homes and analyzing their gut microbiota, the researchers found that nitrogen oxides (nitrogen monoxide and dioxide from road traffic or energy generation) disrupt the intestinal flora. However, it appears that the most significant damage is caused by ozone, a pollutant formed through reactions between various other pollutants. Ozone reduces diversity within the gut microbiota, thereby disrupting its functioning. The study found that almost 130 bacterial species are affected by ozone, with only 9 influenced by nitrogen oxides.

Metabolism disrupted

High ozone exposure is thought to impact important cellular mechanisms, such as cell growth, insulin secretion or fatty acid synthesis and degradation. Some of these processes may also affect the integrity of the intestinal barrier and the metabolism. The researchers suggest that, through their impact on the gut microbiota, air pollutants may lay the groundwork for metabolic disorders such as type 2 diabetes mellitus or obesity.

Fighting pollution to protect the microbiota

This hypothesis should be evaluated in future epidemiological studies and in studies on animals in order to identify the exact mechanisms whereby pollution impacts the intestinal flora and promotes the onset of diseases among humans. However, these preliminary results are a reminder that pollution is a major public health issue that urgently needs to be addressed.