Dinesh Velu Rajan: Exploring the Role of Dysbiosis in ART Outcomes

Dinesh Velu Rajan, Junior embryologist at Dr Aravind’s IVF, shared a post on LinkedIn about a paper by F. Giangrazi et al. published in Human Reproduction:

“Endometrial Microbiome: A Missing Link in Implantation Failure.

Key Results

• Implantation failure is associated with endometrial microbiome dysbiosis
• ↓ Lactobacillus dominance
• ↑ Microbial diversity
• Dysbiosis produces butyrate
• Butyrate induces inflammation
• Endometrial barrier weakens
• Receptivity markers increase
• Implantation still fails
• Inflammation-driven false receptivity

Key Concepts

• Endometrial Microbiome
• Microbes in the uterine lining
• Lactobacillus Dominance
• Healthy, implantation-supportive state
• Dysbiosis
• ↓ Lactobacillus + ↑ diversity + inflammation
• Butyrate

Results:

The endometrial microbiome is different in implantation failure:

• Healthy women had a Lactobacillus-dominant endometrium
• Failed cases showed reduced Lactobacillus
• Anaerobic bacteria such as Prevotella were more common in failure cases
• This shows that a non-Lactobacillus-dominant microbiome is associated with implantation failure.

Dysbiosis is linked to inflammation, not hormone failure

Receptivity markers were increased, not reduced

Surprisingly, the study found that:

• Many classical receptivity markers were higher in women who failed to implant
• Markers like ITGAV and SPP1 were increased
• Decidualization markers such as PRL and IGFBP1 were also elevated

This means:

The endometrium looked ‘ready’ at a molecular level

But implantation still did not occur

This introduces the concept of false or dysfunctional receptivity.

Butyrate is the key mediator connecting microbiome and inflammation

The authors tested bacterial metabolites to understand the mechanism.

They found that:

Dysbiotic bacteria produce butyrate

Butyrate strongly affected endometrial cells

Other metabolites like acetate had minimal effects

Lactate (from Lactobacillus) was protective

This identified butyrate as the main harmful mediator.

Butyrate increases receptivity markers in epithelial cells

When endometrial epithelial cells were exposed to butyrate:

Expression of ITGAV and SPP1 increased

Receptivity signals were amplified

Effects were stronger in the presence of progesterone

This mimics:

A strongly receptive endometrium

But without successful implantation

Butyrate creates a molecular illusion of receptivity.

Butyrate damages the epithelial barrier

Despite increasing receptivity markers, butyrate also caused harm.

The study showed that butyrate:

Reduced epithelial barrier strength

Decreased TEER values

Made the endometrium more permeable

Altered tight junction proteins

This allows:

More microbial products to enter

More immune activation

A weak barrier promotes chronic inflammation.

Butyrate activates inflammatory signalling in the endometrium

Butyrate exposure led to:

Increased pro-inflammatory cytokines

Upregulation of IL-1β, IL-6, TNF-α, and IL-8

Increased antimicrobial peptides

Importantly:

The endometrium behaves as if it is under microbial attack.

Source.”

Title: Contribution of endometrial microbiome to inflammation-mediated infertility in women undergoing ART

Authors: F Giangrazi, J A Sugrue, V M Sularea, A A I Brugman, M Horan, M Wingfield, D A Crosby, L E Glover, C O’Farrelly

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