Chronic fatigue: the four leads explored first
Faced with chronic fatigue, four hypotheses come naturally: iron deficiency, overlooked hypothyroidism, adrenal dysregulation linked to chronic stress, and what some call cold infections, meaning a continuous demand on the immune system that carries an energy cost.
According to Dr Serge Balon-Perin, a fifth lead often stays outside the scope of the consultation: the state of the gut. It is not anecdotal. The number of recent studies devoted to the link between the microbiota and chronic fatigue makes it a seriously documented subject.
Butyrate, the pivot of the intestinal barrier
In patients with chronic fatigue syndrome or myalgic encephalomyelitis, a reduced capacity of the microbiota to produce butyrate is found repeatedly. The two main producers involved are Faecalibacterium prausnitzii and Eubacterium rectale, along with Roseburia.
The most telling point in consultation: according to Dr Balon-Perin, the abundance of Faecalibacterium is inversely correlated with the severity of fatigue. The less there is, the more marked the fatigue.
What butyrate does
This short-chain fatty acid acts on three levels at once. It feeds the colonocyte, for which it is the main fuel. It acts on the NF-κB pathway and helps limit intestinal inflammation, and therefore the hyperpermeability that results from it. And it stimulates mucus production, which renews and protects the barrier.
On top of this comes an effect independent of butyrate production: the surface antigenic determinants of these bacteria are picked up by the gut immune system and steer cytokine production in a direction that calms inflammation.
When LPS cross the barrier
A wall that has become porous often goes hand in hand with bacterial overgrowth in the small intestine. Yet the small intestine hosts Gram-negative bacteria whose LPS are aggressive, and it lacks the protective double mucus layer of the colon. LPS then reach the immune system via TLR4 receptors, with production of inflammatory cytokines that then reach the brain.
Not all LPS are equal. Some strains carry highly inflammatory LPS, others almost neutral LPS. This is why research measures IgA directed against enterobacterial LPS: a high level signals exposure to aggressive LPS. According to Dr Balon-Perin, the study presented found these elevated IgA in 67% of patients with chronic fatigue syndrome, compared with 0% of controls.
The kynurenine pathway, or how inflammation cuts off energy production
The second mechanism concerns the fate of tryptophan, and it is probably the one that best explains the flat-battery feeling.
An imbalanced microbiota produces an excess of inflammatory cytokines, including interferon gamma and TNF alpha. These cytokines reach the brain and liver through the humoral route and the immune route, and they overactivate the enzyme IDO.
The metabolic side
Overactivated IDO massively diverts tryptophan towards kynurenine, with a shunt towards kynurenic acid. The problem is not only the resulting drop in serotonin. It is that this diversion cuts off nicotinamide production, and therefore the only de novo synthesis pathway for NAD, in the liver as in the brain.
Without NADH, oxidative phosphorylation runs at a slow pace. Dr Balon-Perin also recalls the cofactors essential at this level: iron, coenzyme Q10, vitamins B2 and B3, and magnesium for ATP release. B2 plays a double role, since it is also a cofactor in the conversion of kynurenine to nicotinamide.
The central side
Kynurenic acid has an inhibitory effect on NMDA receptors. Glutamatergic neurotransmission decreases in prefrontal and hypothalamic circuits, cortical excitability drops, and dopamine release decreases. The resulting clinical picture is that of central fatigue: asthenia, psychomotor slowing, reduced motivation.
Animal models support the hypothesis. Injecting kynurenic acid into the third ventricle of the rat causes dose-dependent exertional fatigue, and chronic sleep deprivation, which increases kynurenic acid production, impairs treadmill performance.
Sulphur metabolites and complex IV
A third, more recent mechanism: certain bacteria such as Desulfovibrio and Bilophila produce a lot of hydrogen sulphide. In excess, it blocks complex IV of the mitochondrial respiratory chain and slows ATP production.
An experiment in mice points in the same direction. Three months of short-chain fatty acid supplementation give an anti-fatigue capacity 1.6 times higher than in the control group, with less LPS and fewer circulating cytokines, better-quality mucus (MUC2), improved claudin-1 and more glycogen.
Antigen persistence, the most recent hypothesis
Dr Balon-Perin presents this fourth lead as the least solid of the four, but it is worth knowing. In a study of 46 patients with post-infectious long COVID, viral RNA was found in a digestive segment in 32 of them. Among the 14 patients with no RNA detected, none had significant fatigue. Among the 32 positive patients, 56% did.
The hypothesis put forward is insufficient mucosal clearance. Mucus renewal depends on a balance between the bacteria that produce it and those that break it down. When this balance is disrupted, the antigen stays in contact with the immune system for longer and keeps it engaged.
What unbalances the microbiota
The factors are known and cumulative: ultra-processed food, lack of prebiotics, additives, alcohol, repeated antibiotics, pesticides. Infections come on top of these.
The figure to remember here: according to Dr Balon-Perin, about one in ten people who have had food poisoning or a significant intestinal viral infection go on to develop irritable bowel, about 63% of them in the SIBO form. The causes are no longer considered solely bacterial: some intestinal viral and parasitic infections are also involved.
Chronic stress, often underestimated
Chronic stress acts on the gut through a specific route. After an initial adaptation phase comes the hypercortisolism phase, which is usually the longest. Excess cortisol depletes mucus cells and lowers MUC2: the mucus becomes more penetrable. In parallel, it promotes cytokine production by the gut immune system.
The loop then closes: these cytokines block the receptors of hypothalamic negative feedback, cortisol production is no longer held back, and they generate mitochondrial oxidative stress that further reduces energy production. Chronic stress therefore acts on energy directly, and indirectly through the gut.
What to work on in consultation
Support mucus and butyrate production
The bacteria documented as stimulating mucus production are Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis and Lactobacillus rhamnosus GG. On the butyrate producer side, they are Faecalibacterium, Eubacterium and Roseburia. They enrich mucus in MUC2, improve the barrier and increase the number of producing cells.
Keep an eye on mucus-degrading bacteria
Akkermansia muciniphila illustrates the nuance well. It is considered beneficial at between 1 and 4% of the microbiota, thanks to a surface protein that acts on TLR2 and strengthens tight junctions. But it feeds on mucus. Dr Balon-Perin cites a recent case at 16%, or one bacterium in six, where the reference is of the order of one in a hundred. Bacteroides thetaiotaomicron raises the same question. Ruminococcus gnavus, Prevotella copri and Alistipes, for their part, are clearly mucin-degrading.
Transit effect or colonisation effect
The distinction is useful when choosing a probiotic. Some strains act even when inactivated, through their surface antigenic determinants: this is the transit effect. If the goal is to increase Faecalibacterium durably, a colonisation effect is needed, so bifidobacteria able to survive gastric acidity and bile, plus prebiotics.
The underlying mechanism is cross-feeding. The fibres supplied are used by bifidobacteria, which produce lactate. This lactate acidifies the environment, which limits the establishment of problematic bacteria, and it serves as a substrate for Faecalibacterium, which then produces butyrate. Dr Balon-Perin also observes that fibres benefit Faecalibacterium more when bifidobacteria are present than when they are not.
Support the intestinal wall
For the small intestine, glutamine remains the foundation, together with turmeric, gamma-oryzanol for its action on the mucosa, digestive enzymes, ginger and zinc. For the colon, a direct intake of butyrate can be considered initially.
How to assess the microbiota
Stool culture only provides information on culturable bacteria, less than 20% of the microbiota. 16S rRNA metagenomic analysis remains the most referenced technique and is largely sufficient in clinical practice. Shotgun approaches, at their various depths, go further down to species and sometimes strains. Dr Balon-Perin is also working on a fluorescence technique from a university spin-off, more precise at strain level.
The aim of the analysis is simple: to know whether the patient has enough mucus- and butyrate-producing bacteria, and whether there is an excess of enterobacteria.
Two points of caution
SIBO first. With SIBO, prebiotics and probiotics are poorly tolerated. The order matters: address the overgrowth, then assess its cause (small intestine motility disorder, bile insufficiency, lack of stomach acid, post-infectious sequela, stress-related autonomic component, adhesions after abdominal surgery), and only then rebalance the microbiota. SIBO is now considered by some more as a dysbiosis than as a simple overgrowth.
Glutamine next. Dr Balon-Perin flags a reservation in cases of cerebral hyperexcitability, in children as in adults: glutamine is converted into glutamate, and a vitamin B6 deficiency impairs the conversion to GABA. On the question of active cancer, he points out that the literature is not settled, as tumour cells can use glutamine as an energy substrate, while a very damaged intestinal wall sustains an inflammation that is not favourable either.
What the practitioner takes away
The link between the intestinal wall, the microbiota and chronic fatigue rests on a coherent body of evidence: a deficit in butyrate-producing bacteria, impaired barrier, passage of cytokines, diversion of tryptophan, drop in NAD, mitochondrial slowdown. Faced with fatigue that persists and for which the standard work-up shows nothing, exploring the microbiota and intestinal permeability deserves its place in the decision tree.
Watch the webinar
The full replay (in French) is available below. The second half is devoted to practitioners' questions: SIBO, choice of tests, yeasts, glutamine and prebiotics.
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